Miller R L, Bukowski R M, Budd G T, Purvis J, Weick J K, Shepard K, Midha K K, Ganapathi R
Department of Hematology-Oncology, Cleveland Clinic Foundation, OH 44106.
J Clin Oncol. 1988 May;6(5):880-8. doi: 10.1200/JCO.1988.6.5.880.
Drug resistance to chemotherapy agents such as doxorubicin appears to be an important cause of therapeutic failure in cancer treatment. Based on preclinical information demonstrating that the phenothiazine calmodulin-inhibitor trifluoperazine can enhance retention and cytotoxicity of doxorubicin in resistant cells, a phase I/II trial of the combination was performed to determine the maximally tolerated dose (MTD) of trifluoperazine that could be administered with doxorubicin. Patients with intrinsic (no previous response) and acquired (previous response with relapse) doxorubicin resistance were eligible. Doxorubicin was administered as a 96-hour continuous infusion (60 mg/m2) on days 2 through 5. Trifluoperazine was administered in divided doses orally on days 1 through 6, with dose escalation from 20 to 100 mg/d. Thirty-six patients were evaluable. The MTD of trifluoperazine was 60 mg/d, with dose-limiting toxicity being extrapyramidal side effects. No alteration of doxorubicin toxicity was observed. Seven of the 36 patients responded (one complete response [CR], six partial responses [PR]), with seven of 21 patients having acquired resistance, and zero of 15 with intrinsic resistance demonstrating responses. Doxorubicin plasma levels were not affected by trifluoperazine, and the maximal trifluoperazine plasma levels achieved were 129.83 ng/mL. This trial demonstrates the combination of trifluoperazine and doxorubicin is well tolerated, and the schedule recommended for phase II trials is doxorubicin, 60 mg/m2 (continuous infusion) days 2 through 5, and trifluoperazine, 15 mg four times per day orally days 1 through 6. Continued investigation of this combination is indicated for patients with acquired doxorubicin resistance.
对多柔比星等化疗药物产生耐药性似乎是癌症治疗中治疗失败的一个重要原因。基于临床前信息表明吩噻嗪类钙调蛋白抑制剂三氟拉嗪可增强多柔比星在耐药细胞中的滞留和细胞毒性，开展了一项该联合用药的I/II期试验，以确定可与多柔比星联合使用的三氟拉嗪的最大耐受剂量（MTD）。具有原发性（既往无反应）和获得性（既往有反应但复发）多柔比星耐药性的患者符合条件。多柔比星在第2至5天以96小时持续输注（60mg/m²）的方式给药。三氟拉嗪在第1至6天口服分次给药，剂量从20mg/d逐步递增至100mg/d。36例患者可进行评估。三氟拉嗪的MTD为60mg/d，剂量限制性毒性为锥体外系副作用。未观察到多柔比星毒性的改变。36例患者中有7例有反应（1例完全缓解[CR]，6例部分缓解[PR]），21例获得性耐药患者中有7例有反应，15例原发性耐药患者中无1例有反应。多柔比星的血浆水平不受三氟拉嗪影响，三氟拉嗪达到的最大血浆水平为129.83ng/mL。该试验表明三氟拉嗪和多柔比星联合用药耐受性良好，推荐用于II期试验的给药方案为：多柔比星，60mg/m²（持续输注）第2至5天；三氟拉嗪，15mg，口服，每天4次，第1至6天。对于获得性多柔比星耐药的患者，建议继续对该联合用药进行研究。
