Preclinical analysis of resistance and cross-resistance to low-dose metronomic chemotherapy
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Low-dose metronomic chemotherapy is an emerging form of chemotherapy with distinct mechanisms of action from conventional chemotherapy (e.g., antiangiogenesis). Although developed to overcome resistance to conventional chemotherapy, metronomic chemotherapy is subject to resistance on its own. However, there is a paucity of information on mechanisms of resistance, on cross-resistance between metronomic regimens using different cytotoxic drugs, and on cross-resistance between metronomic versus conventional chemotherapy, or versus targeted antiangiogenic therapy. Herein we show that PC-3 human prostate cancer xenografts were sensitive to both metronomic cyclophosphamide and metronomic docetaxel, but resistant to metronomic topotecan. Conventional docetaxel was only moderately active in parental PC-3 and in metronomic cyclophosphamide resistant PC-3 tumors. However, in metronomic cyclophosphamide resistant PC-3 tumors combining conventional docetaxel or bolus cyclophosphamide therapy with continued metronomic cyclophosphamide was superior to each treatment alone. Furthermore, bevacizumab had single-agent activity against metronomic cyclophosphamide resistant PC-3 tumors. Microarray analyses identified altered regulation of protein translation as a potential mechanism of resistance to metronomic cyclophosphamide. Our results suggest that sensitivity to metronomic chemotherapy regimens using different cytotoxic drugs not only depends on shared mechanisms of action such as antiangiogenesis, but also on as yet unknown additional antitumor effects that appear to be drug-specific. As clinically observed with targeted antiangiogenic agents, the continued use of metronomic chemotherapy beyond progression may amplify the effects of added second-line therapies or vice versa. However, metronomic chemotherapy is no different from other systemic therapies in that predictive biomarkers will be essential to fully exploit this novel use of conventional chemotherapeutics.
KeywordsLow-dose metronomic chemotherapy Maximum tolerated dose chemotherapy Drug resistance Prostate cancer Cyclophosphamide Docetaxel
These studies were conducted with the support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario as well as by a Prostate Cancer Canada Clinician-Scientist Award to U. Emmenegger, and by grants to Robert S. Kerbel from the Canadian Institutes for Health Research (CIHR) and the National Institutes of Health (CA-41233), USA. Robert S. Kerbel is a Tier I Canada Research Chair in Tumor Biology, Angiogenesis, and Antiangiogenic Therapy. G. Francia was in part supported by University of Texas at El Paso URI and IDR2 grants. We thank Cynthia M. Rodriguez and Karla Parra for their help with the preparation of this manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
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