Interaction of cis-diamminedichloro-platinum(ll) and its analogues cis-1,1-cyclobutanedicarboxylato(2r)-2-methyl-1,4 butanediammineplatinum(ll) and cis-diammine(glycolato)platinum with hyperthermia in vivo

The interaction of cis -1,1-cyclobutanedicarboxylato(2R)-2-methyl-1,4-buta-nediammineplatinum(II) (NK121) and ds-diammme(glycolato)platinum(II) (254-S), analogues of cis -diamminedichloroplatinum(II) (CDDP), with hyperthermia was examined in vivo. Antitumor activity of the platinum complexes at the maximum tolerated dose (MTD) with or without hyperthermia was evaluated by the tumor growth delay assay using B16F10 melanoma growing in the legs of C57BL/6J mice. MTD of CDDP, NK121 or 254-S at the single intraperitoneal injection with hyperthermia was 8, 50 or 30 mg/kg, respectively. Treatment of the tumor-bearing limb at 43 °C for 30min resulted in a tumor growth delay of 1.1 days. A single dose of CDDP produced a 3.3-day tumor growth delay. When CDDP was injected just before hyperthermia (43°C, 30 min), the growth delay increased to 5.5 days (1.7-fold increase). With NK121, there was a 1.5-day growth delay. In combination with hyperthermia, the tumor growth delay by NK121 was 3.2 days (2.1-fold increase). Injection of 254-S led to a growth delay of 3.5 days, and this delay was extended to 5.7 days (1.6-fold increase) when combined with hyperthermia. Changes in serum blood urea nitrogen (BUN) were determined 5 days after intraperitoneal drug administration with or without hyperthermia. A single administration of CDDP 8 mg/kg resulted in an elevated BUN level, and this was enhanced in combination with hyperthermia (66.3 mg/dl, 2.7-fold over control). NK121 50 mg/kg at 37°C did not result in elevation of BUN, but mild nephrotoxicity was noted in combination with hyperthermia (40.3 mg/ dl, 1.6-fold increase over control). The administration of 254-S 30 mg/kg resulted in an elevated BUN level, and this elevation was enhanced in combination with hyperthermia (48.6 mg/dl, 2.0-fold increase over control). Our data showed that NK121 and 254-S as well as CDDP produced greater tumor growth delay together with hyperthermia than did the drug alone. Though these new compounds were designed with reduced nephrotoxicity, attention should be paid to increased nephrotoxicity when combined with hyperthermia.