Samuels B L, Hollis D R, Rosner G L, Trump D L, Shapiro C L, Vogelzang N J, Schilsky R L
Division of Hematology/Oncology, Lutheran General Hospital, Park Ridge, Illinois 60068, USA.
Clin Cancer Res. 1997 Nov;3(11):1977-84.
Multidrug resistance mediated by P-glycoprotein may be an important cause of chemotherapy failure. Renal cell carcinoma is a disease known to demonstrate a high degree of intrinsic chemotherapy drug resistance, and this has been shown to be related to intrinsic overexpression of P-glycoprotein. Cyclosporine A and tamoxifen have been shown to reverse multidrug resistance in renal cell carcinoma cell lines in vitro. Phase I studies have defined appropriate doses of cyclosporine A and tamoxifen that can be combined with continuous-infusion vinblastine and safely achieve serum levels associated in vitro with resistance reversal. A randomized Phase II study was carried out by the Cancer and Leukemia Group B to evaluate the potential of high doses of cyclosporine A or tamoxifen to modulate clinical vinblastine resistance in patients with advanced renal cell carcinoma. Patients were treated initially with continuous-infusion vinblastine alone (1.2 mg/m2/day for 4 days or 1.5 mg/m2/day for 5 days); patients with stable or progressive disease were then treated with the same vinblastine regimen, combined with a high-dose regimen of either cyclosporine A (12.5 mg/kg/day for 5 days) or tamoxifen (400 mg/m2 as a loading dose and 300 mg/m2/day for 13 days). Sixty-three patients were randomized to each arm. Eighty patients on both arms were evaluable for response to vinblastine alone; of these, only one patient achieved a partial response. Thirty-three patients went on to be treated with vinblastine and high-dose cyclosporine A. No responses were observed, although four patients with progressive disease on prior vinblastine achieved stabilization of disease after cyclosporine A was added. Addition of cyclosporine resulted in more leukopenia (5% versus 25%) and in transient hyperbilirubinemia (24%) and neurocortical changes (11%). No significant azotemia was observed. Thirty-five patients received high-dose tamoxifen with continuous-infusion vinblastine. One complete remission was seen in a patient who had stable disease only with prior vinblastine alone; no other responses were observed. Leukopenia was not more severe with the addition of tamoxifen to vinblastine, nor was hyperbilirubinemia observed. However, 9% of patients developed transient ataxia with or without neurocortical changes as a result of high-dose tamoxifen therapy, and 11% developed phlebitis. We conclude that advanced renal cell carcinoma is a highly chemoresistant tumor, that continuous-infusion vinblastine has no appreciable activity in the therapy of this disease, and that addition of high doses of cyclosporine A or tamoxifen was not able to modulate this resistance in these patients. Suggestions regarding study design for future drug resistance modulation trials were made based on the design and conduct of this study.
由P-糖蛋白介导的多药耐药可能是化疗失败的一个重要原因。肾细胞癌是一种已知具有高度内在化疗耐药性的疾病，并且已证明这与P-糖蛋白的内在过表达有关。环孢素A和他莫昔芬已被证明在体外可逆转肾癌细胞系中的多药耐药。I期研究确定了环孢素A和他莫昔芬的合适剂量，这些剂量可与持续输注长春碱联合使用，并能安全达到体外与耐药逆转相关的血清水平。癌症与白血病B组进行了一项随机II期研究，以评估高剂量环孢素A或他莫昔芬调节晚期肾细胞癌患者临床长春碱耐药的潜力。患者最初单独接受持续输注长春碱治疗（1.2mg/m²/天，共4天或1.5mg/m²/天，共5天）；病情稳定或进展的患者随后接受相同的长春碱治疗方案，并联合高剂量的环孢素A（12.5mg/kg/天，共5天）或他莫昔芬（400mg/m²作为负荷剂量，300mg/m²/天，共13天）。每组随机分配63例患者。两组共80例患者可评估对单独长春碱的反应；其中只有1例患者获得部分缓解。33例患者继续接受长春碱和高剂量环孢素A治疗。未观察到反应，尽管4例先前接受长春碱治疗病情进展的患者在加用环孢素A后病情稳定。加用环孢素导致更多白细胞减少（5%对25%）以及短暂性高胆红素血症（24%）和神经皮质改变（11%）。未观察到明显的氮质血症。35例患者接受高剂量他莫昔芬联合持续输注长春碱治疗。仅1例先前仅接受长春碱治疗病情稳定的患者出现完全缓解；未观察到其他反应。加用他莫昔芬后白细胞减少并不更严重，也未观察到高胆红素血症。然而，9%的患者因高剂量他莫昔芬治疗出现伴有或不伴有神经皮质改变的短暂性共济失调，11%的患者出现静脉炎。我们得出结论，晚期肾细胞癌是一种高度化疗耐药的肿瘤，持续输注长春碱在该疾病治疗中无明显活性，并且加用高剂量环孢素A或他莫昔芬不能调节这些患者的耐药性。基于本研究的设计和实施，对未来耐药性调节试验的研究设计提出了建议。
