Department of Pharmaceutical Sciences, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2.
Mol Cancer Ther. 2011 Jul;10(7):1289-99. doi: 10.1158/1535-7163.MCT-11-0058. Epub 2011 May 6.
Drug resistance leads to chemotherapy failure and is responsible for the death of a great majority of patients with metastatic, late-stage ovarian cancer. The present study addressed whether changes in the chemotherapy dosing schedule affect the development, further worsening, or circumvention of drug resistance in chemosensitive and chemoresistant ovarian cancer. Severe combined immunodeficient mice bearing HeyA8 and HeyA8-MDR xenografts were treated with docetaxel intermittently (1×/wk or 3×/wk) or continuously for 21 days. Tumor mRNA expression of genes implicated in docetaxel resistance was measured by quantitative real-time-PCR. Analyzed genes included those encoding for the drug efflux transporters mdr1 and mrp7 and for molecules that interfere with or overcome the effects of docetaxel, including β-tubulinIII, actinin4, stathmin1, bcl2, rpn2, thoredoxin, and akt2. In both models, continuous docetaxel resulted in greater antitumor efficacy than 1×/wk or 3×/wk dosing and did not induce upregulation of any analyzed genes. Once weekly dosing caused upregulation of various drug resistance-related genes, especially in chemoresistant xenografts. More frequent, 3×/wk dosing diminished this effect, although levels of various genes were higher than for continuous chemotherapy. Drug efflux transporter expression was further examined by Western blotting, confirming that intermittent, but not continuous, docetaxel induced significant upregulation. Overall, our results show that the presence and length of treatment-free intervals contribute to the development of drug resistance. Elimination of these intervals by continuous dosing resulted in superior antitumor efficacy and prevented drug resistance induction in chemosensitive and chemoresistant disease. These results encourage the clinical implementation of continuous chemotherapy to overcome and/or prevent drug resistance in newly diagnosed and recurrent, refractory ovarian cancer.
耐药性导致化疗失败，是绝大多数转移性晚期卵巢癌患者死亡的主要原因。本研究旨在探讨化疗剂量方案的改变是否会影响化疗敏感和耐药卵巢癌细胞耐药的发展、进一步恶化或规避。严重联合免疫缺陷小鼠携带 HeyA8 和 HeyA8-MDR 异种移植物，分别接受多西紫杉醇间歇（1×/周或 3×/周）或连续治疗 21 天。通过实时定量 PCR 测定与多西紫杉醇耐药相关的肿瘤 mRNA 表达。分析的基因包括编码药物外排转运蛋白 mdr1 和 mrp7 的基因，以及干扰或克服多西紫杉醇作用的分子，包括β-微管蛋白 III、肌动蛋白 4、stathmin1、bcl2、rpn2、硫氧还蛋白和 akt2。在两种模型中，连续多西紫杉醇的抗肿瘤疗效优于 1×/周或 3×/周的剂量，并且不会诱导任何分析基因的上调。每周一次的剂量导致各种耐药相关基因上调，尤其是在耐药异种移植物中。更频繁的 3×/周剂量减少了这种效应，尽管各种基因的水平仍高于连续化疗。通过 Western blot 进一步检查药物外排转运蛋白的表达，证实间歇而非连续多西紫杉醇诱导了显著的上调。总的来说，我们的结果表明无治疗间期的存在和长度有助于耐药的发展。通过连续给药消除这些间隔可提高抗肿瘤疗效，并防止化疗敏感和耐药疾病的耐药性诱导。这些结果鼓励临床实施连续化疗以克服和/或预防新诊断和复发性难治性卵巢癌的耐药性。
