The interaction of cis-1,1-cyclobutanedicarboxylato(2R)-2-methyl-1,4- butanediammineplatinum(II) (
NK121) and
cis-diammine(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 degrees C for 30 min 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 degrees 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 degrees 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.