COMBINATION TREATMENT OF CISPLATIN AND CARBOPLATIN IN CANCERS RESTRICTED TO THE PERITONEAL-CAVITY IN THE RAT

In the present study, cisplatin (cDDP) and carboplatin (CBDCA) were co mbined in different in vitro and in vivo assays to determine whether c ombined cDDP and CBDCA treatment would eventually lead to a better ant itumor response. Co-incubation of CC531 cells with cDDP and CBDCA led to higher intracellular Pt concentrations (130.5+/-3.4 ng Pt/10(6) cel ls) 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 c ell kill was seen after combined treatment with cDDP and CBDCA. DNA bi nding experiments using isolated salmon-sperm DNA exposed to the drugs separately or in combination were in agreement with the survival stud ies (for cDDP a binding of 12.42 mug Pt/mg DNA; for CBDCA, 0.49 mug Pt /mg DNA; and for combined CBDCA and cDDP, 12.9 mug 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 dos e could be maintained. Pharmacokinetics studies showed higher AUCs and t1/2beta in plasma as well as the peritoneal cavity after combined tr eatment with cDDP and CBDCA (both given i.p.) or following cDDP given i.p. and CBDCA given i.v. Pt concentrations in peritoneal tumors corre sponded with these observations, with higher Pt concentrations followi ng combined treatment than after single-agent injection. In addition, combined administration of cDDP i.p. and CBDCA i.v. led to higher Pt c oncentrations in peritoneal tumors than did administration of both dru gs i.p. (3.93+/-0.9 vs 2.76+/-0.2 mg Pt/g tissue). The higher Pt conce ntrations in the peritoneal tumors after combined treatment was associ ated 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 al one and 10.8+/-4.2 days for CB DCA alone).