Biological Sciences Platform, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
Invest New Drugs. 2014 Feb;32(1):47-59. doi: 10.1007/s10637-013-9974-3. Epub 2013 Jun 2.
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.
低剂量节拍化疗是一种新兴的化疗形式，与传统化疗（如抗血管生成）具有不同的作用机制。尽管节拍化疗是为了克服对传统化疗的耐药性而开发的，但它本身也会产生耐药性。然而，关于耐药机制、不同细胞毒性药物的节拍化疗方案之间以及节拍化疗与传统化疗或靶向抗血管生成治疗之间的交叉耐药性的信息仍然很少。在此，我们表明 PC-3 人前列腺癌异种移植物对节拍环磷酰胺和节拍多西他赛均敏感，但对节拍拓扑替康耐药。常规多西他赛在亲本 PC-3 和节拍环磷酰胺耐药的 PC-3 肿瘤中仅具有中度活性。然而，在节拍环磷酰胺耐药的 PC-3 肿瘤中，将常规多西他赛或推注环磷酰胺联合继续进行节拍环磷酰胺治疗与单独每种治疗相比更有效。此外，贝伐单抗对节拍环磷酰胺耐药的 PC-3 肿瘤具有单药活性。微阵列分析鉴定出蛋白质翻译的改变调节作为对节拍环磷酰胺耐药的潜在机制。我们的结果表明，对使用不同细胞毒性药物的节拍化疗方案的敏感性不仅取决于抗血管生成等共同作用机制，还取决于未知的额外抗肿瘤作用，这些作用似乎是药物特异性的。与靶向抗血管生成剂在临床上观察到的一样，在进展后继续使用节拍化疗可能会放大添加二线治疗的效果，反之亦然。然而，与其他全身治疗一样，预测生物标志物对于充分利用这种传统化疗的新用途至关重要。
