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Old 01-13-2010, 10:44 PM   #1
Rich66
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Join Date: Feb 2008
Location: South East Wisconsin
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Cyclophosphamide

(immune enhancing in range, metronomic compatible, ER+ response, w/Capecitabine, w/mTOR inhib,w/Resveratrol,w/Doxycycline,Dox+Cyt=Dox+Doc, w/resveratrol,w/Traz)




Cancer Res. 2009 May 15;69(10):4309-18. Epub 2009 May 12.
Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model.

Wada S, Yoshimura K, Hipkiss EL, Harris TJ, Yen HR, Goldberg MV, Grosso JF, Getnet D, Demarzo AM, Netto GJ, Anders R, Pardoll DM, Drake CG.
Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
To study the immune response to prostate cancer, we developed an autochthonous animal model based on the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse in which spontaneously developing tumors express influenza hemagglutinin as a unique, tumor-associated antigen. Our prior studies in these animals showed immunologic tolerance to hemagglutinin, mirroring the clinical situation in patients with cancer who are generally nonresponsive to their disease. We used this physiologically relevant animal model to assess the immunomodulatory effects of cyclophosphamide when administered in combination with an allogeneic, cell-based granulocyte-macrophage colony-stimulating factor-secreting cancer immunotherapy. Through adoptive transfer of prostate/prostate cancer-specific CD8 T cells as well as through studies of the endogenous T-cell repertoire, we found that cyclophosphamide induced a marked augmentation of the antitumor immune response. This effect was strongly dependent on both the dose and the timing of cyclophosphamide administration. Mechanistic studies showed that immune augmentation by cyclophosphamide was associated with a transient depletion of regulatory T cells in the tumor draining lymph nodes but not in the peripheral circulation. Interestingly, we also noted effects on dendritic cell phenotype; low-dose cyclophosphamide was associated with increased expression of dendritic cell maturation markers. Taken together, these data clarify the dose, timing, and mechanism of action by which immunomodulatory cyclophosphamide can be translated to a clinical setting in a combinatorial cancer treatment strategy.

PMID: 19435909 [PubMed - indexed for MEDLINE]



J Clin Oncol. 2009 Dec 10;27(35):5911-8. Epub 2009 Oct 5.
Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation.

Emens LA, Asquith JM, Leatherman JM, Kobrin BJ, Petrik S, Laiko M, Levi J, Daphtary MM, Biedrzycki B, Wolff AC, Stearns V, Disis ML, Ye X, Piantadosi S, Fetting JH, Davidson NE, Jaffee EM.
Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. emensle@jhmi.edu
PURPOSE: Granulocyte-macrophage colony-stimulating factor (GM-CSF) -secreting tumor vaccines have demonstrated bioactivity but may be limited by disease burdens and immune tolerance. We tested the hypothesis that cyclophosphamide (CY) and doxorubicin (DOX) can enhance vaccine-induced immunity in patients with breast cancer. PATIENTS AND METHODS: We conducted a 3 x 3 factorial (response surface) dose-ranging study of CY, DOX, and an HER2-positive, allogeneic, GM-CSF-secreting tumor vaccine in 28 patients with metastatic breast cancer. Patients received three monthly immunizations, with a boost 6 to 8 months from study entry. Primary objectives included safety and determination of the chemotherapy doses that maximize HER2-specific immunity. RESULTS: Twenty-eight patients received at least one immunization, and 16 patients received four immunizations. No dose-limiting toxicities were observed. HER2-specific delayed-type hypersensitivity developed in most patients who received vaccine alone or with 200 mg/m(2) CY. HER2-specific antibody responses were enhanced by 200 mg/m(2) CY and 35 mg/m(2) DOX, but higher CY doses suppressed immunity. Analyses revealed that CY at 200 mg/m(2) and DOX at 35 mg/m(2) is the combination that produced the highest antibody responses. CONCLUSION: First, immunotherapy with an allogeneic, HER2-positive, GM-CSF-secreting breast tumor vaccine alone or with CY and DOX is safe and induces HER2-specific immunity in patients with metastatic breast cancer. Second, the immunomodulatory activity of low-dose CY has a narrow therapeutic window, with an optimal dose not exceeding 200 mg/m(2). Third, factorial designs provide an opportunity to identify the most active combination of interacting drugs in patients. Further investigation of the impact of chemotherapy on vaccine-induced immunity is warranted.

PMID: 19805669 [PubMed - indexed for MEDLINE]






Estrogen Receptor Status and Response to Chemotherapy in Advanced Breast Cancer
[older regimens using Cyclophosphamide..better than current for ER+?]


http://www3.interscience.wiley.com/c...79448/PDFSTART


DAVID T. KIANG, MD, PHD, DANIEL H. FRENNING, MD, JULIETTE GAY, RN, ANNE I . GOLDMAN, PHD, AND B. J. KENNEDY, MD Cancer 46:2814-2817, 1980.

Tumor estrogen receptor status in women with advanced breast cancer was correlated with clinical response to cytotoxic chemotherapy in a retrospective study. Following an extramural review of the clinical data of 40 patients, 26 responded to chemotherapy (65%). The response rate in 19 receptor-rich tumors was 89% and in 21 receptor-poor tumors, 43% (P < 0.01). The lowest response rate (14%) was observed in seven postmenopausal patients with receptor-poor tumors. Clinical characteristics of patients and variants in chemotherapy programs failed to explain the favorable response of receptor-rich tumors to cytotoxic chemotherapy.
Cancer 46:2814-2817, 1980.



Clin Cancer Res. 2009 Oct 15;15(20):6358-66. Epub 2009 Oct 13.
Comparative impact of trastuzumab and cyclophosphamide on HER-2-positive human breast cancer xenografts.

Francia G, Man S, Lee CJ, Lee CR, Xu P, Mossoba ME, Emmenegger U, Medin JA, Kerbel RS.
Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada. robert.kerbel@sri.utoronto.ca
Comment in:
PURPOSE: Metronomic chemotherapy is a minimally toxic and frequently effective new treatment strategy that is beginning to show promising phase II clinical trial results, particularly for metastatic breast cancer when combined with various molecularly targeted antitumor agents. Here, we assessed a treatment strategy that uses trastuzumab plus daily oral metronomic cyclophosphamide on metastatic Her-2-positive human breast cancer models. EXPERIMENTAL DESIGN: Treatments were initiated on orthotopic transplanted primary tumors as well as established visceral metastatic disease of two independent Her-2-positive breast cancer models, both independently derived from the human MDA-MB-231 breast cancer cell line. Outcome was assessed by noninvasive measurements of tumor cell-secreted human choriogonadotropin in the urine as a surrogate marker of relative tumor burden, or by whole body bioluminescent imaging, in addition to prolongation of survival. RESULTS: Orthotopic primary tumors responded to trastuzumab monotherapy with significant growth delays, whereas minimal antitumor effect was observed when mice with metastatic disease were treated. Nevertheless, trastuzumab showed a benefit in this latter setting when combined with metronomic low-dose cyclophosphamide as assessed by prolongation of survival. This benefit was similar to trastuzumab plus maximum tolerated dose cyclophosphamide, but was associated with lesser toxicity. CONCLUSIONS: Trastuzumab combined with metronomic cyclophosphamide may be an effective long-term maintenance strategy for the treatment of Her-2-positive metastatic breast cancer.

PMID: 19825954 [PubMed - indexed for MEDLINE]







Nihon Kokyuki Gakkai Zasshi. 2009 Dec;47(12):1082-6.
[A case of early-onset cyclophosphamide-induced pneumonitis diagnosed by rechallenge test]

[Article in Japanese]
Toyoshima M, Chida K, Suda T.
Department of Respiratory Medicine, Hamamatsu Rosai Hospital.
A 59-year-old woman began to complain of cough, dyspnea, and fever 2 weeks after 3 courses of chemotherapy with cyclophosphamide (800 mg) and adriamycin (80 mg) for breast cancer. Chest radiography showed diffuse ground-glass shadows in the central areas of bilateral lung fields. Chest CT also showed diffuse ground-glass opacities in the central areas of bilateral lung fields. Arterial blood gas analysis revealed mild hypoxia. A lymphocyte stimulation test with peripheral blood lymphocytes for cyclophosphamide was negative. A mild increase of lymphocytes was observed in the cell population of bronchoalveolar lavage fluids and no microorganisms were detected. Her respiratory condition improved after glucocorticoid therapy. A rechallenge test with cyclophosphamide was performed after obtaining informed consent. There was no significant change in symptoms or chest radiography results 24 hours after intravenous administration of cyclophosphamide (100 mg). However, a transient decrease of PaO2 with peripheral eosinophilia was observed. Thus, a diagnosis of early-onset cyclophosphamide-induced pneumonitis was established.

PMID: 20058683 [PubMed - in process]




Toxicol Appl Pharmacol. 2005 Feb 1;202(3):268-77.
Doxycycline potentiates antitumor effect of cyclophosphamide in mice.

Chhipa RR, Singh S, Surve SV, Vijayakumar MV, Bhat MK.
National Centre for Cell Science, Pune University, Campus Ganeshkhind, NCCS Complex, Pune, Maharashtra, 411 007, India.
Cyclophosphamide (CPA) is a widely used chemotherapeutic drug in neoplasias. It is a DNA and protein alkylating agent that has a broad spectrum of activity against variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the high-dose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining well-tolerated antibiotic doxycycline (DOX) with CPA and understanding the mechanism of cell killing. Interestingly, we found that DOX significantly enhances the tumor regression activity of CPA on xenograft mice model bearing MCF-7 cells. DOX also potentiates MCF-7 cell killing by CPA in vitro. In presence of DOX (3 microg/ml), the IC50 value of CPA decreased significantly from 10 to 2.5 mM. Additional analyses indicate that the tumor suppressor p53 and p53-regulated proapoptotic Bax were upregulated in vivo and in vitro following CPA treatment in combination with DOX, suggesting that upregulation of p53 may contribute to the enhancement of antitumor effect of CPA by DOX. Furthermore, downregulation of antiapoptotic Bcl-2 was observed in animals treated with CPA and CPA plus DOX when compared to untreated or DOX-treated groups. Our results raise the possibility that this combination chemotherapeutic regimen may lead to additional improvements in treatment of breast cancer.

PMID: 15667832 [PubMed - indexed for MEDLINE]


Results
Effect of doxycycline on the antitumor activity of cyclophosphamide
MTT cytotoxicity assay
Flow cytometric analysis for apoptosis in drug-treated MCF-7 cells
p53 and Bax are upregulated following treatment of MCF-7 cells in vitro with a combination of DOX and CPA
Enhanced cell death in CPA-treated MCF-7 cells is DOX dose dependent
Downregulation of p53 prevents DOX enhanced MCF-7 cell killing by CPA
Quote:
CPA is a cell cycle-dependent DNA and protein alkylating agent that has a broad spectrum of activity against variety of neoplasms, and is widely used in the clinical management of human malignancies including breast cancer.
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Quote:
Potentiation of antitumor effect of CPA by AQ4N and tirapazamine on mammary carcinoma (Friery et al.,2000), and by bis-indole alkaloid on breast cancer cells has been reported (Leung et al., 2000). Very recently it has been demonstrated that coadministration of thalidomide and CPA
gave markedly greater activity against Colon 38 tumor
compared with either drug alone (Ding et al., 2002).
Doxycycline (DOX), a commonly used antibiotic, has antitumor activity against several malignancies (Fife et al., 1998; Rubins et al., 2001). Recently it has been reported that DOX has potential treatment value in bone metastasis of breast cancer cells (Duivenvoorden et al., 2002). DOX
inhibits these effects by inhibiting matrix metalloproteinases (MMPs), not only in breast cancer cells but also in human endothelial, prostate cancer, osteocarcinoma cells of patients (Fife et al., 1997; Hanemaaijer et al., 1998). Moreover, it also inhibits cell proliferation and induces apoptosis in
various cancer cells (Rubins et al., 2001). All these studies demonstrate that this well-tolerated antibiotic may be effective in treatment of various human cancers, either alone or in combination therapy.
DOX is potentially beneficial in bone metastasis of breast cancer cells and CPA is an important component of chemotherapeutic regimen for treatment of breast cancers.

CPA, administered at 100 mg/kg/day ip dose in nude mice bearing tumor derived by injecting MCF-7 cells resulted in decreased tumor size by 50% compared to tumors in untreated animals (Fig. 1B). DOX injection alone did not significantly induce tumor regression. The co-administration of DOX (5 mg/kg/day) along with CPA further enhanced the tumor regression by more than 25% (Figs. 1B and C).
Therefore, it is clear that DOX, one of the better-absorbed antibiotics with longer half-life, can potentiate the antitumor activity of CPA in vivo.
Cancer Res. 2006 Apr 1;66(7):3386-91.
Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy.

Munoz R, Man S, Shaked Y, Lee CR, Wong J, Francia G, Kerbel RS.
Sunnybrook and Women's College Health Sciences Centre S-217, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
Metronomic antiangiogenic chemotherapy, the prolonged administration of relatively low drug doses, at close regular intervals with no significant breaks, has been mainly studied at the preclinical level using single chemotherapeutic drugs, frequently in combination with a targeted antiangiogenic drug, and almost always evaluated on primary localized tumors. We tested a "doublet" combination metronomic chemotherapy treatment using two oral drugs, UFT, a 5-fluorouracil (5-FU) prodrug administered by gavage, and cyclophosphamide, for efficacy and toxicity in a new mouse model of advanced, terminal, metastatic human breast cancer. The optimal biological dose of each drug was first determined by effects on levels of circulating endothelial progenitor cells as a surrogate marker for angiogenesis, which was assessed to be 15 mg/kg for UFT and 20 mg/kg for cyclophosphamide. A combination treatment was then evaluated in mice with advanced metastatic disease using a serially selected metastatic variant of the MDA-MB-231 breast cancer-cell line, 231/LM2-4. UFT or cyclophosphamide treatment showed only very modest survival advantages whereas a combination of the two resulted in a remarkable prolongation of survival, with no evidence of overt toxicity despite 140 days of continuous therapy, such that a significant proportion of mice survived for over a year. In contrast, this striking therapeutic effect of the combination treatment was not observed when tested on primary orthotopic tumors. We conclude that combination oral low-dose daily metronomic chemotherapy, using cyclophosphamide and UFT, is superior to monotherapy and seems to be a safe and highly effective experimental antimetastatic therapy, in this case, for advanced metastatic breast cancer.

PMID: 16585158 [PubMed - indexed for MEDLINE]
Quote:
UFT or cyclophosphamide treatment showed only very modest survival advantages whereas a combination of the two resulted in a remarkable prolongation of survival, with no evidence of overt toxicity despite 140 days of continuous therapy, such that a significant proportion of mice survived for over a year. In contrast, this striking therapeutic effect of the combination treatment was not observed when tested on primary orthotopic tumors. We conclude that combination oral low-dose daily metronomic chemotherapy, using cyclophosphamide and UFT, is superior to monotherapy and seems to be a safe and highly effective experimental antimetastatic therapy, in this case, for advanced metastatic breast cancer



Ann Oncol. 2005 Aug;16(8):1243-52. Epub 2005 May 19.
Cyclophosphamide-methotrexate 'metronomic' chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation.

Bocci G, Tuccori M, Emmenegger U, Liguori V, Falcone A, Kerbel RS, Del Tacca M.
Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies, University of Pisa, Via Roma, Pisa, Italy. g.bocci@med.unipi.it
BACKGROUND: Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks-is a potentially novel approach to the control of advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has, as an advantage, the property of significantly reducing undesirable toxic side-effects. The aim of the present study was to evaluate the cost effectiveness of cyclophosphamide-methotrexate 'metronomic' chemotherapy in the palliative treatment of pretreated metastatic breast cancer. METHODS: Low-dose cyclophosphamide-methotrexate 'metronomic' chemotherapy was compared with outcome and resource utilisation data of published phase II trials regarding metastatic breast cancer, performed in western countries, mostly in Europe. All direct costs associated with metastatic breast cancer treatment were included and adjusted to year 2003 values. Sensitivity analyses were performed and variations to the values of key parameters were assessed. RESULTS: Low-dose cyclophosphamide-methotrexate 'metronomic' therapy was assessed to be a cost-effective/cost-saving therapy for palliative treatment for metastatic breast cancer when compared with novel chemotherapy strategies (phase II trials). Compared with the 11 phase II mono- and combination chemotherapies, metronomic treatment showed marked cost savings in each case and improved cost effectiveness. Sensitivity analyses showed the results were robust to variations to the values of key parameters with very few exceptions. CONCLUSIONS: Metronomic cyclophosphamide-methotrexate is significantly cost effective. If validated by prospective randomized trials, the treatment concept could reduce healthcare costs, especially those associated with the combined use of new, highly expensive, molecularly targeted therapies.

PMID: 15905308 [PubMed - indexed for MEDLINE]




Mol Cancer Ther. 2009 Oct;8(10):2872-81.
Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models.

Daenen LG, Shaked Y, Man S, Xu P, Voest EE, Hoffman RM, Chaplin DJ, Kerbel RS.
Molecular and Cell Biology Research, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada.
Vascular disrupting agents preferentially target the established but abnormal tumor vasculature, resulting in extensive intratumoral hypoxia and cell death. However, a rim of viable tumor tissue remains from which angiogenesis-dependent regrowth can occur, in part through the mobilization and tumor colonization of circulating endothelial progenitor cells (CEP). Cotreatment with an agent that blocks CEPs, such as a vascular endothelial growth factor pathway-targeting biological antiangiogenic drug, results in enhanced antitumor efficacy. We asked whether an alternative therapeutic modality, low-dose metronomic chemotherapy, could achieve the same result given its CEP-targeting effects. We studied the combination of the vascular disrupting agent OXi4503 with daily administration of CEP-inhibiting, low-dose metronomic cyclophosphamide to treat primary orthotopic tumors with the use of the 231/LM2-4 breast cancer cell line and MeWo melanoma cell line. In addition, CEP mobilization and various tumor characteristics were assessed. We found that daily p.o. low-dose metronomic cyclophosphamide was capable of preventing the CEP spike and tumor colonization induced by OXi4503. This was associated with a decrease in the tumor rim and marked suppression of primary 231/LM2-4 growth in nude as well as severe combined immunodeficient mice. Similar results were found in MeWo-bearing nude mice. The delay in tumor growth was accompanied by significant decreases in microvessel density, perfusion, and proliferation, and a significant increase in tumor cell apoptosis. No overt toxicity was observed. The combination of OXi4503 and metronomic chemotherapy results in prolonged tumor control, thereby expanding the list of therapeutic agents that can be successfully integrated with metronomic low-dose chemotherapy.

PMID: 19825805 [PubMed - in process]


Clin Cancer Res. 2009 Oct 15;15(20):6358-66. Epub 2009 Oct 13.
Comparative impact of trastuzumab and cyclophosphamide on HER-2-positive human breast cancer xenografts.
Francia G, Man S, Lee CJ, Lee CR, Xu P, Mossoba ME, Emmenegger U, Medin JA, Kerbel RS.

Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada. robert.kerbel@sri.utoronto.ca
Comment in:

Clin Cancer Res. 2009 Oct 15;15(20):6311-3.
PURPOSE: Metronomic chemotherapy is a minimally toxic and frequently effective new treatment strategy that is beginning to show promising phase II clinical trial results, particularly for metastatic breast cancer when combined with various molecularly targeted antitumor agents. Here, we assessed a treatment strategy that uses trastuzumab plus daily oral metronomic cyclophosphamide on metastatic Her-2-positive human breast cancer models. EXPERIMENTAL DESIGN: Treatments were initiated on orthotopic transplanted primary tumors as well as established visceral metastatic disease of two independent Her-2-positive breast cancer models, both independently derived from the human MDA-MB-231 breast cancer cell line. Outcome was assessed by noninvasive measurements of tumor cell-secreted human choriogonadotropin in the urine as a surrogate marker of relative tumor burden, or by whole body bioluminescent imaging, in addition to prolongation of survival. RESULTS: Orthotopic primary tumors responded to trastuzumab monotherapy with significant growth delays, whereas minimal antitumor effect was observed when mice with metastatic disease were treated. Nevertheless, trastuzumab showed a benefit in this latter setting when combined with metronomic low-dose cyclophosphamide as assessed by prolongation of survival. This benefit was similar to trastuzumab plus maximum tolerated dose cyclophosphamide, but was associated with lesser toxicity. CONCLUSIONS: Trastuzumab combined with metronomic cyclophosphamide may be an effective long-term maintenance strategy for the treatment of Her-2-positive metastatic breast cancer.

PMID: 19825954



J Clin Oncol. 2006 Aug 1;24(22):3623-8.
Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients.

FULL TEXT HERE

Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S, Allevi G, Aguggini S, Bodini G, Milani M, Dionisio R, Bernardi C, Montruccoli A, Bruzzi P, Harris AL, Dogliotti L, Berruti A.
Breast Unit and Anatomia Patologica, Azienda Ospedaliera Istituti Ospitalieri Cremona, Italy.
PURPOSE: To investigate the activity of letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment (PST) in elderly breast cancer patients. METHODS: One hundred fourteen consecutive elderly women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to primary letrozole therapy (2.5 mg daily for 6 months) or a combination of letrozole plus oral cyclophosphamide (50 mg/daily for 6 months) in an open-labeled, randomized phase II trial. Tumor response was assessed clinically, and tumor Ki67 index and vascular endothelial growth factor (VEGF) -A levels were measured before and after treatment. RESULTS: Overall response rate was 71.9% (95% CI, 60.0 to 83.8) in the 57 patients randomly assigned to receive primary letrozole and 87.7% (95% CI, 78.6 to 96.2) in the 57 patients randomly assigned to receive letrozole plus cyclophosphamide. The difference in activity between treatment arms was predominantly confined to patients with ductal histology. There was a significantly greater suppression of Ki67 and VEGF-A expression in the letrozole/cyclophosphamide-treated group than in the letrozole-treated group, leading to lower Ki67 and VEGF expression at post-treatment residual histology (P = .03 and P = .002, respectively). CONCLUSION: Both letrozole and letrozole plus cyclophosphamide treatments appeared active as PST in elderly breast cancer patients. Metronomic scheduling of cyclophosphamide may have an antiangiogenic effect and the combination of letrozole plus cyclophosphamide warrants testing in a randomized phase III trial.

PMID: 16877730 [PubMed - indexed for MEDLINE]

Quote:
Chemotherapy efficacy is dependent mainly on proliferative activity, whereas endocrine therapies are cytostatic, so that an antagonistic interaction between the two treatment modalities is expected when they are administered concomitantly.14 The results of a large randomized clinical trial published recently are in line with these assumptions.15
Because the target of the metronomic chemotherapy is not the proliferating cancer cells, this treatment modality could potentiate the efficacy of endocrine therapy.

Quote:
In this article, we explored the activity of the combination of LET-CYC administration as PST in elderly breast cancer patients as compared to standard LET. The response rate of 72% in patients randomly assigned to the LET arm was higher than the 60% obtained in a previous randomized trial with primary LET therapy.2 The different patient population and the longer exposure of our patients to LET (6 months v 4 months) can account for the observed difference.
The response rate obtained in the LET-CYC arm(88%) was high.
The study design was not aimed at testing the difference in response rates in the two treatment arms, and both passed the test of activity. However, the comparison with the randomized control arm indicates that the high activity of the experimental arm was not caused by a biased sample,22 and suggests that the addition of CYC is associated with an increase in the activity of LET in this patient population (OR, 2.79). Although these results are encouraging, they failed to be confirmed by pathCR, a known predictor of long-term outcome. pathCR was observed in two patients (3.5%), one in each arm. A very low pathCR with primary LET therapy (1.7%) was obtained in the randomized trial comparing LET versus tamoxifen,2 suggesting that this condition is not a sensitive end point for primary endocrine therapy. The addition of metronomic CYC failed to increase the pathCR rate. Others have also found that patients with ER tumors have a low propensity to obtain pathCR after chemotherapy.23,24





The Anti-Angiogenic Basis of Metronomic Chemotherapy

http://www.medscape.com/viewarticle/480745

Robert S. Kerbel; Barton A. Kamen
Published: 06/18/2004

Abstract

In addition to proliferating cancer cells and various types of normal cells, such as those of the bone marrow, conventional cytotoxic chemotherapeutics affect the endothelium of the growing tumour vasculature. The anti-angiogenic efficacy of chemotherapy seems to be optimized by administering comparatively low doses of drug on a frequent or continuous schedule, with no extended interruptions — sometimes referred to as 'metronomic' chemotherapy. In addition to reduced acute toxicity, the efficacy of metronomic chemotherapy seems to increase when administered in combination with specific anti-angiogenic drugs. Gaining better insight into the mechanisms of these effects could lessen or even eliminate the empiricism used to determine the optimal dose and schedule for metronomic chemotherapy regimens.
.......

The combination of cyclophosphamide and methotrexate has already been tested in a clinical trial in Italy, and has spurred additional trials that are underway.[49] Sixty-four women with progressive, advanced and refractory breast cancer received low doses of oral cyclophosphamide on a daily basis and oral methotrexate was given twice per week. Most of the patients had progressive metastatic disease when the trial began and had also previously received first-, second- or third-line treatments. An overall response rate of 32% was observed, which included two complete responders, 10 partial responders and 12 patients with stable disease lasting 6 months or longer.[49] No high-grade adverse events were reported, despite the fact that many patients had previously been treated with chemotherapy. This compares favorably with the standard third-line chemotherapy regimens used in this treatment setting, at least in terms of toxicity. The estimated cost of this outpatient therapy was about US$10 per month.[49]


Phase II clinical trials have been initiated to test the possible benefits of metronomic chemotherapy regimens — particularly when these are combined with an anti-angiogenic drug. Several of these trials are summarized in Table 3 . Most of these involve chemotherapy regimens in which cyclophosphamide is administered orally on a daily basis, sometimes for up to 2 years, with no break periods. In some cases, oral low-dose methotrexate is also given on two consecutive days on a weekly basis. The targeted drugs that are used include a cyclooxygenase-2 (COX2)-specific inhibitor such as celecoxib, which is administered on a daily basis, or a humanized anti-VEGF monoclonal antibody (such as bevacizumab), which is administered intravenously every 2 weeks. Celecoxib was selected for inclusion in the trial because of its commercial availability, ease of administration, excellent side-effect profile and putative anti-angiogenic effects.[101,102]



METRONOMIC CHEMOTHERAPY can be viewed as a variation of dose-dense therapy with the exception that the cumulative dose with metronomic therapy might be significantly less than with MTD-based chemotherapy.[15-16] As metronomic therapy reduces the level of toxicity, it lessens or even removes the need for growth-factor support to accelerate recovery from myelosuppression. Moreover, despite lower cumulative doses of drug administration, the antitumour effects of this approach, in terms of prolonging survival times, might actually be superior to conventional MTD regimens
...........

Chemotherapeutics do not specifically target tumour cells, but rather interfere with cell division, such as by inhibiting enzymes involved DNA replication or metabolism (for example, topoisomerases and thymidylate synthase), or microtubules. These drugs therefore also damage the normal dividing cells of rapidly regenerating tissues, such as those of the bone marrow and gut mucosa, and hair-follicle cells. Host toxicity is therefore often only marginally less than antitumour efficacy, so creating a narrow therapeutic index.
But perhaps there is a silver lining in this otherwise dark cloud, in that dividing endothelial cells are present in the growing blood vessels that are found in tumours[27] and, like other normal dividing cells, should be susceptible to chemotherapeutics.[28] Elimination of these dividing endothelial cells, or inhibition of their division, would presumably lead to an anti-angiogenic effect. Moreover, as host vascular endothelial cells are assumed to be genetically stable and lack the diverse genetic defects characteristic of cancer cells that lead to drug resistance, the putative effects of chemotherapy might be more durable in the face of continued therapy. By way of example, successive cycles of MTD-based chemotherapy can cause myelosuppression each time, the extent of which does not change appreciably.[28] If normal bone-marrow-cell progenitors acquired resistance to chemotherapy in the same way that genetically unstable, highly mutable cancer cells do, myelosuppression would gradually decline and disappear. So, the cancer cells that are resistant to a particular chemotherapeutic agent might indirectly respond to that same drug through a 'side effect' — loss of or damage to its associated vasculature, as first proposed in 1991 (REF. 29). Literature dating back to the mid-1980s shows that virtually every class of chemotherapeutic has anti-angiogenic effects or antivascular effects in various in vitro and in vivo assays.[23]
Many tumours, however, are intrinsically drug resistant or rapidly acquire resistance after showing initial responsiveness to chemotherapy regimens. So it would of dividing endothelial cells in tumour-associated blood vessels is simply too low for chemotherapy to have a significant therapeutic impact. Alternatively, the endothelial cells might be protected from chemotherapy-induced cell death by high local concentrations of endothelial-cell survival factors such as VEGF, basic fibroblast growth factor (bFGF) and angiopoietin 1 (REFS 30,31). A third explanation, uncovered in a pioneering study from Judah Folkman's laboratory,[22] is that the anti-angiogenic effects of chemotherapy are both masked and marginalized by the way chemotherapy is usually administered. In this case, the long breaks between drug administration that are necessary to allow the patient to recover from the harmful side effects of the MTD chemotherapy, especially from myelosuppression, reduce the anti-angiogenic effects of the drugs.


Timothy Browder and colleagues evaluated the anti-angiogenic and antitumour effects of the alkylating agent cyclophosphamide in immune-competent syngeneic mice that had been injected subcutaneously with various tumour types.[22] They found that this drug, when administered at the MTD, caused apoptosis of endothelial cells in the newly formed tumour microvessels.[22] A detailed temporal analysis showed that the endothelial cells were the first in the tumour to undergo apoptosis.[22]This anti-angiogenic effect did not, however, translate into a significant therapeutic benefit, apparently because the damage to the vasculature of the tumour was largely repaired during the long (2-3-week) rest/recovery periods between successive cycles of MTD-based therapy.
It was therefore proposed that if cyclophosphamide was given more frequently (FIG. 1), such as once or more per week with no extended breaks, there would be significantly less opportunity for repair of the damaged endothelium and the anti-angiogenic effects of the chemotherapy would irreversibly accumulate. This, of course, necessitates lowering the dose of the drug administered with each injection. Browder et al. showed that this more frequent, regular, lower-dose therapy, which was administered at one-third of the MTD, had impressive anti-angiogenic and antitumour effects when tested on several mouse tumour cell lines grown subcutaneously in syngeneic mice.[22] This approach allowed even very large established subcutaneous tumours, previously selected in vivo for acquired cyclophosphamide resistance using a conventional MTD regimen, to respond to the same drug and almost completely regress. In short, a state of acquired drug resistance could be reversed simply by apparently shifting the focus of the treatment away from the drug-resistant cancer-cell population to the drug-sensitive tumour endothelium.[3,22]

..............

preclinical results actually have many intriguing clinical precedents.[4,36] For example, 40% of patients with non-small-cell lung cancer (NSCLC) who showed no response to standard doses of intravenous etoposide administered intermittently did respond — that is, their tumours shrank by 50% of more in volume — to the same drug when it was given orally at a much lower dose using a much more frequent basis (every day or every other day), with only a 1-week break every month.[37] Similar results have been shown in patients who have been given other drugs, such as microtubule-inhibiting taxanes, for treatment of advanced metastatic breast or ovarian cancer. In these patients, weekly regimens of drug administration are being increasingly adopted, often using only 30-40% of the MTD given once every 3 weeks.[38] In women who had stopped responding to the MTD of paclitaxel or docetaxel given once every 3 weeks, tumours were found to respond in a high proportion of cases to a regimen of approximately 30-40% the MTD once every week.[13,36,38-40] However, for the most part, these are not standard-of-care regimens and their benefits remain to be validated in randomized prospective Phase III clinical trials.

...........
...if endothelial cells are continuously exposed to a low concentration of drug such as paclitaxel over a 6 day period (replicating metronomic therapy), endothelial cells, but not dermal fibroblasts or tumour cells, undergo apoptosis within about 5 days.[78] This delay in cytotoxicity indicates that the pro-apoptotic effects of low-dose metronomic chemotherapy on endothelial cells might not be direct, but could instead be a secondary result of some other process that is specific to the vascular endothelial cell.


There are two routes by which metronomic chemotherapy could lead to growth arrest or apoptosis of endothelial cells in the tumour neovasculature. A 'direct' pathway (left) assumes that activated, differentiated endothelial cells are intrinsically sensitive to low-dose chemotherapy, for which there is some evidence;[80-85] the same might be true for circulating endothelial progenitor cells.[17] The 'indirect' pathway (right) assumes that the levels of metronomically administered drugs are too low to induce growth arrest or apoptosis of endothelial cells. Instead, an endogenous inhibitor of angiogenesis, such as thrombospondin 1, is induced in certain cells by low-dose chemotherapy. This inhibits tumour angiogenesis and vasculogenesis, leading to a reduction in tumour neovascularization in the absence of side effects such as myelosuppression, hair loss, and nausea or vomiting.




BMC Cancer. 2006 Sep 15;6:225.
Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer.

Orlando L, Cardillo A, Ghisini R, Rocca A, Balduzzi A, Torrisi R, Peruzzotti G, Goldhirsch A, Pietri E, Colleoni M.
Unit of Research in Medical Senology, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. laura.orlando@ieo.it
BACKGROUND: HER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC). METHODS: Between April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks) in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week) and CTX (50 mg daily) (CM). RESULTS: The 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts), and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts), liver (14 pts), bone (12 pts), lymph nodes (8 pts), central nervous system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5-40%), 10 stable disease (SD) (46%, 95% CI 24-68%), and 8 PD (36%, CI 17-59%). The clinical benefit (RP plus RC plus SD for > or = 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24-68%) and 27% (95% CI, 6-61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade > or =2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively. CONCLUSION: The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.

PMID: 16978400 [PubMed - indexed for MEDLINE]




Journal of Clinical Oncology, Vol 26, No 30 (October 20), 2008: pp. 4899-4905
© 2008 American Society of Clinical Oncology.


Metronomic Cyclophosphamide and Capecitabine Combined With Bevacizumab in Advanced Breast Cancer
FULL TEXT LINK (PDF attached)
Silvia Dellapasqua, Francesco Bertolini, Vincenzo Bagnardi, Elisabetta Campagnoli, Eloise Scarano, Rosalba Torrisi, Yuval Shaked, Patrizia Mancuso, Aron Goldhirsch, Andrea Rocca, Elisabetta Pietri, Marco Colleoni
From the Medical Senology Research Unit and Division of Medical Oncology, Department of Medicine; Division of Hematology-Oncology, Department of Medicine; and Division of Epidemiology and Biostatistics, European Institute of Oncology; Department of Statistics, University of Milan-Bicocca, Milan, Italy; Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and Oncology Institute of Southern Switzerland, Bellinzona and Lugano, Switzerland
Corresponding author: Marco Colleoni, MD, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; e-mail: marco.colleoni@ieo.it
Purpose Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in preclinical and clinical studies.
Patients and Methods Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks).
Results In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD 24 weeks) occurred in eight patients, for an overall clinical benefit (CR + PR + SD 24 weeks) of 68% (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04).
Conclusion Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.

Quote:
previously showed that the probability of prolonged CB with metronomic therapy was higher in endocrine-responsive MBC.23 These results might be related to the biology of endocrine-responsive disease, which is characterized by indolent, low-proliferating tumors and, therefore, more likely to have prolonged stabilization.27 Moreover, there is a biologic rationale for improved activity of antiangiogenic treatment in endocrine-responsive tumors.28 Several growth factors influence proliferation and survival of ER-positive hormone-resistant disease.29 In particular, VEGF is elevated in patients with endocrine-responsive disease who do not respond to hormone therapy, therefore contributing to disease progression and resistance to endocrine therapies.30-32

Quote:
We showed that baseline and viable CECs were significantly increased in patients who had a clinical response and in patients who achieved a CB. Moreover, patients who had a baseline increased apoptotic CEC count had a significantly better PFS. Flow cytometry viability studies indicated that apoptotic CEC count was related to total CEC count (data not shown). Therefore, the baseline total, viable, and apoptotic CEC count might represent an indirect measure of the angiogenic turnover and an indicator of better response to antiangiogenic therapy, supporting the use of these treatments in patients expressing high levels of baseline CECs. Further prospective trials are required to confirm the value of these data in patients who are candidates for antiangiogenic agents. If confirmed, future selection of antivascular agents should also be based on the CEC count before treatment. In conclusion, the results of this study indicate that metronomic capecitabine and cyclophosphamide combined with bevacizumab provide long-term disease control in a high proportion of patients, without significant toxicity despite prolonged use. The low burden in terms of personal costs to the patient and the possibility of continuing the treatment for up to several months in responders, as is often required in advanced breast cancer patients, support this regimen as an additional therapeutic tool in MBC patients.


published online ahead of print at www.jco.org on September 15, 2008.
Supported in part by Associazione Italiana per la Ricerca sul Cancro, Instituto Superiore di Sanitá, and the European Union Integrated Project "Angiotargeting."
Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article

__________



Cancer Immunol Immunother. 2007 May;56(5):641-8. Epub 2006 Sep 8.
Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.

Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B.
Unité INSERM 517, Faculté de Médecine, Dijon, France. francois.ghiringhelli@wanadoo.fr
CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as "metronomic" therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy.

PMID: 16960692 [PubMed - indexed for MEDLINE]





J Clin Oncol. 2008 Oct 20;26(30):4899-905. Epub 2008 Sep 15.
Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer.


PDF of Full Text

Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, Shaked Y, Mancuso P, Goldhirsch A, Rocca A, Pietri E, Colleoni M.
Medical Senology Research Unit and Division of Medical Oncology, Department of Medicine, European Institute of Oncology, Milan, Italy.
PURPOSE: Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in preclinical and clinical studies.overall clinical benefit (CR + PR + SD > or = 24 weeks) of 68% PATIENTS AND METHODS: Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks). RESULTS: In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD > or = 24 weeks) occurred in eight patients, for an (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04). CONCLUSION: Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.

PMID: 18794539 [PubMed - indexed for MEDLINE]



Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: Final results of a randomised phase III trial
Annals of Oncology, 01/25/10
Blohmer JU et al. – This randomised phase III trial was carried out to compare the efficacy and safety of epirubicin and cyclophosphamide (EC) with epirubicin and docetaxel (Taxotere) (ED) as first-line chemotherapy for metastatic breast cancer. In this randomised trial, no differences in the efficacy study end points were observed between the two treatment arms.
Methods
  • Patients (n = 240) were randomly assigned to receive either ED (epirubicin 75 mg/m2 and docetaxel 75 mg/m2) or EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2)
  • Primary end point was ORR
  • Secondary end points were PFS, OS, and safety
Results
  • ORR for patients randomly assigned to receive EC and ED were 42% and 47%, respectively
  • Median PFS [10.1 versus 10.3 months; hazard ratio (HR) 0.98; log-rank P = 0.38] and OS (19.9 versus 30.0 months; HR 0.663; log-rank P = 0.21) were comparable in both arms
  • Although grade 3/4 leucopenia occurred more frequently with ED (81% versus 73%; P = 0.01), there were no significant differences in the incidence of febrile neutropenia and grade 3/4 infections
  • Grade 3/4 non-haematologic toxicity was infrequent in both arms
  • Congestive heart failure observed in one patient in each arm






Gan To Kagaku Ryoho. 2009 Sep;36(9):1525-8.
[A case of stage IV breast cancer with large cancer ulcer responding to combination therapy of capecitabine and medroxyprogesterone acetate and cyclophosphamide]

[Article in Japanese]
Konishi K, Hasegawa N, Kaneko H, Iimura Y, Shoji Y, Kawabata M.
Dept. of Surgery, Kushiro City General Hospital.
A 53-year-old woman suffering from nausea and vomiting was admitted to our hospital. There was a large ulcer from her left anterior chest to her right side chest. After pathological examination from the ulcer, she was diagnosed as breast cancer, scirrhous carcinoma. The estrogen and progesterone receptors were positive in the tumor. HER2 score was 1+ in the tumor. The stage was T4bNxM1(OTH). Uterine metastases of the breast cancer caused obstructive nephropathy. Ureteral obstruction was treated by urinary tract catheter. After improvement of renal failure, chemotherapy with 5-FU+epirubicin+cyclophosphamide (FEC) and docetaxel was performed. The efficacy was judged as stable disease (SD). For third-line chemotherapy, she was then treated with oral combination chemoendocrine therapy with capecitabine and medroxyprogesterone acetate. After the combination chemoendocrine therapy, the local tumor was remarkably reduced. With added cyclophosphamide, the partial response (PR) continued for 19 months. She died of peritonitis carcinomatosa and pleuritis carcinomatosa. No adverse reactions occurred with the combination chemoendocrine therapy. It is suggested that this oral combination chemoendocrine therapy may be useful with consideration for treatment effectiveness and the quality of life of the patient.

PMID: 19755825 [PubMed - indexed for MEDLINE]



Bottini A, Generali D, Brizzi MP, Fox S, Bersiaga A, Berruti A, et al. Randomized Phase II trial of Letrozole and Letrozole plus low-dose metronomic oral Cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol 2006;/24:/36238.


Colleoni M, Rocca A, Sandri M, Zorzino L, Masci G, Goldhirsch A, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: Antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 2002;/13:/7380.

Yuong S, Whissell M, Noble J, Cano P, Lopez P, Germond C. Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine and rofecoxib in patients with advanced solid tumors. Clin Cancer Res
2006;/12:/30928.



J Pharmacol Sci. 2009 Apr;109(4):473-85.
Caspase mediated enhanced apoptotic action of cyclophosphamide- and resveratrol-treated MCF-7 cells.

Singh N, Nigam M, Ranjan V, Sharma R, Balapure AK, Rath SK.
Genotoxicity Laboratory, Toxicology Division, Central Drug Research Institute, India. neetuaashi@yahoo.com
Cyclophosphamide (CPA) is a widely used chemotherapeutic drug for neoplasias. It is a DNA and protein alkylating agent having a broad spectrum of activity against a variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the high-dose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining resveratrol (RES) with CPA and aims to increase the understanding of the mechanism of cell killing. Interestingly, we found that RES significantly enhances the caspase-mediated cytotoxic activity of CPA on MCF-7 cells in vitro. RES at 50 microM decreases the IC(50) value of CPA from 10 to 5 mM. FACS data reveals CPA or RES alone mediated G0/G1 and S phase arrest, while the combination of these drugs released both the arrests and results in an increase in the sub G0/G1 peak. Additional analyses indicated the significant up-regulation (P = 0.001) of tumor suppressor p53 and p53-regulated pro-apoptotic Bax and Fas in MCF-7 cells following CPA treatment in combination with RES, which may contribute to the enhancement of the antitumor effect of CPA. Furthermore, downregulation of anti-apoptotic Bcl-2 (P = 0.001) was observed in MCF-7 cells treated with CPA with or without RES when compared to untreated MCF-7. These results suggest the possibility of a new combination chemotherapeutic regimen leading to improvements in the treatment of breast cancer.

PMID: 19372630 [PubMed - indexed for MEDLINE]






YM BIOSCIENCES ANNOUNCES NIMOTUZUMAB RESULTS IN ADVANCED TRIPLE-NEGATIVE BREAST CANCER MODEL PRESENTED AT AACR-NCI-EORTC MEETING
MISSISSAUGA, ON, Nov. 18 /PRNewswire-FirstCall/ - YM BioSciences Inc. (NYSE Amex: YMI; TSX: YM), a life sciences product development company that identifies and advances a diverse portfolio of promising cancer-related products at various stages of development, announced that results from a study evaluating nimotuzumab were presented today in a poster at the 2009 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference in Boston, Massachusetts. The reported results demonstrate that nimotuzumab in combination with metronomic chemotherapy in an advanced triple-negative breast cancer preclinical model is safe and effective.
In this study nimotuzumab, an epidermal growth factor receptor (EGFR) targeting antibody, was administered twice weekly in combination with metronomic (continuous low-dose) cyclophosphamide. This regimen resulted in significant primary tumor growth delay in an aggressive, metastatic, higher EGFR-expressing variant of the MDA-MB-231 human breast cancer breast model, which over-expresses EGFR. In addition, the combination resulted in a significant survival advantage over cyclophosphamide alone.

"The data demonstrate that nimotuzumab in combination with metronomic cyclophosphamide is safe and effective in this aggressive tumor type which has limited therapeutic options. Furthermore, the addition of nimotuzumab would be expected to be minimally toxic to patients and as such, this combination should be considered for this patient population in future clinical trials," said lead author Dr.
Anthony J. Mutsaers of the Division of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre and Department of Medical Biophysics, University of Toronto.
The research poster is entitled "Combination treatment with metronomic cyclophosphamide and the EGFR monoclonal antibody nimotuzumab is efficacious and non-toxic in a preclinical model of advanced triple negative breast cancer". It is being presented today (Poster Session C, Abstract C49) by the author.



Online http://jco.ascopubs.org/cgi/content/full/26/19/3286
PDF http://jco.ascopubs.org/cgi/reprint/26/19/3286
CORRESPONDENCE

Dose-Dense and/or Metronomic Schedules of Specific Chemotherapies Consolidate the Chemosensitivity of Triple-Negative Breast Cancer: A Step Toward Reversing Triple-Negative Paradox

Quote:
A parallel phase III neoadjuvant study demonstrated a pathologic complete response of 43% with denser doxorubicin (weekly) and cyclophosphamide (continuous) compared with 26% with once-every-3-weeks doxorubicin and cyclophosphamide, both arms receiving weekly paclitaxel in locally advanced breast cancer, suggesting an additive benefit of denser administration doxorubicin and cyclophosphamide, in addition to the denser administration of paclitaxel.5 Taken together, studies show benefit of accelerated schedules (weekly or once every 2 weeks) of doxorubicin, cyclophosphamide, and paclitaxel.
Approach that exploits of pro-angionenic weekly therapy:

Curr Cancer Drug Targets. 2009 Sep;9(6):777-88.
Increased tumor oxygenation and drug uptake during anti-angiogenic weekly low dose cyclophosphamide enhances the anti-tumor effect of weekly tirapazamine.

Doloff JC, Khan N, Ma J, Demidenko E, Swartz HM, Jounaidi Y.
Department of Biology, Boston University, MA 02215, USA.
Metronomic cyclophosphamide treatment is associated with anti-angiogenic activity and is anticipated to generate exploitable hypoxia using hypoxia-activated prodrugs. Weekly administration of tirapazamine (TPZ; 5 mg/kg body weight i.p.) failed to inhibit the growth of 9L gliosarcoma tumors grown s.c. in scid mice. However, the anti-tumor effect of weekly cyclophosphamide (CPA) treatment (140 mg/kg BW i.p.) was substantially enhanced by weekly TPZ administration. An extended tumor free period and increased frequency of tumor eradication without overt toxicity were observed when TPZ was given 3, 4 or 5 days after each weekly CPA treatment. Following the 2(nd) CPA injection, Electron Paramagnetic Resonance (EPR) Oximetry indicated significant increases in tumor pO(2), starting at 48 hr, which further increased after the 3(rd) CPA injection. pO(2) levels were, however, stable in growing untreated tumors. A strong negative correlation (-0.81) between tumor pO(2) and tumor volume during 21 days of weekly CPA chemotherapy was observed, indicating increasing tumor pO(2) with decreasing tumor volume. Furthermore, CPA treatment resulted in increased tumor uptake of activated CPA. CPA induced increases in VEGF RNA, which reached a maximum on day 1, and in PLGF RNA which was sustained throughout the treatment, while anti-angiogenic host thrombospondin-1 increased dramatically through day 7 post-CPA treatment. Weekly cyclophosphamide treatment was anticipated to generate exploitable hypoxia. However, our findings suggest that weekly CPA treatment induces a functional improvement of tumor vasculature, which is characterized by increased tumor oxygenation and drug uptake in tumors, thus counter-intuitively, benefiting intratumoral activation of TPZ and perhaps other bioreductive drugs.

PMID: 19754361 [PubMed - indexed for MEDLINE]



J Clin Oncol. 1995 Feb;25(1):10-5.

TEXT

Eyelid metastasis from breast cancer showing marked response to chemotherapy.
Zhang GJ, Adachi I, Yin DF, Narabayashi M, Tokue Y, Watanabe T, Kaneko A, Tsuda H, Abe K.
Department of Medical Oncology,National Cancer Center Hospital Tokyo

A patient with recurrent breast cancer, who was diagnosed with eyelid metastasis as a part of systemic metastases and in whom systemic chemotherapy was markedly effective, is reported. A 50-year-old woman underwent a radical mastectomy for stage II breast cancer in October, 1988. Histologically, the tumor was invasive lobular carcinoma. In October, 1993, the patient consulted our hospital complaining primarily of swelling of the left eyelid and restriction of movement in the left eye. Metastasis from breast cancer was diagnosed on eyelid biopsy. On further examination, metastases were detected in the liver, bone, orbit, peritoneum and pleura. Systemic combined chemotherapy consisting of cyclophosphamide, adriamycin and 5-fluorouracil was administered intravenously at intervals of three weeks. Complete responses were obtained in the eyelid and peritoneal metastases after three courses, and in the liver metastasis after five courses. Partial responses were also observed in the bone and pleural metastases.
The incidence of eyelid metastasis from breast cancer is very low, one case only having been previously reported in Japan and 34 cases abroad. Most of these cases were treated locally by surgical resection or radiotherapy, but the mean survival period was only 14 months, ranging from two months to four years. Eyelid metastasis from breast cancer should be regarded as a manifestation of systemic spread of the tumor and, in principle, treated by systemic therapy.
PMID: 7877258 [PubMed - indexed for MEDLINE



Clin Exp Metastasis. 2009;26(3):179-87. Epub 2008 Dec 14.
Chitosan hydrogel containing GMCSF and a cancer drug exerts synergistic anti-tumor effects via the induction of CD8+ T cell-mediated anti-tumor immunity.

Seo SH, Han HD, Noh KH, Kim TW, Son SW.
Department of Dermatology, Korea University Ansan Hospital, Korea University College of Medicine, Gojan 1-dong, Danwon-gu, Ansan-si, Gyeonggi-do, South Korea.
Cancer treatments consisting of a combination of chemotherapy and immunotherapy have been vigorously exploited to further improve the efficacy of cancer therapies. In this study, we utilized a chitosan hydrogel (CH) system loaded with GMCSF and a cancer drug as a chemo-immunotherapeutic agent in an effort to assess the effects on tumor growth in mice using TC-1 cervical tumor cells, which express the tumor-specific antigen, HPV-16 E7. The growth of TC-1 tumors was significantly reduced in mice treated with a CH harboring a cancer drug (doxorubicin (DOX), cisplatin (CDDP), or cyclophosphamide (CTX)) and GMCSF (CH-a cancer drug + GMCSF), as compared to other groups that were treated with CH containing only a cancer drug(CH-a cancer drug) or GMCSF(CH-GMCSF). Among the cancer drugs, CTX exerted the most potent anti-tumor effects. Interestingly, the intra-tumoral injection of CH-a cancer drug + GMCSF induced a significant E7-specific CD8(+) T cell immune response as compared to CH-GMCSF or CH-a cancer drug. This enhancement of tumor antigen-specific CD8(+) T cell immunity was associated principally with the anti-tumor effects induced by CH-CTX + GMCSF, as demonstrated by antibody depletion. Collectively, the aforementioned results indicate that co-treatment of tumors with a combination of GMCSF and a cancer drug incorporated into a CH system results in synergistic anti-tumor effects, which occur via the induction of a tumor antigen-specific CD8(+) T cell-mediated anti-tumor immunity. This study demonstrates the use of a biodegradable hydrogel system for the co-delivery of an immunoadjuvant and an anti-cancer drug for successful chemo-immunotherapy.

PMID: 19082918 [PubMed - indexed for MEDLINE]




Crit Rev Oncol Hematol. 2000 Jan;33(1):61-6.
Idarubicin and cyclophosphamide--an active oral chemotherapy regimen for advanced breast cancer.

Leonard RC, Cameron DA, Anderson A, Ostrowski J, Howell A.
Department of Clinical Oncology, Western General Hospital NHS Trust, Edinburgh, UK.
Between October 1993 and September 1994, 33 women with metastatic breast cancer aged between 29 and 74 years with a median age of 58 were entered into a study of oral chemotherapy from three UK centres. Patients by definition had metastatic disease and were fit and well with performance status 0 or 1 in 23 cases, 2 in seven cases and 3 in two cases (one missing). Five patients had received prior adjuvant CMF chemotherapy, nine first line non-anthracycline containing chemotherapy for relapse, eight patients second line non-anthracycline containing chemotherapy and all patients had had hormone therapy either as adjuvant or for relapsed disease. Adjuvant radiotherapy had been given to 17 and palliative radiotherapy to 12 patients. In nine patients there was one site of disease at start of therapy, in 10 two sites, in 11 three sites and in three patients four or more sites. The regimen comprised oral idarubicin 15 mg/m2 on day 1, 10 mg/m2 on days 2 and 3 and oral cyclophosphamide 250 mg/m2 (maximum 400 mg) on days 1, 2 and 3. Treatment was continued until disease progression or toxicity. RESULTS: Overall 25% of 32 evaluable patients responded objectively including one complete response; 50% of patients had stable disease and 25% of patients progression. Among patients who had had no prior chemotherapy the objective response rate was 37.5%; 45% of patients had symptomatic improvement. The most common severe toxicity was granulocytopenia WHO grade 3 or more in 69.7% of patients. Thrombocytopenia grade 3 or 4 was seen in four patients. Six patients had documented infections and all but four patients had alopecia. All patients complained of mild or moderate fatigue. Nausea and vomiting occurred in 75% of patients but only four individuals had grade 3 toxicity. Two patients stopped therapy after myocardial infarction and one after impaired cardiac function was noted. The median time to progression was 2.7 months (1-11.5 months) and median survival time 8.8 months (1-13+ months). CONCLUSION: The combination chemotherapy is active in heavily treated patients with manageable toxicity but there are problems in heavily pre-treated patients. There was good compliance in taking medication and at the doses chosen the drugs appear to be suitable for younger fitter patients.

PMID: 10714963 [PubMed - indexed for MEDLINE]



Eur J Cancer. 2010 Feb 13. [Epub ahead of print]
Treating triple-negative breast cancer by a combination of rapamycin and cyclophosphamide: An in vivo bioluminescence imaging study.

Zeng Q, Yang Z, Gao YJ, Yuan H, Cui K, Shi Y, Wang H, Huang X, Wong ST, Wang Y, Kesari S, Ji RR, Xu X.
Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.
Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to inhibit the growth of oestrogen positive breast cancer. However, triple-negative (TN) breast cancer is resistant to rapamycin treatment in vitro. We set to test a combination treatment of rapamycin with DNA-damage agent, cyclophosphamide, in a TN breast cancer model. By binding to and disrupting cellular DNA, cyclophosphamide kills cells via interfering with their normal functions. We assessed the responses of nude mice bearing tumour xenografts of TN MDA-MB-231 cells to the combination of rapamycin and cyclophosphamide in both orthotopic mammary and lung-metastasis models. We tracked tumour growth and metastasis by bioluminescent imaging and examined the expression of Ki67, CD34 and HIF-1alpha in tumour tissues by immunohistochemistry and apoptosis index with TUNEL assay, and found that MDA-MB-231 cells are sensitive to rapamycin therapy in orthotopic mammary, but not in lung with metastasis. Rapamycin when combined with cyclophosphamide is found to have a more significant effect in reducing tumour volume and metastasis with a much improved survival rate. Our data also show that the sensitivity of TN tumours to rapamycin is associated with the microenvironment of the tumour cells. The data indicate that in a relatively hypoxic environment HIF-1alpha may play a role in mediating the anti-cancer effect of rapamycin and cyclophosphamide may prevent the feedback activation of Akt by rapamycin. Overall our results show that rapamycin plus cyclophosphamide can achieve an improved efficacy in suppressing tumour growth and metastasis, suggesting that the combination therapy can be a promising treatment option for TN cancer. Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20156674 [PubMed - as supplied by publisher]
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Old 02-01-2010, 05:00 PM   #2
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Re: Cyclophosphamide

Chemother. 2010 Jun;22(3):201-4. Oral metronomic chemo-hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate.

Licchetta A, Correale P, Migali C, Remondo C, Francini E, Pascucci A, Magliocca A, Guarnieri A, Savelli V, Piccolomini A, Carli AF, Francini G.
Section of Medical Oncology, Department Giorgio Segre of Pharmacology, Siena University School of Medicine, Italy.



Abstract

Metronomic chemotherapy is an anticancer strategy which uses conventional cytotoxic drugs administered at very low dose in close intervals. We have designed a phase II trial to investigate the safety and antitumor activity of the newest metronomic chemo-hormonal-therapy with daily cyclophosphamide and twice daily megestrol acetate (mCM regimen) in patients with metastatic pretreated breast cancer.Twenty-nine pretreated post-menopausal patients with multiple metastatic sites were enrolled. four patients had a triple negative status, nineteen a positive hormonal ER and PgR status, and three ERB-B2 over-expression. Patients received treatment with cyclophosphamide (50 mg/daily day 1-21/q28) and fractionated megestrol acetate (80 mg twice a day). The overall objective response rate was 31.0%, disease control rate 41.3%, mean time to tumor progression 7.4 months (CI 95%, 3.8-10.88, range 1-48 months) and mean overall survival 13.4 months (CI 95%, 7.24-17.18, range 1-53 months). The mCM regimen was active and well tolerated.

PMID: 20566427 [PubMed - in process]


Transl Oncol. 2010 Jun 1;3(3):149-52.
Loss of tumor-initiating cell activity in cyclophosphamide-treated breast xenografts.

Zielske SP, Spalding AC, Lawrence TS.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
Address all correspondence to: Steven P. Zielske, PhD, 4310 Med Sci I, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109. E-mail: szielske@med.umich.edu

FREE TEXT

Abstract


Cancer stem cells (CSCs) are a subpopulation of tumor cells with preferential tumor-initiating capacity and have been purported to be resistant to chemotherapy. It has been shown that breast CSC are, on average, enriched in patient tumors after combination neoadjuvant chemotherapy including docetaxel, doxorubicin, and cyclophosphamide (CPA). Here, we investigate the resistance of breast CSC to CPA alone in a xenograft model. CPA treatment led to a 48% reduction in tumor volume during a 2-week period. Cells bearing the CD44(+) CD24(-) phenotype were reduced by 90% (2.5% to 0.24%) in CPA-treated tumors, whereas cells with aldehyde dehydrogenase activity were reduced by 64% (4.7% to 1.7%). A subsequent functional analysis showed that CPA-treated tumors were impaired in their ability to form tumors, indicating loss of functional tumor-initiating activity. These results are consistent with a CSC phenotype that is sensitive to CPA and indicate that some patient CSC may not display the expected resistance to therapy. Deciphering the mechanism for this difference may lead to therapies to counteract resistance.

PMID: 20563255 [PubMed - in process]PMCID: PMC2887643Free PMC Article





Cancer Chemother Pharmacol. 2008 Oct;62(5):787-97. Epub 2008 Jan 10.
Toxicity and antitumor activity of the vitamin D analogs PRI-1906 and PRI-1907 in combined treatment with cyclophosphamide in a mouse mammary cancer model.

Wietrzyk J, Nevozhay D, Milczarek M, Filip B, Kutner A.
Department of Experimental Oncology, Institute of Immunology and Experimental Therapy, 12 R. Weigla St., 53-114, Wroclaw, Poland, wietrzyk@iitd.pan.wroc.pl.
PURPOSE: Active and less toxic vitamin D analogs could be useful for clinical applications. In the present study, we evaluated the toxicity and antitumor effect of two new synthetic analogs of vitamin D, namely PRI-1906 [(24E)-24a-Homo-(1S)-1,25-dihydroxyergocalciferol] and its side-chain unsaturated homo analog PRI-1907. METHODS: The toxicity and calcemic activity, as well as antitumor effect of calcitriol analogs was investigated in vivo. The studies were performed in a mouse mammary 16/C cancer model. Since calcitriol and its analogs inhibited 16/C tumor growth only slightly, we applied them in the combined therapy with cyclophosphamide (CY). Moreover, cell cycle analysis and VDR and p27 expression were investigated. RESULTS: The LD50 values after five daily subcutaneous (s.c.) injections were 7.8, 10.0 and 2.4 microg/kg per day for calcitriol, PRI-1906 and PRI-1907, respectively. The serum calcium level increased to 40, 23 and 63% over the control for these compounds. We also compare the antitumor activity of the PRI-1906 with the calcitriol and previously studied PRI-2191 (1,24-dihydroxyvitamin D3, tacalcitol). Statistically significant inhibition of tumor growth by calcitriol up to the eighth day was observed in all schedules applied. PRI-1906 inhibited the tumor growth at doses 1 and 5 microg/kg per day, and PRI-2191 only at the dose 5 microg/kg per day. CONCLUSION: Addition of vitamin D analogs increased the antitumor effect of CY. PRI-1906 exhibited toxicity higher than PRI-2191 but lower than calcitriol and antitumor activity similar to both PRI-2191 and calcitriol. This new analog seems to be a good candidate for the combined treatment of mammary cancer.

PMID: 18188568 [PubMed - indexed for MEDLINE]





J BUON. 2009 Sep;14 Suppl 1:S103-9.
How immunotherapy can enhance the response to other modalities and improve outcome and quality of life.

Liu WM, Meyer B, Dalgleish AG.
Department of Oncology, Division of Cellular and Molecular Medicine, St George's, University of London, UK.
Early studies suggested that the induction of an effective immune response could lead to elimination of residual tumour. Over a hundred years ago Coley invented his eponymous named "toxins" that appeared to induce a strong inflammatory response, leading to tumour reduction. Subsequent attempts to enhance the immune response have essentially been on a vaccine basis, trying to induce a specific response against the tumour. Numerous vaccine approaches have claimed to give significant clinical benefit in clinical response but very few of these have survived a randomised trial. A major reason for this is the heterogeneity of many tumours, as well as the various forms of defence against an immune response that they employ. It was thought that chemotherapy and radiotherapy were mutually exclusive for immunotherapy using the vaccine approach. More recently, however, it has become appreciated that vaccine approaches may enhance subsequent responses to radiotherapy and that certain chemotherapies actually enhance responses to vaccines. It has been suggested that one of the mechanisms of action of chemotherapy is to reduce the cells that suppress T-cells. These cells primarily defend the tumour from an immunological attack, but more recently it has been suggested that the benefit may encompass other aspects, such as enhancing antiangiogenic responses. One reason why immunostimulatory approaches may be so useful in cancer is that many cancers evolve out of a chronic inflammatory environment that actively suppresses cell mediated immune responses and enhances tumour angiogenesis. An ideal cancer drug would therefore be expected to have these properties. One such drug is lenalidomide, which features include marked immune stimulatory properties as well being able to inhibit regulatory T-cells. They have also been shown to enhance anticancer activity with vaccines in both preclinical models and more recently in clinical observations, where the responses to vaccines in patients with myeloma is much higher when they are on lenalidomide than other treatments. A number of regularly used chemotherapy regimens have marked activity in modulating the immune response. These maybe of benefit and the regimens will be reviewed, which include gemcitabine, cyclophosphamide and the IMiDs.

PMID: 19785052 [PubMed - in process]



What???

Neoplasia. 2009 Feb;11(2):187-95.
Cyclophosphamide enhances human tumor growth in nude rat xenografted tumor models.

Wu YJ, Muldoon LL, Dickey DT, Lewin SJ, Varallyay CG, Neuwelt EA.
Department of Neurology, Oregon Health & Sciences University, Portland, OR 97239, USA.
The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.

PMID: 19177203 [PubMed - indexed for MEDLINE]




J Environ Biol. 2009 Sep;30(5):663-6.
Modulatory effects of garlic extract against the cyclophosphamide induced genotoxicity in human lymphocytes in vitro.

Sowjanya BL, Devi KR, Madhavi D.
Department of Zoology, Osmania University, Hyderabad-500 007, India. soujanya27@gmail.com
Cyclophosphamide (CP) is a commonly used chemotherapeutic and immunosuppressive agent which is used in the treatment of wide range of cancers and autoimmune diseases. Besides that it is a well known carcinogen. In this study by using chromosomal aberrations (CA) and sister chromatid exchanges (SCE) assays method, the modulatory effects exerted by the extract of garlic against the CP induced genotoxicity in the human lymphocyte cultures in vitro were tested. Three different doses of garlic extract were tested for their modulatory capacity on the mutagenecity exerted by 100 microg ml(-1) of CR The results indicate a significant decrease in the frequency of CA and SCE suggesting that the garlic extract modulates the CP induced genotoxicity in a dose dependent manner. These findings provide the future directions for the research on design and development of possible modulatory drugs containing garlic extract.

PMID: 20136045 [PubMed - in process]





Z Naturforsch C. 2008 Nov-Dec;63(11-12):857-63.
Antimutagenic efficacy of some natural compounds on cyclophosphamide-induced p53 alterations.

Gouda EM, Elbehairy AM, Ghoneim MA.
Biochemistry Department and Biotechnology Center, Faculty of Veterinary Medicine, Cairo University, 12211 Giza, Egypt. emanmgouda@hotmail.com
Mutations in the p53 tumour suppressor gene have been associated with chemical carcinogens. Natural antimutagens are promising modulators for reducing the cancer risk. The present study was carried out to assess the protective efficacy of some natural antimutagens against p53 alterations. We investigated the ability of curcumin (100 mg/kg BW) and chlorophyllin (3 mg/kg BW) pretreatment, for three times per week for three successive weeks, to inhibit mutations induced by intraperitoneal injection of a single dose of 40 mg/kg BW of cyclophosphamide (CP). Forty male albino rats were assigned into four groups: control nontreated group, CP-treated group, curcumin-CP-treated group, and chlorophyllin-CP-treated group. Liver samples were collected for DNA isolation two days after CP injection. The isolated DNA was used in single-strand conformational polymorphism (SSCP) analysis of polymerase chain reaction (PCR)-amplified products of four regions: two in exon 5, one in exon 6, and one in exon 7. The amplified products of p53 different regions were found to be in the expected molecular size of the designed primers. SSCP analysis of these amplified products showed that CP-induced mutation in the p53 gene was found only in exon 7 shifting its electrophoretic mobility. Chlorophyllin treatment prior to CP injection had a more potent protective efficacy (80%) than that with curcumin (33.3%).

PMID: 19227835 [PubMed - indexed for MEDLINE]



Int J Hematol. 2010 Feb 13. [Epub ahead of print]
A case of treatment-related myelodysplastic syndrome spontaneously resolved by drug discontinuance.

Nakagawa Y, Miura K, Yamazaki T, Ishizuka H, Takei K, Sawada U, Kura Y, Hatta Y, Takeuchi J.
Division of Medicine, Department of Hematology and Rheumatology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi Ward, Tokyo, Japan.
Although great advancements have been witnessed in treatment results for hematopoietic tumors in recent years, development of secondary malignant tumors induced by anti-cancer drugs still remains a serious issue. We experienced a case of secondary myelodysplastic syndrome (MDS), possibly induced by cyclophosphamide (CY), which was spontaneously resolved by discontinuance of CY. A 24-year-old woman was diagnosed with follicular lymphoma in January 1998: she had developed bulky intra-abdominal lymphadenopathy, with repeated relapse and remission by several chemotherapy treatments. Remission was induced by rituximab, administered at the time of relapse in 2001, followed by administration of 50 mg/day of CY since December 2001 for the prevention of relapse. Anemia and thrombocytopenia developed around January 2003. Bone marrow aspiration revealed abnormality in two lineages and a complicated chromosomal anomaly, and the patient was diagnosed with MDS. Discontinuance of CY and administration of an anabolic steroid improved anemia and thrombocytopenia within 2 years. Bone marrow aspiration in 2006 showed improvement in morphological abnormality and disappearance of chromosomal abnormality.

PMID: 20155339 [PubMed - as supplied by publisher]


Gan To Kagaku Ryoho. 2010 Mar;37(3):511-5.
[A case of multidrug-resistant breast cancer associated with multiple hepatic and bone metastases for which cyclophosphamide, methotrexate, and 5-Fluorouracil chemotherapy proved effective.]

[Article in Japanese]
Tanaka T, Tanino H, Hirai I, Hata K, Maebeya S, Oota F, Miki Y.
Dept. of Pharmacy, Naga Municipal Hospital.
A 5 1-year-old patient had recurrent breast cancer with liver metastases. After mastectomy, she received CEF and many kinds of hormone therapy and chemotherapy after recurrence. Her liver metastases had been controlled by CMF therapy for 9 months. CMF therapy is good at maintaining the QOL of recurrent patients during treatment because of less toxicity and is even useful for multidrug-resistant tumors like this patient with liver metastases after anthracycline and taxane treatment. CMF is thought to be still useful after development of new drugs for recurrent breast cancer.

PMID: 20332694 [PubMed - in process]


J Pharmacol Exp Ther. 2009 Aug;330(2):596-601. Epub 2009 Apr 30.Cyclophosphamide Unmasks an Antimetastatic Effect of Local Tumor Cryoablation


  1. Moshe Yair Levy,
  2. Abhinav Sidana,
  3. Wasim H. Chowdhury,
  4. Steven B. Solomon,
  5. Charles G. Drake,
  6. Ronald Rodriguez and
  7. Ephraim J. Fuchs
+ Author Affiliations
  1. Departments of Oncology (M.Y.L., C.G.D., R.R., E.J.F.), Urology (A.S., W.H.C., C.G.D., R.R.), and Radiology (S.B.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland
  1. Address correspondence to:
    Dr. Ephraim J. Fuchs, 488 Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231. E-mail: fuchsep@jhmi.edu

Abstract



Cryoablation of a solitary tumor mass releases intact tumor antigens and can induce protective antitumor immunity but has limited efficacy in the treatment of established metastatic cancer. Cyclophosphamide (Cy), an anticancer drug, selectively depletes regulatory T cells (Tregs) and attenuates suppression of antitumor immunity. We used a BALB/c mouse model of metastatic colon cancer to investigate the systemic antitumor effects of in situ cryotherapy alone or in combination with 200 mg/kg i.p. Cy. When combined with Cy, cryoablation was significantly more effective than either surgical excision or cautery at inducing systemic antitumor immunity, resulting in the cure of a fraction of animals with established metastatic disease and resistance to tumor rechallenge. Lymphocytes from cured animals contained an expanded population of tumor-specific, interferon-γ producing T cells and transferred antitumor immunity to naive recipients. Depletion of CD8+ cells significantly impaired the adoptive transfer of antitumor immunity. Furthermore, treatment with Cy and cryoablation was associated with a significant decrease in the ratio of regulatory to effector CD4+ T cells. The combination of tumor cryoablation and Cy induces potent, systemic antitumor immunity in animals with established metastatic disease.






Cancer Biol Ther. 2010 Jul 26;10(2). [Epub ahead of print]
Potentiation of the anti-tumor effects of imidazoquinoline immune response modifiers by cyclophosphamide.

Dumitru CD, Antonysamy MA, Tomai MA, Lipson KE.
Merck Research Laboratories, Rahway, NJ, USA. calin_dumitru@merck.com. cddumitru@yahoo.com.
Abstract

The aim of the current study was to evaluate the influence of chemotherapeutic drugs on immunotherapy with Imidazoquinoline Toll-like Receptor (TLR) agonists in cancer. First, the previously described antitumor efficacy of TLR agonists (i.e. a TLR7 agonist (852A) and a dual TLR7/8 agonist (3M-011)) was confirmed in additional cancer models, and second the therapeutic potential of TLR agonists in combination with cyclophosphamide was investigated. The Systemic administration of either 3M-011 or 852A in these various syngeneic models induced significant anti-tumor activity as evidenced by delays in tumor growth curves. antitumor potential was evaluated against a panel of syngeneic tumor models; namely B16-F10 melanoma, M3 melanoma and MC-26 colon carcinoma.Combination of cyclophosphamide with either 3M-011 or 852A demonstrated that cyclophosphamide does not negatively interfere with the TLR agonist's antitumor effects, but may, depending on the dosing schedule, to actually potentiate the effect. These findings suggest that the immunomodulatory TLR agonists may be used in combination with cytotoxic agents in the treatment of cancer.

PMID: 20519933 [PubMed - as supplied by publisher]




Gan To Kagaku Ryoho. 2010 Aug;37(8):1561-3.
[Weekly Injection of Paclitaxel Plus Weekly Oral Administration of Cyclophosphamide were Very Effective for a Case of Advanced Accessory Breast Cancer.]

[Article in Japanese]
Yoneyama K, Hata K, Kanamoto A, Tsurita G, Ito A, Shinozaki M, Tahara H.
Dept. of Surgery, Hospital of the Institute of Medical Science, University of Tokyo.
Abstract

Reported is a case of advanced accessory breast cancer to which weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide proved very effective. The patient was a 49-year-old woman who noticed a tumor in the right axilla around October 2007 but then left it alone. In October 2008, the patient visited a nearby physician who made a diagnosis of locally advanced accessory breast cancer. Because the tumor enlarged despite endocrinotherapy, the patient was referred to our hospital in July 2009. CT scan showed a tumor with a size of infant's head, multiple lymph node metastases and metastases to the skin, liver and bones. Following weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide for 4 months, the tumor in the right axilla and metastases to the lymph nodes, skin and liver disappeared. Adverse events were alopecia and grade 1 peripheral neuropathy. The treatment continues at present. Weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide has few adverse reactions and can be performed at an outpatient clinic, suggesting that it is a useful treatment.

PMID: 20716887 [PubMed - in process]
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Old 03-22-2010, 06:55 AM   #3
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Re: Cyclophosphamide

keep it up man very well post. i wish you Good Luck for your better Future>>
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