Elliott W L, Roberts B J, Howard C T, Leopold W R
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, Michigan 48105.
Cancer Res. 1994 Aug 15;54(16):4412-8.
[SP-4-3-(R)]-[1,1-cyclobutanedicarboxylato(2-)](2-methyl-1,4- butane-diamine-N,N')platinum (CI-973) is a cisplatin analogue that is currently in clinical trial. Preclinically, CI-973 retained activity against L1210, P388, K562, and human ovarian carcinoma sublines resistant to cisplatin in vitro. CI-973 also retained substantial activity [ratio of median life span of treated to control groups x 100% (%T/C) > 190] against cisplatin resistant L1210 and P388 sublines in vivo. Good activity (stasis or tumor burden reduction) was also obtained against five murine solid tumors including breast, colon, and sarcoma. Binary combination therapy with CI-973 and seven clinically utilized anticancer agents was evaluated against murine tumors in vivo for the ability of each combination to produce a superior therapeutic response compared to optimal single agent therapy alone at tolerated doses. The seven agents combined with CI-973 were mitomycin C, cyclophosphamide, doxorubicin, vinblastine, etoposide, ifosfamide, and methotrexate. Of the combination regimens evaluated, only the combination of CI-973 and methotrexate was therapeutically superior to single agent therapy. Against i.v. inoculated P388 leukemia, combination therapy with CI-973 at 32 mg/kg/injection and methotrexate at 43 mg/kg/injection produced 5.3 logs greater cell kill (%T/C = 284, with one cell surviving therapy) than either methotrexate therapy (%T/C = 208, with 2.5 x 10(5) cells surviving therapy) or CI-973 therapy (%T/C = 193 with 2.5 x 10(6) cells surviving therapy) alone. The combination toxicity index of 1.0 indicated additive normal host tissue toxicity with the same target organs for dose limiting toxicity. To better understand the enhanced cell kill in vivo, the combination of CI-973 and methotrexate was evaluated against P388 leukemia in vitro. Clonogenic survival studies showed that the combination of CI-973 and methotrexate was additive rather than synergistic with respect to cell killing in vitro. The lack of greater than additive cell kill in vitro suggested that the mechanism responsible for synergistic kill in vivo was not operative in vitro. The in vivo results suggest that the combination of CI-973 and methotrexate may be useful in the clinic.
[SP-4-3-(R)]-1,1-环丁烷二羧酸根合(2-)铂(CI-973)是一种顺铂类似物，目前正处于临床试验阶段。临床前研究表明，CI-973在体外对L1210、P388、K562以及对顺铂耐药的人卵巢癌亚系具有活性。CI-973在体内对顺铂耐药的L1210和P388亚系也保持着显著活性[治疗组与对照组的中位生存期之比×100%(%T/C)>190]。对包括乳腺癌、结肠癌和肉瘤在内的五种小鼠实体瘤也有良好活性(停滞或肿瘤负荷降低)。评估了CI-973与七种临床使用的抗癌药物的联合疗法在体内对小鼠肿瘤的作用，以确定每种联合疗法在耐受剂量下与单独使用最佳单药疗法相比产生更优治疗反应的能力。与CI-973联合的七种药物分别是丝裂霉素C、环磷酰胺、阿霉素、长春碱、依托泊苷、异环磷酰胺和甲氨蝶呤。在所评估的联合治疗方案中，只有CI-973与甲氨蝶呤的联合疗法在治疗上优于单药疗法。对于静脉注射接种的P388白血病，CI-973以32mg/kg/注射剂量与甲氨蝶呤以43mg/kg/注射剂量联合治疗产生的细胞杀伤比单独使用甲氨蝶呤疗法(%T/C = 208，治疗后有2.5×10⁵个细胞存活)或CI-973疗法(%T/C = 193，治疗后有2.5×10⁶个细胞存活)高5.3个对数(%T/C = 284，治疗后仅1个细胞存活)。联合毒性指数为1.0表明正常宿主组织毒性呈相加性，且剂量限制性毒性的靶器官相同。为了更好地理解体内增强的细胞杀伤作用，在体外评估了CI-973与甲氨蝶呤联合对P388白血病的作用。克隆形成存活研究表明，CI-973与甲氨蝶呤联合在体外细胞杀伤方面是相加而非协同的。体外缺乏大于相加的细胞杀伤表明体内协同杀伤的机制在体外不起作用。体内结果表明，CI-973与甲氨蝶呤联合可能在临床上有用。
