INTERACTION OF CIS-DIAMMINEDICHLOROPLATINUM(II) AND ITS ANALOGS XYLATO(2R)-2-METHYL-1,4-BUTANEDIAMMINEPLATINUM(11) AND CIS-DIAMMINE(GLYCOLATO)PLATINUM WITH HYPERTHERMIA IN-VIVO
I. Takahashi et al., INTERACTION OF CIS-DIAMMINEDICHLOROPLATINUM(II) AND ITS ANALOGS XYLATO(2R)-2-METHYL-1,4-BUTANEDIAMMINEPLATINUM(11) AND CIS-DIAMMINE(GLYCOLATO)PLATINUM WITH HYPERTHERMIA IN-VIVO, Oncology, 53(1), 1996, pp. 68-72
The interaction of xylato(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 examine
d in vivo. Antitumor activity of the platinum complexes at the maximum
tolerated dose (MTD) with or without hyperthermia was evaluated by th
e tumor growth delay assay using B16F10 melanoma growing in the legs o
f C57BL/6J mice. MTD of CDDP, NK121 or 254-S at the single intraperito
neal injection with hyperthermia was 8, 50 or 30 mg/kg, respectively.
Treatment of the tumor-bearing limb at 43 degrees C for 30 min resulte
d 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 hyper
thermia (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 o
f 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 nitroge
n (BUN) were determined 5 days after intraperitoneal drug administrati
on with or without hyperthermia. A single administration of CDDP 8 mg/
kg resulted in an elevated BUN level, and this was enhanced in combina
tion with hyperthermia (66.3 mg/dl, 2.7-fold over control). NK121 50 m
g/kg at 37 degrees C did not result in elevation of BUN, but mild neph
rotoxicity was noted in combination with hyperthermia (40.3 mg/dl, 1.6
-fold increase over control). The administration of 254-S 30 mg/kg res
ulted in an elevated BUN level, and this elevation was enhanced in com
bination 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 great
er tumor growth delay together with hyperthermia than did the drug alo
ne. Though these new compounds were designed with reduced nephrotoxici
ty, attention should be paid to increased nephrotoxicity when combined
with hyperthermia.