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

  • Original Articles
  • Cisplatin, Carboplatin, Combination Treatment
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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/106 cells) than did cDDP (16.9±9.4 ng Pt/106 cells) or CBDCA (1.28±0.72 ng Pt/106 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 μg Pt/mg DNA; for CBDCA, 0.49 μg 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 andt 1/2β 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 adminstration 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).

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Author notes

  1. Gerrit Los

    Present address: Department of Medicine/0812, University of California, San Diego, UCSD Cancer Center, 9500 Gilman Drive, 92093-0812, La Jolla, CA, USA

Authors and Affiliations

  1. Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands

    Gerrit Los, Leonore Tuyt, Marianne van Vugt, Jan Schornagel & Herbert M. Pinedo

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  1. Gerrit Los
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  3. Marianne van Vugt
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  5. Herbert M. Pinedo
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Los, G., Tuyt, L., van Vugt, M. et al. Combination treatment of cis- and carboplatin in cancers restricted to the peritoneal cavity in the rat. Cancer Chemother. Pharmacol. 32, 425–433 (1993). https://doi.org/10.1007/BF00685885

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  • DOI: https://doi.org/10.1007/BF00685885

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