Combination treatment of cis- and carboplatin in cancers restricted to the peritoneal cavity in the rat

Abstract

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).