Schedule dependent tumour growth delay, DNA cross-linking and pharmacokinetic parameters in target tissues with cis-diamminedichloroplatinum(II) and etanidazole with or without hyperthermia or radiation

Abstract

It has been reported previously that striking increases in tumour growth delay and cytotoxicity are seen when cis-diamminedichloroplatinurn(II) (CDDP) is combined with mild local hyperthermia (43°C, 30 min) and/or etanidazole (ETA). This paper reports a study of CDDP pharmacology and the in vivo tumour DNA cross-linking produced by these combinations. In C3H mice bearing the FSaIIC murine fibrosarcoma, Pt plasma pharmacokinetics were not significantly altered by any of the combination of treatments. Although ETA caused no significant change in CDDP tissue pharmacokinetics, treatment of the tumour-bearing limb with hyperthermia immediately following an i.p. injection of CDDP (10 mg/kg) resulted in an increased peak Pt concentration (3.5 versus 2.8 μg Pt/g tumour wet weight) and doubled the t_1/2 elimination of Pt (15 to 30 h) from the tumour. Similar heat-induced changes were observed in the Pt pharmacokinetics in skin. There was about a three-fold increase in the Pt area under the curve (AUC) for the tumour, a 1.5-fold increase in the AUC for skin and little change in the AUC for muscle with hyperthermia. When the tumour DNA cross-linking factor (CLF) was determined, it was found that local hyperthermia treatment (43°C, 30 min) increased the CLF of CDDP from 1.7 to 2.7 and hyperthermia (43°C, 1 h) further increased the CLF to 6.1. Misonidazole (MISO) (1 g/kg) increased the CDDP CLF to 2.0, 6.3 and 15.1 in conjunction with 37, 43 (30 min) and 43°C (1 h), respectively. ETA (1 g/kg) was more effective than MISO at increasing the CDDP CLF, producing CLFs of 2.8, 9.1 and 21.5 at 37, 43 (30 min) and 43°C (1 h), respectively. These changes in CLF were reflected in an increased tumour growth delay in the FSaIIC murine fibrosarcoma with CDDP (5 mg/kg) alone from 4.4 to 5.9 days with 43°C (30 min) and then to 11.9 days with ETA (1 g/kg) and 20.9 days with both ETA and local hyperthermia (43°C, 30 min). When CDDP, ETA and hyperthermia were added to a radiation schedule of 300 cGy daily for five days, it was found that giving ETA (1 g/kg), CDDP (5 mg/kg) and hyperthermia (43°C, 30 min) together on day 1 produced the largest tumour growth delay (43 days) and that other schedules which divided the dose of ETA over the other days of the radiation treatment (including one schedule with a second heat treatment on day 4) were significantly inferior. Thus, local hyperthermia increased tumour versus normal tissue exposure to Pt, probably by altering the vascular physiology of the tumour, and both hyperthermia and ETA markedly increased CDDP-induced DNA damage, leading to commensurate increases in tumour growth delay. These results suggest that the addition of both ETA and hyperthermia to CDDP should be effective clinically, and they indicate that treatment once a week with hyperthermia, CDDP and ETA at the maximum tolerated dose will be the most successful.

Key Words:

• tumour growth delay
• pharmacokinetics
• DNA cross-linking
• trimodal treatments