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Old 02-01-2010, 05:00 PM   #2
Rich66
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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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