(w/Pac, w/Cis, monotherapy, low dose metro, metro w/Zol, w/Abrax, w/Cap, w/Lapat, w/Carbo, w/Vino, w/aspirin, w/supps, immunomodulator, w/Hydralizine to reverse resistance, w/lipo dox for skin mets)
J Oncol. 2012;2012:198412. Epub 2012 Mar 26.
Trastuzumab and Gemcitabine in Pretreated HER2 Overexpressing Metastatic Breast Cancer Patients: Retrospective Analysis of Our Series.
Di Lauro V,
Torrisi E,
Bidoli E,
Quitadamo D,
Cecco S,
Veronesi A.
Free PMC Article
Source
Division of Medical Oncology C, Centro di Riferimento Oncologico, 33081 Aviano, Italy.
Abstract
Trastuzumab-based regimes improved clinical outcome in women with overexpressing HER2 metastatic breast cancer, mainly due to the availability of different combination therapies, clinically active and well tolerated. In this study we retrospectively evaluated clinical activity and toxicity of trastuzuamb plus gemcitabine regimen in heavily pretreated HER2 positive metastatic breast cancer patients.
Although the observed population was heavily pretreated, the evaluated regimen was notably effective in terms of response rate, time to progression and survival, with very mild toxicity. These data suggest that in over expressing HER2 metastatic breast cancer patients, sequential trastuzumab based chemotherapeutic regimens can achieve good response rate with prolonged TTP in responding patients, even after other target therapy such as lapatinib based combinations.
- PMID:
- 22536237
- [PubMed - in process]
- PMCID:
- PMC3321447
Hematol Oncol Stem Cell Ther. 2012;5(1):42-8. doi: 10.5144/1658-3876.2012.42.
A phase 2 study of the combination of gemcitabine and cisplatin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines with/without taxanes.
Kohail H,
Shehata S,
Mansour O,
Gouda Y,
Gaafar R,
Hamid TA,
El Nowieam S,
Al Khodary A,
El Zawahry H,
Wareth AA,
Halim IA,
Taleb FA,
Hamada E,
Barsoum M,
Abdullah M,
Meshref M.
Source
Cancer Centre, Alexandria University, Alexandria.
mmeshref@hotmail.com
Abstract
BACKGROUND AND OBJECTIVES:
Many patients with relapsed metastatic breast cancer are pre-treated with taxanes and anthracyclines, which are usually given in the neoadjuvant/adjuvant setting or as first-line treatment for metastatic disease. The primary objective of this study was to determine the overall response rate for combination treatment with gemcitabine and cisplatin in patients with locally advanced or metastatic breast cancer who had relapsed after receiving one adjuvant/neoadjuvant or first-line metastatic chemotherapy regimen containing an anthracycline with/without a taxane. Secondary endpoints included duration of response, time to progression, one-year survival probability, and toxicity.
DESIGN AND SETTING:
A single-arm, open-label, phase 2 study conducted at 17 investigative sites in Egypt.
PATIENTS AND METHODS:
treatment consisted of gemcitabine (1250 mg/m2) on Days 1 and 8 and cisplatin (70 mg/m2) on Day 1 of each 21-day cycle. Treatment continued until disease progression or a maximum of 6 cycles.
RESULTS:
Of 144 patients all were evaluable for safety and 132 patients were evaluable for efficacy. The overall response rate was 33.3% and 45.5% of the patients with stable disease as their best response. The median time-to-progression was 5.1 months and the one-year survival probability was 73%. The most common grade 3/4 adverse events were nausea/vomiting (20.1%), neutropenia (19.4%), anemia (13.9%), asthenia (11.1%), diarrhea (9.7%), stomatitis (7.6%), leucopenia (7.6%), and thrombocytopenia (6.2%). twelve (8.3%) patients had serious adverse events.
CONCLUSIONS:
The results of this study indicate that gemcitabine and cisplatin were active and generally well tolerated in pretreated patients with locally advanced or metastatic breast cancer.
- PMID:
- 22446614
- [PubMed - in process]
Med Oncol. 2011 Jan 25. [Epub ahead of print]
Safety and efficacy of gemcitabine plus cisplatin combination in pretreated metastatic breast cancer patients.
Brito LG,
de Andrade JM,
Lins-Almeida T,
Zola FE,
Pinheiro MN,
Marana HR,
Tiezzi DG,
Peria FM.
Department of Gynecology and Obstetrics, School of Medicine of Ribeirão Preto, São Paulo University, Avenida Bandeirantes, 3900, 8th Floor, Ribeirão Preto, SP, 14048-900, Brazil,
lgobrito@gmail.com.
LINK
Abstract
Metastatic breast cancers (MBC) previously treated with anthracyclines (A) and taxanes (T) have a complicated management.
Gemcitabine (G)-cisplatin (C) combinations have been used as synergistic salvage therapy in MBC and are considered as another option for patients with important symptoms and aggressive visceral disease. We analyzed the safety and efficacy of GC in AT-pretreated MBC, as well as overall survival (OS) and time to progression (TTP). Forty-nine subjects received IV G 750 mg/m(2) and C 30 mg/m(2), both d1 and d8 every 3 weeks. Response evaluation was performed every second cycle and in the end of treatment. GC protocol was the first-line palliative chemotherapy in half of the cases, and median number of cycles/patient were 4(2-12).
Lung (75.5%) was the most frequent site of metastasis. Most of the patients related clinical improvement with chemotherapy with minimal/mild tolerable collateral effects in 85.7% of cases. Following 34 months, mean OS/TTP was 13.12/6.6 months. Objective-responded patients (40.3%) were statistically associated with the improvement in symptoms after CT (P < 0.01), and OS was directly correlated with chemotherapy response (P < 0.01). HER-2 overexpression was a prognostic factor with reduced OS (P = 0.01). GC protocol was effective and tolerable in objective-responded patients.
PMID: 21264546 [PubMed - as supplied by publisher]
Ann Oncol. 2009 Nov 25. [Epub ahead of print]
Gemcitabine and capecitabine in previously anthracycline-treated metastatic breast cancer: a multicenter phase II study (SOLTI 0301 trial).
Ciruelos EM,
Cortés J,
Cortés-Funes H,
Mayordomo JI,
Bermejo B,
Ojeda B,
Garc*a E,
Rodr*guez CA,
Muñoz M,
Gómez P,
Manso L,
Andrés R,
Lluch A,
Saura C,
Mendiola C,
Baselga J.
Medical Oncology Department, University Hospital 12 de Octubre, Madrid.
BACKGROUND: On the basis of clinical activity of capecitabine and gemcitabine for metastatic breast cancer, we carried out a multicenter phase II clinical trial on the combination of these two agents in advanced anthracycline-pretreated breast cancer patients. Main objectives were to assess its efficacy and safety profile. PATIENTS AND METHODS: Seventy-six anthracycline-pretreated breast cancer patients were evaluated and were stratified according to previous treatment of advanced disease (group-1: not previously treated and group-2: previously treated). Study treatment consisted of gemcitabine 1000 mg/m(2), i.v., as 30 min-infusion, days 1 and 8 every 21 days, plus oral capecitabine 830 mg/m(2) b.i.d., days 1-14 every 21 days. RESULTS: Overall response rate was 61% for group-1, 48.5% for group-2 and 55.2% for the whole population.
Clinical benefit rate was 73% for group-1, 80% for patients in group-2 and 76% for all patients. Median time to progression was 13.0 months for group-1, 8.2 months for group-2 and 11.1 months for the whole population. Most frequent grade 3-4 observed toxic effects per patient were neutropenia (60%), asymptomatic liver toxicity (13.5%), asthenia (14%) and hand-foot syndrome (16%). Only one patient presented febrile neutropenia. No treatment-related deaths occurred. CONCLUSION: Combination of gemcitabine and capecitabine is an active and safe regimen in anthracycline-pretreated breast cancer patients.
PMID: 19940004 [PubMed - as supplied by publisher]
Cancer Chemother Pharmacol. 2012 May;69(5):1345-52. Epub 2012 Feb 17.
A multicenter phase II trial of docetaxel plus gemcitabine as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer.
Karachaliou N,
Kouroussis Ch,
Papakotoulas P,
Kalbakis K,
Tryfonidis K,
Vardakis N,
Poppis E,
Georgoulias V,
Mavroudis D.
LINK
Source
Hellenic Oncology Research Group (HORG), 55 Lomvardou str, 11470, Athens, Greece.
Abstract
OBJECTIVE:
To evaluate the docetaxel-gemcitabine (DG) combination administered every 2 weeks as salvage therapy in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC).
PATIENTS AND TREATMENT:
Thirty women with MBC who had disease progression after chemotherapy with anthracyclines, or anthracyclines and taxanes were treated with docetaxel 50 mg/m² and gemcitabine 1,500 mg/m² on days 1 and 14 in cycles of 28 days. All patients had received prior anthracyclines, and fourteen (46.6%) had also received prior taxanes. All patients were evaluable for toxicity and 24 for response to treatment.
RESULTS:
Complete response occurred in four (13.3%) patients and partial response in 10 (33.3%) for an overall response rate of 46.7% (95% CI 28.8-64.5). Seven patients (23.3%) had stable disease and nine (30%) progressive disease.
Of the 14 patients previously treated with both anthracyclines and taxanes, seven (50%) responded. The median duration of response was 4.8 months (range 1.9-15.3), the median time to disease progression 6.6 months (range 0.5-16.9) and the median overall survival 16.8 months (range 1.3-53.2).
There was no treatment-related toxic death. Neutropenia was the only grade 4 toxicity occurring in three (10%) patients. None of them developed neutropenic fever. Grade 3 thrombocytopenia occurred in two (6.7%) patients. Non-hematological toxicities were manageable.
CONCLUSION:
The
DG combination administered biweekly is very well tolerated and effective in anthracycline- and taxane-pretreated patients with MBC. A previous treatment with taxanes does not preclude a good clinical response to this regimen.
- PMID:
- 22349809
- [PubMed - in process]
Acta Pharmacol Sin. 2009 Dec 7. [Epub ahead of print]
Aspirin inhibits proliferation of gemcitabine-resistant human pancreatic cancer cells and augments gemcitabine-induced cytotoxicity.
Ou YQ,
Zhu WB,
Li Y,
Qiu PX,
Huang YJ,
Xie J,
He SM,
Zheng XK,
Leng TD,
Xu D,
Yan GM.
Department of Pharmacology, Zhong-shan Medical College, Sun Yat-Sen University, Guangzhou 510089, China.
AbstractAim:To investigate whether aspirin is able to augment gemcitabine-induced cytotoxicity in human pancreatic cancer cells.Methods:Two gemcitabine-insensitive human pancreatic cancer cell lines, PANC-1 and Capan-1, were used. Cells were treated with either aspirin or gemcitabine alone or both of them. Cell growth and apoptosis were determined by MTT assay, Annexin V or Hoechest 33258 staining. Cell cycle distribution was examined by flow cytometry. Western blot with specific phosphorylated protein antibodies was used to detect the activation of protein kinase. RT-PCR and Western blot were applied to assess the transcription and protein level for cyclin D1 and Bcl-2.Results:Aspirin alone significantly inhibits the proliferation of PANC-1 cells by causing cell cycle arrest at G(1) phase. Aspirin potentiates the anti-survival effect of gemcitabine as well as its pro-apoptotic effect in PANC-1 cells, although aspirin per se does not trigger apoptosis. Aspirin inhibits GSK-3beta activation and suppresses the expression of its downstream gene products (cyclin D1 and Bcl-2), which are implicated in proliferation, survival and chemoresistance of pancreatic cancer. The effects of aspirin on Capan-1, were similar to that on PANC-1.Conclusion: Our results suggest that aspirin inhibits the proliferation of gemcitabine-resistant pancreatic cancer cells and augments the antisurvival effect of gemcitabine, probably by suppressing the activity of GSK-3beta and its downstream gene products.
PMID: 19966835 [PubMed - as supplied by publisher]
Treatment for Pancreatic Cancer May Target Tumor Microenvironment
Researchers have found some clues to suggest why
combining nab-paclitaxel (Abraxane) with gemcitabine may be a more effective treatment for advanced pancreatic cancer than gemcitabine alone, the current standard of care.
This spring, updated results from an early stage clinical trial testing the combination therapy
showed a promising response, particularly in patients whose tumors produced an abundance of the protein known as SPARC. Results from a mouse model study presented today at the AACR-NCI-EORTC
Molecular Targets and Cancer Therapeutics conference in Boston indicate that
adding nab-paclitaxel to gemcitabine may improve response to treatment in part by altering the supportive tissue around the tumor, or stroma, allowing more gemcitabine to reach tumor cells.
The finding “shows that
effective treatment does not necessarily require a fancy new molecular therapy, but just the smart combination of what is already available,” said the study’s lead investigator, Dr. Anirban Maitra from the Johns Hopkins University School of Medicine. Gemcitabine is the standard first-line treatment for pancreatic cancer, and nab-paclitaxel, a different form of paclitaxel (Taxol) that is bound to the protein albumin to improve its delivery, is approved for metastatic breast cancer.
To conduct the study, the research team tested the combination in pancreatic cancer mouse models generated at Johns Hopkins.
Mice that received the combination were twice as likely to respond to the treatment as those that received gemcitabine alone, with an overall response rate (at least some tumor shrinkage) of 57 percent. They also found that mice given the combination therapy had
significantly less of the “abundant fibrotic stroma” that typically surrounds pancreatic tumors and which was always seen in mice given only gemcitabine or no treatment at all. The
concentration of gemcitabine in tumors from mice that received the combination therapy was 3.7-fold higher than in the animals given only gemcitabine.
Nab-paclitaxel was recently granted orphan drug status by the FDA (making it eligible for expedited FDA review and extended patent protection, among other things) for use in patients with pancreatic cancer and advanced melanoma. Enrollment is
currently open for a phase III trial for pancreatic cancer that will compare gemcitabine plus nab-paclitaxel against gemcitabine alone.
Clin Transl Oncol. 2007 Jul;9(7):459-64.
Low dose gemcitabine plus cisplatin in a weekly-based regimen as salvage therapy for relapsed breast cancer after taxane-anthracycline-containing regimens.
Sánchez-Escribano Morcuende R, Alés-Mart*nez JE, Aramburo González PM.
Unidad de Oncolog*a Médica, Hospital Ruber Internacional, Madrid, Spain.
PURPOSE: Cisplatin-gemcitabine is a synergistic chemotherapy (CT) combination highly proven in a broad spectrum of epithelial neoplasms and shows a non-cross-resistance profile with the most active drugs in metastatic breast cancer (MBC). We have conducted an exploratory study to determine if treatment with low doses of a combination of fixed-rate gemcitabine infusion and cisplatin was clinically meaningful in women relapsing after a minimum of 2 prior lines of CT for advanced disease (range 2-6), which had to have necessarily included both anthracyclines and taxanes. Another goal was to find the optimal individual schedule by adjusting frequency and dosage according to patient tolerability. PATIENTS AND METHODS: From May 2002 to November 2003, 22 patients with relapsed advanced BC and a minimum of two prior CT lines were offered treatment with gemcitabine (G) (initial dose 750 mg/m(2), or 600 mg/m(2) if the patient had received more than two previous CT lines) plus cisplatin (P) (initial dose 30 mg/m(2), or 20 mg/m(2) in case of > or =3 prior CT lines) on days 1 and 8 of a 21-day cycle. Treatment was postponed to day 15 if it could not be given on day 8, without dose reduction. If treatment could not be given on day 15, a 20% dose reduction was allowed and treatment given the next week. Further dose reductions were allowed as needed up to a maximum of three. Treatment continued until disease progression or intolerable toxicity. Median age was 54.5 years (35-75). Median Karnofsky was 90 (range 80-90). Median number of prior CT lines was 3 (2-6). 90.9% of patients had received adjuvant CT. All had prior anthracyclines and taxanes. Other agents used included 5-FU/eniluracil, MTA, RPR 109881A, trastuzumab, cisplatin, VP16, vinorelbine, capecitabine and irinotecan. 72.7% had received radiotherapy and 68.1% hormonal therapy (median 2 lines, range 1-4). RESULTS: Partial responses (PR) were seen in 9.1% of patients and stable disease (SD) in 36.4%. Clinical Benefit Rate (PR+SD) was derived in 45.5% of patients. Median time to progression was 4 months (95% CI, 3-5) in general and 6 months (95% CI, 4-8) in patients with clinical benefit. Median survival for the entire group was 8 months (95% CI, 5-11) and 19 months when clinical benefit was obtained (95% CI, 11-25). Patients received a median of 8.5 CT administrations (range, 2-45). Forty-three percent of doses were delayed. Sixteen out of 22 patients needed a delay and/or reduction of initial dose. Cisplatin and gemcitabine doses were reduced in 75% and 62% of all cycles, respectively. Sixteen out of 22 patients needed a delay and/or reduction of initial dose. Toxicities grade >3 were neutropenia 35% and thrombocytopenia 15%. All other toxicities were grade 2 or less, including sensorial neuropathy (30%), asthenia (34%), nausea/vomiting (20%) and oral mucositis (15%). There were no treatment-related deaths. Reasons for discontinuation were progression (18 patients), death (3 patients) and patient decision (1 patient). CONCLUSION: Weekly cisplatin-gemcitabine with flexible downwards individual tailoring is a safe and effective salvage treatment in heavily pretreated MBC patients with good PS.
PMID: 17652060 [PubMed - indexed for MEDLINE]
Int J Clin Oncol. 2012 Feb 17. [Epub ahead of print]
Gemcitabine and carboplatin for pretreated metastatic breast cancer: the predictive value of immunohistochemically defined subtypes.
Nelli F, Moscetti L, Natoli G, Massari A, D'Auria G, Chilelli M, Fabbri MA, Frittelli P, Ruggeri EM.
LINK
Source
Department of Medical Oncology, Central Hospital of Belcolle, Strada Sammartinese snc, 01100, Viterbo, Italy, f.nelli@asl.vt.it.
Abstract
BACKGROUND:
We evaluated the efficacy of gemcitabine and carboplatin for patients affected by pretreated metastatic breast cancer. A subgroup analysis was performed to evaluate the predictive value of immunohistochemically defined breast cancer subtypes.
METHODS:
We included human epidermal growth factor 2 (HER-2) negative metastatic breast cancer resistant to previous anthracycline-based and taxane-based chemotherapy, and HER-2 positive metastatic breast cancer with at least two progressions of disease during protracted trastuzumab-based therapy. Treatment consisted of gemcitabine (1000 mg/m(2) intravenous (iv) on days 1 and 8) and carboplatin (area under the curve 5 iv on day 1) applied every 3 weeks.
RESULTS:
Forty-two patients were registered. Disease control was 58%, with a median time-to-progression (TTP) of 7 months (range 1-12) and a median overall survival of 10.5 months (range 1-34). Patients were grouped as triple negative (ER and PR negative, HER-2 negative), HER-2 (HER-2 positive, ER and PR negative), luminal B (ER and/or PR positive and either HER-2 positive and/or high Ki67), and luminal A (ER and/or PR positive and HER-2 negative and low Ki67). For luminal A patients, disease control was lower (luminal A 34 vs. others 67%; P = 0.02), TTP was shorter (luminal A 2.4 months vs. others 6.3 months, P = 0.015), and overall survival was shorter (luminal A 7.5 months vs. others 11.7 months, P = 0.034) than for other subtypes.
CONCLUSIONS:
Gemcitabine and carboplatin are effective for pretreated patients with metastatic breast cancer. Luminal A subtype seems to fare poorly compared with other subtypes. Specific difference in gene expression might account for the different outcome.
- PMID:
- 22350024
- [PubMed - as supplied by publisher]
Cancer Chemother Pharmacol. 2012 May;69(5):1315-22. Epub 2012 Feb 4.
Gemcitabine in combination with vinorelbine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer.
Dong N, Wang M, Li H, Cui Y, Guo Q.
LINK
Source
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Medical Oncology Department, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52 Fucheng Rd, Beijing, 100142, China, dongnn83@163.com.
Abstract
PURPOSE:
To evaluate the efficacy and safety of gemcitabine in combination with vinorelbine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC).
PATIENTS AND METHODS:
Elderly patients with MBC received gemcitabine 1,000 mg m(-2) and vinorelbine 25 mg m(-2) on days 1 and 8 every 3 weeks for a maximum of 6 cycles. The primary end points were objective response and toxicity. The secondary end points included progression-free survival (PFS), overall survival (OS), and prognostic factors associated with disease control, PFS, and OS.
RESULTS:
Fifty-one patients with a median age of 73 years (range, 65-84 years) were included. The response rate according to Response Evaluation Criteria in Solid Tumors was 33.3% (95% confidence interval [CI], 20.4 to 46.2%). At a median follow-up of 16.2 months, median PFS and OS were 6.2 (95% CI, 4.6 to 7.8) and 17.0 months (95% CI, 14.5 to 19.5), respectively. Grade 3 to 4 adverse events included neutropenia (25.5%), anemia (13.7%), thrombocytopenia (9.8%), fatigue (5.9%), constipation (3.9%), neuropathy (3.9%), and hepatotoxicity (3.9%). Neutropenic fever occurred in 2 patients. There was one toxic death due to massive gastrointestinal hemorrhage. The study of prognostic factors did not reveal any predictive factor of disease control, while response to treatment and Eastern Cooperative Oncology Group performance status was the main factor conditioning PFS and OS, respectively.
CONCLUSION:
Gemcitabine in combination with vinorelbine is active and safe in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer.
- PMID:
- 22307763
- [PubMed - in process]
Excellent Response to Gemcitabine in a Massively Pre-Treated Woman with Extensive Cutaneous Involvement after Recurrence of Breast Cancer
|
|
|
PDF (131.0 KB)Free Preview
Excellent Response to Gemcitabine in a Massively Pre-Treated Woman with Extensive Cutaneous Involvement after Recurrence of Breast Cancer
J. Arends
1 and C. Unger
1
| (1) | Department of Medical Oncology, Tumor Biology Center, Albert-Ludwigs-Universität, Freiburg, Germany |
Abstract A 50-year-old woman presented with local relapse ofbreast cancer 6 years after partial mastectomy. Relapse was accompanied by extended skin induration due to tumor cell embolization of dermal lymphatics. During the following yearsthe patient was exposed to 11 different anti-tumor regimensincluding 13 cytotoxic drugs (including alkylating agents,antitumor antibiotics, vinca alcaloids, epipodophyllo toxins,and taxanes), 4 anti-hormonal, and 2 immunologic attempts. Paclitaxel achieved a prolonged local improvement for some 7months, but further various treatments were ineffective. At that time
gemcitabine therapy was initiated and tumor infiltration of the skin was visibly diminished only 2 weekslater. After that tumor regressed further for 5 months and remained stable with continued doses of gemcitabine during much of the woman's last year. The patient died of acutemyeloid leukemia (AML) 4 years after the local recurrence ofbreast cancer.
Since multiple treatments using a plethora of aggressive cytotoxic drugs may render several classes of chemotherapy agents ineffective due to cross-resistance, it seems advisable to select mild agents that are not subject to multidrug resistance mechanisms and display a unique mode of action as demonstrated in this case by gemcitabine.
Curr Oncol. 2010 Apr;17(2):64-8.
One year of complete clinical response in a metastatic breast cancer patient treated with a combination of lapatinib and gemcitabine.
Gasent Blesa JM,
Laforga Canales J,
Candel VA.
Abstract
The treatment of metastatic breast cancer is challenging. We recently assisted in the development of targeted therapies (in combination with chemotherapy or as monotherapy) that have improved results for selected groups of patients.
Lapatinib is a dual tyrosine kinase inhibitor that has shown efficacy in breast cancer. Consequently, its use has been approved, in combination with capecitabine, for the treatment of disease positive for the human epidermal growth factor receptor. Here, we present a case of complete clinical response to a combination of lapatinib and gemcitabine that was maintained for 1 year.
PMID: 20404981 [PubMed - in process]
Mol Cancer Ther. 2008 Mar;7(3):638-47.
Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model.
Laquente B,
Lacasa C,
Ginest* MM,
Casanovas O,
Figueras A,
Galán M,
Ribas IG,
Germ* JR,
Capell* G,
Viñals F.
Laboratori de Recerca Translacional, Institut Catal* d'Oncologia-IDIBELL, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Spain.
Gemcitabine shows a marked antitumor effect as a result of its cytotoxic action toward proliferative cells. In this article, we aim to investigate the potential antitumor and antiangiogenic effect of gemcitabine following a metronomic schedule that involves the regular administration of cytotoxic drugs at doses lower than standard treatment. In vitro results showed that human endothelial cells are more sensitive to gemcitabine (IC(50) 3 nmol/L) than pancreatic tumor cells (IC(50) 20 nmol/L). For in vivo studies, we used an orthotopic implantation model of human pancreatic carcinoma in nude mice.
Gemcitabine was administered i.p. following a low-dose schedule (1 mg/kg/d for a month) and compared with the conventional schedule (100 mg/kg days 0, 3, 6, and 9 postimplantation). Metronomic treatment effect on established tumor was equivalent to standard administration. The measure of CD31 endothelial marked area allowed us to show an in vivo antiangiogenic effect of this drug that was further enhanced by using metronomic administration. This effect correlated with an induction of thrombospondin-1, a natural inhibitor of angiogenesis. Our results allow us to hypothesize that, in addition to a direct antiproliferative or cytotoxic antiendothelial cell effect, a secondary effect involving thrombospondin-1 induction might provide an explanation for the specificity of the effects of metronomic gemcitabine treatment.
PMID: 18347150 [PubMed - indexed for MEDLINE]
Cancer Sci. 2011 Sep 28. doi: 10.1111/j.1349-7006.2011.02113.x. [Epub ahead of print]
Significance of combination therapy of zoledronic acid and gemcitabine on pancreatic cancer.
Zhao M,
Tominaga Y,
Ohuchida K,
Mizumoto K,
Cui L,
Kozono S,
Fujita H,
Maeyama R,
Toma H,
Tanaka M.
LINK
Source
Department of Surgery and Oncology Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Kyushu University Hospital Cancer Center, Fukuoka, Japan.
Abstract
In this study, we examined the cytotoxic effects of combination therapy with zoledronic acid (ZOL) and gemcitabine (GEM) on pancreatic cancer cells in vitro and in vivo. Four human pancreatic cancer cell lines were treated with ZOL, GEM or a combination of both, and the effects of the respective drug regimens on cell proliferation, invasion and matrix metalloproteinase (MMP) expression were examined. A pancreatic cancer cell line was also intrasplenically or orthotopically implanted into athymic mice and the effects of these drugs on tumor metastasis and growth in vivo were evaluated by histologic and immunohistochemical analyses.
Combination treatment with low doses of ZOL and GEM efficiently inhibited the proliferation (P < 0.001) and invasion (P < 0.001) of pancreatic cancer cells in vitro. Western blotting assay revealed that MMP-2 and MMP-9 expression levels were decreased after ZOL treatment. In vivo, combined treatment significantly inhibited tumor growth (P < 0.05) and the development of liver metastasis (P < 0.05). These data revealed that, when used in combination, ZOL and GEM have significant antitumor, anti-metastatic and anti-angiogenic effects on pancreatic cancer cells. In the present study, we first reported the significance of the combination treatment of ZOL and GEM in pancreatic cancer using an in vivo model. These data show promise for the future application of this drug regimen in patients with pancreatic cancer.
© 2011 Japanese Cancer Association.
Ann Oncol. 2009 Mar;20(3):449-53. Epub 2008 Dec 15.
Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531).
Roy V,
LaPlant BR,
Gross GG,
Bane CL,
Palmieri FM;
North Central Cancer Treatment Group.
Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL 32224, USA.
roy.vivek@mayo.edu
Nanoparticle albumin-bound (nab)-paclitaxel has better efficacy and practically eliminates the risk of hypersensitivity reactions associated with solvent-based paclitaxel. We studied weekly nab-paclitaxel and gemcitabine combination in an open-label one-stage, phase II trial in patients with previously untreated metastatic breast cancer (MBC). Nab-paclitaxel (125 mg/m(2)) and gemcitabine (1000 mg/m(2)) were administered on days 1 and 8 of a 21-day cycle until disease progression. Fifty patients were enrolled.
Forty (80%) had visceral organ involvement and 30 (60%) had >or= 3 sites of metastases. Four (8%) and 21 (42%) patients had complete and partial responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Median duration of response was 6.9 months [95% confidence interval (CI) 5.7, not reached], median progression-free survival (PFS) 7.9 months (95% CI 5.4-10 months), and median overall survival (OS) was not reached. PFS and OS at 6 months were 60% (95% CI 48% to 76%) and 92% (95% CI 85% to 100%), respectively. Therapy was well tolerated. Neutropenia was commonest toxicity (42% and 12% grades 3 and 4 neutropenia). Only one patient developed febrile neutropenia.
Significant activity and favorable toxicity profile provides a basis for considering this regimen for further evaluation in phase III trials or in combination with biologic agents.
PMID: 19087987 [PubMed - indexed for MEDLINE]
Int J Cancer. 2009 Nov 11. [Epub ahead of print]
Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer.
Harikumar KB,
Kunnumakkara AB,
Sethi G,
Diagaradjane P,
Anand P,
Pandey MK,
Gelovani J,
Krishnan S,
Guha S,
Aggarwal BB.
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
Gemcitabine, while a standard treatment of advanced pancreatic cancer (PaCa), alone is not very effective. New agents that are safe and effective are highly needed. Resveratrol is one such agent which is safe and multitargeted; and has been linked with suppression of survival, proliferation, invasion and angiogenesis of cancer. Whether resveratrol can sensitize PaCa to gemcitabine in vitro and in vivo was investigated. We established PaCa xenografts in nude mice, randomized into 4 groups, and treated with vehicle, gemcitabine, resveratrol and with combination. Modulation of NF-kappaB and markers of proliferation, angiogenesis and invasion were ascertained using electrophoretic mobility shift assay (EMSA), immunohistochemistry and western blot analysis.
Resveratrol inhibited the proliferation of 4 different human PaCa cell lines, synergized the apoptotic effects of gemcitabine, inhibited the constitutive activation of NF-kappaB and expression of bcl-2, bcl-xL, COX-2, cyclin D1 MMP-9 and VEGF. In an orthotopic model of human PaCa, we found that resveratrol significantly suppressed the growth of the tumor (p < 0.001) and this effect was further enhanced by gemcitabine (p < 0.001). Both the markers of proliferation index Ki-67 and the micro vessel density CD31 were significantly downregulated in tumor tissue by the combination of gemcitabine and resveratrol (p < 0.001 vs. control; p < 0.01 vs. gemcitabine). As compared to vehicle control, resveratrol also suppressed the NF-kappaB activation and expression of cyclin D1, COX-2, ICAM-1, MMP-9 and survivin. Overall
our results demonstrate that resveratrol can potentiate the effects of gemcitabine through suppression of markers of proliferation, invasion, angiogenesis and metastasis.
PMID: 19908231 [PubMed - as supplied by publisher]
In the last year or so papers have appeared informing us of
natural agents that potentially increase the effect of Gemcitabine against pancreatic cancer and which we should consider using in these patients. They include:
a. Thymoquione extracts of black cumin seed, Nigella sativa
b. Curcumin, an extract of the spice turmeric, Curcuma longa
c. Genestein, an extract of the soybean plant, Glycine max.
d. Resveratrol, and extract of grape skins, Vitis vinifera
e. Epigallocatechin gallate, the extract from green tea, Camellia sinensis
f. Gamma linolenic acid (GLA) from evening primrose oil and other seeds
g. Diindolymethane (DIM) and Sulforaphane from cruciferous vegetables of the Brassicaceae family
h. Apogossypolone an analogue of gossypol, an extract of the cotton plant, Gossypium malvaceae
Nigella sativa:
In vitro studies revealed that preexposure of cells with thymoquinone (25 mumol/L) for 48 h followed by gemcitabine or oxaliplatin resulted in 60% to 80% growth inhibition compared with 15% to 25% when gemcitabine or oxaliplatin was used alone. [6] Black cumin seeds have a very long history of medical use in the Muslim world. The Koran reports that the Prophet Mohammed extolled the virtues of these seeds.
[more info on Nigella:
http://denvernaturopathic.com/Nigella.htm ]
Genestein:
Recent publications have reminded us of the potential of soy bean rich diets. A Last March a study published in Cancer Research told us that this compound almost completely prevented the spread of human prostate cancer in mice. The study used amounts of genistein that were no higher than what a human would eat in a soybean-rich diet.
Investigators from Northwestern University found that genistein decreased metastasis of prostate cancer to the lungs by 96 percent compared with mice that did not eat the compound in their chow - making the study the first to demonstrate genistein can stop prostate cancer metastasis in a living organism.
A 2005 suggests that combining genistein with Gemcitabine might increase benefit in treating pancreatic cancer. The researchers reported that, “…studies were done to measure growth inhibition and degree of apoptotic cell death induced by either genistein alone, gemcitabine alone, or genistein followed by gemcitabine. Our results show that pretreatment of cells with genistein for 24 hours followed by gemcitabine resulted in 60% to 80% growth inhibition compared with 25% to 30% when gemcitabine was used alone.” [7]
Curcumin:
The concentrated extract of turmeric root is well enough known for its anticancer effect that there is no need to elaborate on it here. A 2007 study from MD Anderson tells us that we must include curcumin on our list of agents that might potentiate the effect of Gemcitabine. The title alone should suffice: “Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products.” [8]
Resveratrol:
One has to hand it to those MD Anderson researchers. They are good at summing up an entire study in the title. The International Journal of Cancer published another paper from this same group from MD Anderson last month, November 2009. It is titled, “Resveratrol, a multi-targeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer.” Though that says it all, let’s add one more line from the abstract: “Resveratrol inhibited the proliferation of four different human PaCa cell lines, synergized the apoptotic effects of gemcitabine, inhibited the constitutive activation of NF-kappaB and expressions of bcl-2, bcl-xL, COX-2, cyclin D1, MMP-9 and VEGF.” [9] When translated, this means you should probably give resveratrol to patients with pancreatic cancer.
Green tea
Researchers from Texas A&M in a May 2009 publication, wrote that, “Epigallocatechin-gallate (EGCG)…. sensitized cells to apoptosis induced by gemcitabine (GEM), mitomycin C or 5-fluorouracil…” [10] This work did not involve pancreatic cancer; they were testing green tea’s effect on cholangiocarcinoma, a cancer of the bile ducts. Though probably reasonable to assume the same effect will be seen in pancreatic cancer, it does not appear to have been reported at the time of this review.
Gamma-linolenic acid:
This is the omega-6 fatty acid found in a number of vegetable sources, most notably Evening primrose oil, borage seed oil and hemp seed oil. It is also found in spirulina. Borage seed oil has the highest concentration of GLA. A 2003 report in Pancreatology tells us that, “GLA has a synergistic effect with gemcitabine at concentrations that correspond to in vivo therapeutic doses.” [11]
Cruciferous vegetables:
Diindolymethane (DIM) is a chemical readily available from cruciferous vegetables. A May 2009 paper tells us, “DIM pretreatment of pancreatic cancer cells led to a significantly increased apoptosis (P < 0.01) with suboptimal concentrations of chemotherapeutic agents (cisplatin, gemcitabine and oxaliplatin) compared with monotherapy.” [12] A June 2008 paper tells us that DIM also enhances the effect of Tarceva, another drug used to treat pancreatic cancer. [13]
A July 2009 paper suggests that sulforaphane, another chemical isolated from cruciferous vegetables, especially broccoli, may also be useful. This study looked at, “highly treatment-resistant tumour-initiating cells (TICs) [that] play a central role in the pathogenesis of pancreatic cancer.”
“Sulforaphane prevented NF-kappaB binding, downregulated apoptosis inhibitors and induced apoptosis,” in these TICs more effectively than Gemcitabine or other cancer preventing agents. “…sulforaphane strongly blocked tumour growth and angiogenesis, while combination with TRAIL had an additive effect without obvious cytotoxicity in normal cells…” [14] It would appear both of these phytonutrients from broccoli have arguments that support their use.
Gossypol:
Gossypol is isolated from cotton seeds and is the only one of these suggested supplements that we may have any hesitation to use. Gossypol has pro-apoptotic properties, probably due to the regulation of the Bax and Bcl2. [15] A July 2009 paper suggests gossypol might be useful in treating B-cell lymphomas. [16] A November 2009 study suggests using gossypol in combination with Xeloda in treating drug resistant prostate cancer. [17]
The study of interest though for our discussion is an October 2009 paper that says it may potentiate the effect of Gemcitabine against pancreatic cancer. The researchers reported that when their synthetic analog of gossypol, “…was combined with gemcitabine, increased cytotoxicity and apoptosis was evident.” [18]
Though this is promising, there is reason to be hesitant. This analog used by the researchers is not readily available. Gossypol itself has the potential to cause adverse effects. Chronic ingestion can lead to fertility disorders in men leading to interest in using it as a male contraceptive agent. [19] One might question whether potential infertility is a significant contraindication for someone with pancreatic cancer? Still, we have not routinely used gossypol with our patients at this time.
Pancreatic cancer is lousy. The common treatments, usually Gemcitabine either alone or more frequently in combination with other drugs, provides only limited benefit. Researchers are looking to combine other chemotherapy drugs with Gemcitabine in the hope of getting some increase in benefit. To date these increases have been minimal. There is published data on a growing number of natural substances that may increase benefit. Most are already in widespread use with cancer patients and show little potential for side effects or adverse reactions. Given the desperate nature of this disease, it seems reasonable to consider using them in conjunction with chemotherapy to enhance the benefits of drug treatment.
References:
[1] Burris HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403-2413, 1997.
[2] Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the national cancer institute of Canada clinical trials group. J Clin Oncol 25:1960-1966, 2007.
[3] Cunningham, D, Chau I, Stocken D, et al: Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer (abstract PS11). Eur J Cancer 3:4, 2005.
[4] Herrmann R, Bodoky G, Ruhstaller T, et al: Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: A randomized, multicenter, phase III trial of the Swiss group for clinical cancer research and the central European cooperative oncology group. J Clin Oncol 25:2212-2217, 2007.
[5] CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC).
2008 ASCO Annual Meeting Abstract No: LBA4504
[6] Banerjee S, Kaseb AO, Wang Z, Kong D, Mohammad M, Padhye S, et al. Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res. 2009 Jul 1;69(13):5575-83. Epub 2009 Jun 23.
[7] Banerjee S, Zhang Y, Ali S, Bhuiyan M, Wang Z, Chiao PJ, et al. Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res. 2005 Oct 1;65(19):9064-72.
[8] Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007 Apr 15;67(8):3853-61.
[9] Harikumar KB, Kunnumakkara AB, Sethi G, Diagaradjane P, Anand P, Pandey MK, et al. Resveratrol, a multi-targeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer. Int J Cancer. 2009 Nov 11. [Epub ahead of print]
[10] Lang M, Henson R, Braconi C, Patel T. Epigallocatechin-gallate modulates chemotherapy-induced apoptosis in human cholangiocarcinoma cells. Liver Int. 2009 May;29(5):670-7. Epub 2009 Feb 17.
[11] Whitehouse PA, Cooper AJ, Johnson CD. Synergistic activity of gamma-linolenic acid and cytotoxic drugs against pancreatic adenocarcinoma cell lines. Pancreatology. 2003;3(5):367-73; discussion 373-4.
[12] Banerjee S, Wang Z, Kong D, Sarkar FH. 3,3'-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer. Cancer Res. 2009 Jul 1;69(13):5592-600. Epub 2009 Jun 16.
[13] Ali S, Banerjee S, Ahmad A, El-Rayes BF, Philip PA, Sarkar FH. Apoptosis-inducing effect of erlotinib is potentiated by 3,3'-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer. Mol Cancer Ther. 2008 Jun;7(6):1708-19.
[14] Kallifatidis G, Rausch V, Baumann B, Apel A, Beckermann BM, Groth A, et al. Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Gut. 2009 Jul;58(7):949-63. Epub 2008 Oct 1.
[15] Wei J, Kitada S, Rega MF, Emdadi A, Yuan H, Cellitti J, et al. Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins. Mol Cancer Ther. 2009 Apr;8(4):904-13.
[15] Wei J, Kitada S, Rega MF, Stebbins JL, Zhai D, Cellitti J, Yuan H, Emdadi A, Dahl R, Zhang Z, Yang L, Reed JC, Pellecchia M. Apogossypol derivatives as pan-active inhibitors of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. J Med Chem. 2009 Jul 23;52(14):4511-23.
[16] Sanli UA, Gorumlu G, Erten C, Gul MK, Cengiz E, Kucukzeybek Y, Karaca B, Atmaca H, Uzunoglu S, Karabulut B, Uslu R. Targeting apoptosis in the hormone- and drug-resistant prostate cancer cell line, DU-145, by gossypol/zoledronic acid combination. Cell Biol Int. 2009 Nov;33(11):1165-72. Epub 2009 Aug 28.
[17] Banerjee S, Choi M, Aboukameel A, Wang Z, Mohammad M, Chen J, Yang D, Sarkar FH, Mohammad RM. Preclinical Studies of Apogossypolone, a Novel Pan Inhibitor of Bcl-2 and Mcl-1, Synergistically Potentiates Cytotoxic Effect of Gemcitabine in Pancreatic Cancer Cells. Pancreas. 2009 Oct 8. [Epub ahead of print]
[18] ] Cao J, Fei R, Zhao Y, Chen H, Jin W, Chen S. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. [Effect of low dose gossypol treatment on male sperm nuclear basic protein][Article in Chinese] 2000 Jun;22(3):220-2.
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]
Expert Opin Drug Saf. 2008 Nov;7(6):703-16.
Gemcitabine: vascular toxicity and prothrombotic potential.
LINK
Dasanu CA.
Source
Practicing Hematologist and Medical Oncologist, University Place, 2202 70th Ave W, Suite # 5, WA 98466, USA.
c_dasanu@yahoo.com
Abstract
BACKGROUND:
Gemcitabine has been associated with important thrombotic and vascular side effects. As indications for its use in oncology and hematology are expanding, comprehensive characterization of these complications becomes imperative.
OBJECTIVE:
This article reviews the prothrombotic potential and other vascular effects of gemcitabine and experience accrued through its use in research laboratories, clinical trials and clinical practice.
METHODS:
The most relevant publications were identified through the PubMed database and by reviewing the drug information released by the FDA.
RESULTS/CONCLUSIONS:
In the author's opinion, the incidence of thrombotic and vascular toxicity with gemcitabine is higher than previously estimated.
Venous thromboembolism (VTE) and acute arterial events, digital ischemia and necrosis, vasculitis and thrombotic microangiopathy, potentially fatal systemic capillary leak and reversible posterior leukoencephalopathy syndromes are only a few items on the long list of vascular-toxic effects of gemcitabine. These toxicities seem to be more frequent with the use of gemcitabine-platinum doublets than with gemcitabine alone. Careful consideration of gemcitabine use should be given in the setting of pre-existing arterial vascular disease, venous thromboembolism, collagenoses, heart failure, liver damage and advanced hepatic metastases. Specific treatment requirements of individual patients, their comorbidities and the gemcitabine risk:benefit ratio should be always sought before using this agent in antineoplastic therapy.
- PMID:
- 18983217
- [PubMed - indexed for MEDLINE]
PLoS One. 2012;7(3):e29181. Epub 2012 Mar 12.
DNA methylation-independent reversion of gemcitabine resistance by hydralazine in cervical cancer cells.
Candelaria M,
de la Cruz-Hernandez E,
Taja-Chayeb L,
Perez-Cardenas E,
Trejo-Becerril C,
Gonzalez-Fierro A,
Chavez-Blanco A,
Soto-Reyes E,
Dominguez G,
Trujillo JE,
Diaz-Chavez J,
Duenas-Gonzalez A.
Free PMC Article
Source
Division of Clinical Research, Instituto Nacional de Cancerologia, Mexico City, Mexico.
Abstract
BACKGROUND:
Down regulation of genes coding for nucleoside transporters and drug metabolism responsible for uptake and metabolic activation of the nucleoside gemcitabine is related with acquired tumor resistance against this agent.
Hydralazine has been shown to reverse doxorubicin resistance in a model of breast cancer. Here we wanted to investigate whether epigenetic mechanisms are responsible for acquiring resistance to gemcitabine and if hydralazine could restore gemcitabine sensitivity in cervical cancer cells.
METHODOLOGY/PRINCIPAL FINDINGS:
The cervical cancer cell line CaLo cell line was cultured in the presence of increasing concentrations of gemcitabine. Down-regulation of hENT1 & dCK genes was observed in the resistant cells (CaLoGR) which was not associated with promoter methylation. Treatment with hydralazine reversed gemcitabine resistance and led to hENT1 and dCK gene reactivation in a DNA promoter methylation-independent manner. No changes in HDAC total activity nor in H3 and H4 acetylation at these promoters were observed. ChIP analysis showed H3K9m2 at hENT1 and dCK gene promoters which correlated with hyper-expression of G9A histone methyltransferase at RNA and protein level in the resistant cells. Hydralazine inhibited G9A methyltransferase activity in vitro and depletion of the G9A gene by iRNA restored gemcitabine sensitivity.
CONCLUSIONS/SIGNIFICANCE:
Our results demonstrate that
acquired gemcitabine resistance is associated with DNA promoter methylation-independent hENT1 and dCK gene down-regulation and hyper-expression of G9A methyltransferase. Hydralazine reverts gemcitabine resistance in cervical cancer cells via inhibition of G9A histone methyltransferase.
- PMID:
- 22427797
- [PubMed - in process]
- PMCID:
- PMC3299634
Cancer Biol Ther. 2012 May 1;13(7). [Epub ahead of print]
Activity of pegylated liposomal doxorubicin in combination with gemcitabine in triple negative breast cancer with skin involvement: Two case reports.
Franchina T,
Adamo B,
Ricciardi GP,
Caristi N,
Agostino RM,
Proto C,
Adamo V.
LINK
Source
Unit of Integrated Therapies in Oncology; Department of Human Pathology; University Policlinic; G Martino, Italy.
Abstract
Breast carcinoma (BC) is a heterogeneous disease in terms of histology, therapeutic response, dissemination patterns to distant sites and patient outcomes. Triple-negative breast cancer (TNBC), defined by the lack of protein expression of estrogen and progesterone receptors and the absence of HER2 protein overexpression (ER-/PR-/HER2-) has significant clinical implications due to their poor prognosis and the lack of targeted agents. Skin involvement is one of the most distressing presentations of locally recurrent breast cancer and few studies have identified effective agents in this setting. In fact, the increasing use of anthracycline/taxane-based chemotherapy in the neoadjuvant and/or adjuvant settings has led to investigate new cytotoxic therapies such as the combination of pegylated liposomal doxorubicin (PLD) with gemcitabine.
Here, we report two cases of disseminated TNBC with extensive cutaneous metastases and a remarkable response to PLD in combination with gemcitabine. Further investigations are needed to confirm the efficacy of this regimen in skin involvement and TNBC.
- PMID:
- 22526226
- [PubMed - as supplied by publisher]
Linear Mode
