Potentiation of cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) by amphotericin B in BALB/c nude mice bearing human ovarian carcinoma cells.

Human ovarian carcinoma cells (HRA) were sensitized to cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) 1.2-, 2.1- and 3.4-fold by treatment with amphotericin B (AMB) at concentrations of 2.1, 5.4, and 10.8 microM, respectively. Moreover, the intracellular accumulation of platinum after 2-h exposure to CBDCA was increased significantly by AMB treatment. For estimating the enhancing effect of AMB on CBDCA cytotoxicity in vivo, we prepared HRA cell-inoculated nude mice. Ascites was evident 7 to 9 days after intraperitoneal (i.p.) inoculation of HRA cells, and the mice died of intraabdominal carcinomatosis 11 to 14 days (mean survival time (MST): 12.0 +/- 1.0 days) after inoculation. Treatment with AMB (2.0 mg/kg) alone increased the MST by only 1.2 days. Simultaneous treatment with CBDCA (12 or 15 mg/kg) and AMB (0.5 to 2.0 mg/kg) produced a significant increase in MST compared to treatment with CBDCA alone. Maximal MST (38.5 days) was obtained by treatment with 15 mg/kg CBDCA plus 2.0 mg/kg AMB, whereas the MST with 15 mg/kg CBDCA alone was 15.8 days. A drug accumulation study demonstrated that platinum accumulation in tumor tissues after i.p. treatment with CBDCA and AMB in tumor-bearing nude mice was increased significantly compared to treatment with CBDCA alone. These findings indicate that intraperitoneal combination chemotherapy with CBDCA and AMB is useful in nude mice with advanced ovarian carcinoma.