Oncology Research, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Anticancer Drugs. 2011 Jan;22(1):58-78. doi: 10.1097/CAD.0b013e3283400a20.
The aim was to determine the potential of the allosteric mammalian target of rapamycin inhibitor, everolimus, to act in combination with cytotoxic anticancer compounds in vitro and in vivo. A concomitant combination in vitro showed no evidence of antagonism, but enhanced the antiproliferative effects (additive to synergistic) with cisplatin, doxorubicin, 5-fluorouracil, gemcitabine, paclitaxel, and patupilone. Everolimus (1-5 mg/kg/d orally) was evaluated for antitumor activity in vivo alone or in combination with suboptimal cytotoxic doses using athymic nude mice bearing subcutaneous human H-596 lung, KB-31 cervical, or HCT-116 colon tumor xenografts. Everolimus monotherapy was very well tolerated and caused inhibition of tumor growth, rather than regression, and this was associated with a dose-dependent decline in tumor pS6 levels, a key downstream protein of mammalian target of rapamycin. At the doses used, the cytotoxics inhibited tumor growth and caused tolerable body-weight loss. Concomitant combinations of cisplatin, doxorubicin, paclitaxel, or patupilone with everolimus produced cooperative antitumor effects, in some cases producing regressions without clinically significant increases in toxicity. In contrast, combinations with gemcitabine and 5-fluorouracil were less well tolerated. Alternative administration schedules were tested for cisplatin, gemcitabine, or paclitaxel combined with everolimus: these did not dramatically affect cisplatin or gemcitabine activity or tolerability but were antagonistic for paclitaxel. Everolimus showed promising maintenance activity after treatment with doxorubicin or paclitaxel ceased. Overall, the results confirm that everolimus is an effective, well-tolerated suppressor of experimental human tumor growth, and although it did not show strong potentiation of efficacy, antitumor activity in vivo was increased without marked increases in toxicity, supporting clinical use of everolimus as a partner for conventional cytotoxics.
目的在于确定别构哺乳动物雷帕霉素靶蛋白抑制剂依维莫司与细胞毒性抗癌化合物在体外和体内联合应用的潜力。体外同时联合用药并未显示拮抗作用，但增强了顺铂、阿霉素、5-氟尿嘧啶、吉西他滨、紫杉醇和帕他珠单抗的抗增殖作用（相加至协同）。采用荷有人源 H-596 肺、KB-31 宫颈或 HCT-116 结肠肿瘤异种移植物的裸鼠皮下模型，单独或与亚最佳细胞毒性剂量联合评估依维莫司的体内抗肿瘤活性。依维莫司（每天口服 1-5mg/kg）单独应用或与顺铂、阿霉素、紫杉醇或帕他珠单抗联合应用时，耐受性良好，仅能抑制肿瘤生长而不能使肿瘤消退，这与肿瘤 pS6 水平（哺乳动物雷帕霉素靶蛋白的关键下游蛋白）的剂量依赖性下降有关。在所用剂量下，细胞毒性药物抑制肿瘤生长并引起可耐受的体重减轻。顺铂、阿霉素、紫杉醇或帕他珠单抗与依维莫司联合应用产生协同抗肿瘤作用，在某些情况下，在没有明显增加毒性的情况下产生消退。相比之下，与吉西他滨和 5-氟尿嘧啶联合应用的耐受性较差。测试了顺铂、吉西他滨或紫杉醇与依维莫司联合应用的替代给药方案：这些方案对顺铂或吉西他滨的活性或耐受性没有显著影响，但对紫杉醇具有拮抗作用。在停止阿霉素或紫杉醇治疗后，依维莫司显示出有希望的维持活性。总的来说，这些结果证实依维莫司是一种有效的、可耐受的实验性人类肿瘤生长抑制剂，虽然它没有显示出很强的增效作用，但体内抗肿瘤活性增加而毒性没有明显增加，支持将依维莫司用于与传统细胞毒性药物联合应用。
