Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance.
Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance.
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DOI：
10.1200/jco.1992.10.10.1624
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发表时间：
1992-10
期刊：
影响因子：
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通讯作者：
A. Yahanda;K. M. Alder;G. Fisher;N. Brophy;J. Halsey;R. Hardy;M. Gosland;B. Lum;B. Sikic
中科院分区：
文献类型：
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作者：
A. Yahanda;K. M. Alder;G. Fisher;N. Brophy;J. Halsey;R. Hardy;M. Gosland;B. Lum;B. Sikic
目的：探讨环孢素（CsA）与依托泊苷输注3天对癌症患者的最大耐受剂量（MTD）。患者和方法在72例注册患者中，26例最初使用CsA和依托泊苷治疗。46例患者仅接受依托泊苷治疗直至疾病进展，其中31例继续接受CsA和依托泊苷治疗。CsA以2小时负荷剂量（LD）和3天连续输注（CI）的方式给药；剂量从2 mg/kg LD增加到8 mg/kg，从5 mg/kg/d CI增加到24 mg/kg。结果57例患者接受依托泊苷113个周期的CsA治疗。在91%的循环中，CsA剂量为>或= 5mg /kg LD和>或= 15mg /kg/d CI时，稳态血清CsA水平（非特异性免疫测定）超过2000 ng/mL。CsA的主要剂量相关毒性是可逆性高胆红素血症，在CsA水平为20 000 ng/mL的疗程中，有78%发生了高胆红素血症。CsA和依托泊苷组骨髓抑制和恶心更严重。其他CsA毒性包括低镁血症，60%；高血压,29%;头痛占21%。轻度肾毒性占12%，重度肾毒性占2%。4例患者在添加CsA后出现肿瘤消退（1例非霍奇金淋巴瘤，1例霍奇金病和2例卵巢癌）。对4例有反应的患者中的3例进行肿瘤活检，结果显示mdr1表达阳性。结论：当与依托泊苷联合使用时，可在短期内实现高达4mumol /L （4800 ng/mL）的血清CsA水平，且毒性可接受。成人CsA的推荐剂量是LD为5 - 6mg /kg， CI为15 - 18mg /kg/d，持续60小时。应监测CsA血液水平，并调整剂量，使CsA水平达到2.5至4 μ mol/L（3,000至4,800 ng/mL）。可逆性高胆红素血症可能是CsA抑制p -糖蛋白功能的有用标志。当与高剂量CsA一起使用时，应减少大约50%的CsA剂量，以补偿CsA对etopo苷的药代动力学影响（Lum等，journal clinical oncology, 1992, 10:1635-1642）。
PURPOSE To determine the maximum-tolerated dose (MTD) of cyclosporine (CsA) infusion administered with etoposide for 3 days in patients with cancer. PATIENTS AND METHODS Of the 72 registered patients, 26 were treated initially with CsA and etoposide. Forty-six received etoposide alone until disease progression, and 31 of these proceeded to CsA and etoposide. CsA was administered as a 2-hour loading dose (LD) and as a 3-day continuous infusion (CI); doses were escalated from 2 to 8 mg/kg LD and 5 to 24 mg/kg/d CI. RESULTS Fifty-seven patients were treated with 113 cycles of CsA with etoposide. Steady-state serum CsA levels (nonspecific immunoassay) more than 2,000 ng/mL were achieved in 91% of the cycles at CsA doses > or = 5 mg/kg LD and > or = 15 mg/kg/d CI. The major dose-related toxicity of CsA was reversible hyperbilirubinemia, which occurred in 78% of the courses with CsA levels > 2,000 ng/mL. Myelosuppression and nausea were more severe with CsA and etoposide. Other CsA toxicities included hypomagnesemia, 60%; hypertension, 29%; and headache, 21%. Nephrotoxicity was mild in 12% and severe in 2% of the cycles. Tumor regressions occurred in four patients after the addition of CsA (one non-Hodgkin's lymphoma, one Hodgkin's disease, and two ovarian carcinomas). Biopsy procedures for tumors from three of the four patients who responded were performed, and the results were positive for mdr1 expression. CONCLUSIONS Serum CsA levels of up to 4 mumol/L (4,800 ng/mL) are achievable during a short-term administration with acceptable toxicities when administered in combination with etoposide. The CsA dose that is recommended in adults is a LD of 5 to 6 mg/kg, followed by a CI of 15 to 18 mg/kg/d for 60 hours. CsA blood levels should be monitored and the doses should be adjusted to achieve CsA levels of 2.5 to 4 mumol/L (3,000 to 4,800 ng/mL). Reversible hyperbilirubinemia may be a useful marker of inhibition by CsA of P-glycoprotein function. When used with high-dose CsA, etoposide doses should be reduced by approximately 50% to compensate for the pharmacokinetic effects of CsA on etoposide (Lum et al, J Clin Oncol, 10:1635-1642, 1992).