Ravdin P M
Department of Medicine, The University of Texas Health Science Center, San Antonio 78284-7884, USA.
Semin Oncol. 1997 Aug;24(4 Suppl 10):S10-18-S10-21.
Until the introduction of the taxoids, docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ), in the 1990s, anthracyclines were widely recognized as the best single agents for the treatment of breast cancer. However, even when anthracyclines are used in combination regimens with response rates of over 50%, including complete responses in 17% of patients, few women (3%) with metastatic disease remain disease free at 5 years after treatment. The low level of sustained responses is largely due to the phenomenon of drug resistance. Anthracycline resistance often involves multidrug resistance efflux mechanisms, but also can involve factors affecting topoisomerase II and apoptosis. When combining other cytotoxic agents with anthracyclines, it is of value to use non-cross-resistant drugs so that the induction of anthracycline-resistance mechanisms does not also affect the efficacy of other agents in the combination therapy. Clinical studies have shown that docetaxel, which is highly active against metastatic breast cancer as a single agent, has a high level of non-cross-resistance with anthracyclines. The overall response rate to docetaxel monotherapy in patients with anthracycline-resistant or refractory metastatic disease has been shown to be 41%. The response rate to first-line docetaxel monotherapy for metastatic breast cancer has been shown to be 61%, suggesting that two thirds of the activity of docetaxel is retained in anthracycline-resistant disease. Treatment with a simultaneous combination of docetaxel and doxorubicin has been found to be very active, with a response rate of 89%, and trials to exploit the lack of cross-resistance between these agents, in sequential regimens and adjuvant therapies, are under way.
在20世纪90年代紫杉烷类药物多西他赛（泰索帝；法国安托尼罗纳-普朗克-乐仁公司）和紫杉醇（泰素；美国新泽西州普林斯顿百时美施贵宝肿瘤公司）问世之前，蒽环类药物被广泛认为是治疗乳腺癌的最佳单一药物。然而，即使蒽环类药物用于联合治疗方案时缓解率超过50%，包括17%的患者完全缓解，但很少有转移性疾病的女性（3%）在治疗后5年仍无疾病。持续缓解率低主要是由于耐药现象。蒽环类药物耐药通常涉及多药耐药外排机制，但也可能涉及影响拓扑异构酶II和细胞凋亡的因素。当将其他细胞毒性药物与蒽环类药物联合使用时，使用非交叉耐药药物很有价值，这样蒽环类药物耐药机制的诱导不会影响联合治疗中其他药物的疗效。临床研究表明，多西他赛作为单一药物对转移性乳腺癌具有高度活性，与蒽环类药物具有高度的非交叉耐药性。对于蒽环类药物耐药或难治性转移性疾病患者，多西他赛单药治疗的总体缓解率已显示为41%。转移性乳腺癌一线多西他赛单药治疗的缓解率已显示为61%，这表明多西他赛三分之二的活性在蒽环类药物耐药疾病中得以保留。已发现多西他赛和阿霉素同时联合治疗非常有效，缓解率为89%，目前正在进行试验，以探索在序贯治疗方案和辅助治疗中这些药物之间缺乏交叉耐药性的情况。
