Low-Dose Metronomic Oral Dosing of a Prodrug of Gemcitabine (LY2334737) Causes Antitumor Effects in the Absence of Inhibition of Systemic Vasculogenesis

Molecular Cancer Therapeutics - Tập 11 Số 3 - Trang 680-689 - 2012
Giulio Francia1, Yuval Shaked1, Kae Hashimoto1, John Sun1, Melissa Yin1, Carolyn E. Cesta1, Ping Xu1, Shan Man1, Christina Hackl1, Julie Stewart1, Mark Uhlik1, Anne H. Dantzig1, F. Stuart Foster1, Robert S. Kerbel1
1Authors' Affiliation: Department of Medical Biophysics, Platform Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada

Tóm tắt

Abstract Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low, minimally toxic doses, with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials and is currently undergoing phase III trial evaluation. It is thought to cause antitumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow–derived cells, including circulating endothelial progenitor cells (CEP). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, antiangiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T-cell responses or by direct antitumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 in nontumor–bearing mice and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6 mg/kg/d), the schedules tested were devoid of toxicity and caused antitumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly, metronomic LY2334737 administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts, and this effect, readily measured using contrast micro-ultrasound, coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant antitumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis. Mol Cancer Ther; 11(3); 680–9. ©2011 AACR.

Từ khóa


Tài liệu tham khảo

Browder, 2000, Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer, Cancer Res, 60, 1878

Klement, 2000, Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity, J Clin Invest, 105, R15, 10.1172/JCI8829

Kerbel, 2004, Antiangiogenic basis of low-dose metronomic chemotherapy, Nature Rev Cancer, 4, 423, 10.1038/nrc1369

Pietras, 2005, A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer, J Clin Oncol, 23, 939, 10.1200/JCO.2005.07.093

Pasquier, 2010, Metronomic chemotherapy: new rationale for new directions, Nat Rev Clin Oncol, 7, 455, 10.1038/nrclinonc.2010.82

Garcia, 2007, Phase II clinical trial of bevacizumab and low dose metronomic oral cyclophosphamide in recurrent ovarian cancer. A trial of the California, Chicago and Princess Margaret Hospital Phase II Consortia, J Clin Oncol, 26, 76, 10.1200/JCO.2007.12.1939

Bottini, 2006, 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, 24, 3623, 10.1200/JCO.2005.04.5773

Dellapasqua, 2008, Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer: clinical and biological activity, J Clin Oncol, 26, 4899, 10.1200/JCO.2008.17.4789

Bellmunt, 2010, Activity of a multitargeted chemo-switch regimen (sorafenib, gemcitabine, and metronomic capecitabine) in metastatic renal-cell carcinoma: a phase 2 study (SOGUG-02–06), Lancet Oncol, 11, 350, 10.1016/S1470-2045(09)70383-3

Klink, 2006, Metronomic trofosfamide inhibits progression of human lung cancer xenografts by exerting anti-angiogenic effects, J Cancer Res Clin Oncol, 132, 643, 10.1007/s00432-006-0112-x

Bertolini, 2003, Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells, Cancer Res, 63, 4342

Shaked, 2005, The optimal biological dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity, Blood, 106, 3058, 10.1182/blood-2005-04-1422

Ng, 2006, Influence of formulation vehicle on metronomic taxane chemotherapy: albumin-bound versus cremophor EL-based paclitaxel, Clin Cancer Res, 12, 4331, 10.1158/1078-0432.CCR-05-2762

Munoz, 2006, Highly efficacious non-toxic treatment for advanced metastatic breast cancer using combination UFT-cyclophosphamide metronomic chemotherapy, Cancer Res, 66, 3386, 10.1158/0008-5472.CAN-05-4411

Shaked, 2005, Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis: implications for cellular surrogate marker analysis of antiangiogenesis, Cancer Cell, 7, 101

Ghiringhelli, 2007, Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients, Cancer Immunol Immunother, 56, 641, 10.1007/s00262-006-0225-8

Hermans, 2003, Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model, Cancer Res, 63, 8408

Folkins, 2007, Anti-cancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors, Cancer Res, 67, 3560, 10.1158/0008-5472.CAN-06-4238

Zhang, 2008, Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth, Proc Natl Acad Sci U S A, 105, 19579, 10.1073/pnas.0809763105

Rapisarda, 2009, Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition, Mol Cancer Ther, 8, 1867, 10.1158/1535-7163.MCT-09-0274

Semenza, 2003, Targeting HIF-1 for cancer therapy, Nat Rev Cancer, 3, 721, 10.1038/nrc1187

Man, 2002, Antitumor and anti-angiogenic effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water, Cancer Res, 62, 2731

Hashimoto, 2010, Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer, Mol Cancer Ther, 9, 996, 10.1158/1535-7163.MCT-09-0960

Bender, 2009, Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine, J Med Chem, 52, 6958, 10.1021/jm901181h

Shaked, 2005, Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy, Cancer Res, 65, 7045, 10.1158/0008-5472.CAN-05-0765

du Manoir, 2006, Strategies for delaying or treating in vivo acquired resistance to trastuzumab (Herceptin®) in human breast cancer xenografts, Clin Cancer Res, 12, 904, 10.1158/1078-0432.CCR-05-1109

Francia, 2008, Long term progression and therapeutic response of visceral metastatic disease non-invasively monitored in mouse urine using beta-hCG choriogonadotropin secreting tumor cell lines, Mol Cancer Ther, 7, 3452, 10.1158/1535-7163.MCT-08-0200

Franco, 2006, Targeted anti-VEGFR-2 therapy leads to short and long term impairment of vascular function and increases in tumor hypoxia, Cancer Res, 66, 3639, 10.1158/0008-5472.CAN-05-3295

Shaked, 2006, Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors, Science, 313, 1785, 10.1126/science.1127592

Merriman, 1996, Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models, Invest New Drugs, 14, 243, 10.1007/BF00194526

Emmenegger, 2007, Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice, Mol Cancer Ther, 6, 2280, 10.1158/1535-7163.MCT-07-0181

Laquente, 2008, Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model, Mol Cancer Ther, 7, 638, 10.1158/1535-7163.MCT-07-2122

Kindler, 2005, Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer, J Clin Oncol, 23, 8033, 10.1200/JCO.2005.01.9661

Perry, 2010, Phase II trial of continuous (28/28) dose-intense temozolomide in recurrent malignant glioma: the RESCUE study, J Clin Oncol, 28, 2051, 10.1200/JCO.2009.26.5520

Takahashi, 2005, A pilot study of individualized maximum repeatable dose (iMRD), a new dose finding system, of weekly gemcitabine for patients with metastatic pancreas cancer, Pancreas, 30, 206, 10.1097/01.mpa.0000153335.73352.c7

Emmenegger, 2005, A dynamic de-escalating dosing strategy to determine the optimal biological dose for antiangiogenic drugs, Clin Cancer Res, 11, 7589, 10.1158/1078-0432.CCR-05-1387

Goel, 2011, Normalization of the vasculature for treatment of cancer and other diseases, Physiol Rev, 91, 1071, 10.1152/physrev.00038.2010

Carmeliet, 2011, Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases, Nat Rev Drug Discov, 10, 417, 10.1038/nrd3455

Mupparaju, 2011, Tumor pO as a surrogate marker to identify therapeutic window during metronomic chemotherapy of 9L gliomas, Adv Exp Med Biol, 701, 107, 10.1007/978-1-4419-7756-4_15

Doloff, 2009, Increased tumor oxygenation and drug uptake during anti-angiogenic weekly low dose cyclophosphamide enhances the anti-tumor effect of weekly tirapazamine, Curr Cancer Drug Targets, 9, 777, 10.2174/156800909789271503

Cham, 2010, Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma, Br J Cancer, 103, 52, 10.1038/sj.bjc.6605727

Thông tin
Thông tin xuất bản

Molecular Cancer Therapeutics

Tập 11 Số 3

680-689

Thông tin tác giả