Los G, Tuyt L, van Vugt M, Schornagel J, Pinedo H M
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
Cancer Chemother Pharmacol. 1993;32(6):425-33. doi: 10.1007/BF00685885.
In the present study, cisplatin (cDDP) and carboplatin (CBDCA) were combined in different in vitro and in vivo assays to determine whether combined cDDP and CBDCA treatment would eventually lead to a better antitumor response. Co-incubation of CC531 cells with cDDP and CBDCA led to higher intracellular Pt concentrations (30.5 +/- 3.4 ng Pt/10(6) cells) than did cDDP (16.9 +/- 9.4 ng Pt/10(6) cells) or CBDCA (1.28 +/- 0.72 ng Pt/10(6) cells) incubation alone. In survival assays an additive cell kill was seen after combined treatment with cDDP and CBDCA. DNA binding experiments using isolated salmon-sperm DNA exposed to the drugs separately or in combination were in agreement with the survival studies (for cDDP a binding of 12.42 micrograms Pt/mg DNA; for CBDCA, 0.49 microgram Pt/mg DNA; and for combined CBDCA and cDDP, 12.9 micrograms Pt/mg DNA at 76 h). Toxicity studies in rats treated with cDDP plus CBDCA required a dose reduction for cDDP amounting to 20% of the MTD, whereas the CBDCA dose could be maintained. Pharmacokinetics studies showed higher AUCs and t1/2 beta in plasma as well as the peritoneal cavity after combined treatment with cDDP and CBDCA (both given i.p.) or following cDDP given i.p. and CBDCA given i.v. Pt concentrations in peritoneal tumors corresponded with these observations, with higher Pt concentrations following combined treatment than after single-agent injection. In addition, combined administration of cDDP i.p. and CBDCA i.v. led to higher Pt concentrations in peritoneal tumors than did administration of both drugs i.p. (3.93 +/- 0.9 vs 2.76 +/- 0.2 mg Pt/g tissue). The higher Pt concentrations in the peritoneal tumors after combined treatment was associated with a significantly better antitumor response in comparison with that observed after single-agent treatment (a growth delay of 30.2 +/- 5.6 days for cDDP i.p. plus CBDCA i.v. vs 16.1 +/- 5.4 days for cDDP alone and 10.8 +/- 4.2 days for CBDCA alone).
在本研究中，顺铂（cDDP）和卡铂（CBDCA）在不同的体外和体内试验中联合使用，以确定cDDP和CBDCA联合治疗最终是否会带来更好的抗肿瘤反应。CC531细胞与cDDP和CBDCA共同孵育导致细胞内铂浓度（30.5±3.4 ng Pt/10⁶细胞）高于单独使用cDDP（16.9±9.4 ng Pt/10⁶细胞）或CBDCA（1.28±0.72 ng Pt/10⁶细胞）孵育时的浓度。在生存试验中，cDDP和CBDCA联合治疗后出现了相加的细胞杀伤作用。使用分别或联合暴露于药物的分离鲑鱼精子DNA进行的DNA结合实验与生存研究结果一致（对于cDDP，结合量为12.42 μg Pt/mg DNA；对于CBDCA，为0.49 μg Pt/mg DNA；对于联合使用的CBDCA和cDDP，在76小时时为12.9 μg Pt/mg DNA）。用cDDP加CBDCA治疗的大鼠的毒性研究表明，cDDP的剂量需要减少至最大耐受剂量（MTD）的20%，而CBDCA的剂量可以维持。药代动力学研究表明，cDDP和CBDCA联合治疗（均腹腔注射）后或cDDP腹腔注射和CBDCA静脉注射后，血浆以及腹腔中的曲线下面积（AUC）和半衰期（t1/2β）更高。腹腔肿瘤中的铂浓度与这些观察结果一致，联合治疗后的铂浓度高于单药注射后的浓度。此外，cDDP腹腔注射和CBDCA静脉注射联合给药导致腹腔肿瘤中的铂浓度高于两种药物均腹腔注射时的浓度（3.93±0.9 vs 2.76±0.2 mg Pt/g组织）。与单药治疗后观察到的情况相比，联合治疗后腹腔肿瘤中较高的铂浓度与明显更好的抗肿瘤反应相关（cDDP腹腔注射加CBDCA静脉注射的生长延迟为30.2±5.6天，单独使用cDDP为16.1±5.4天，单独使用CBDCA为10.8±4.2天）。
