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Cis-diamminedichloroplatinum (II) (cis-DDP) is a square-planar platinum coordination complex that is the parent compound representing a relatively new family of anti-cancer agents and is a potent radiosensitizer. This study was undertaken to identify the combined treatment effect of cis-DDP and irradiation in a rat brain tumor model. The brain tumor model was produced in CDF male rats by stereotaxic inoculation of cells (D-74, F-98 glioma clone). For the first series using F-98, the median survival time of the control group was 31 days. Cis-DDP alone, 5 mg/kg dose of cis-DDP on Day 10, produced 37 days (P=0.002). Irradiation alone, 750 rads X-ray dose on Day 10, 13, and 15, produced 44 days (P<0.001). The combined treatment of cis-DDP plus irradiation resulted in 55 days with a 77.4% increase in the life span (%ILS). The median survival time of the combined treatment was significantly longer than that of the irradiation alone (P=0.038). For the second series using D-74, the median survival time of the control group was 21.5 days. Cis-DDP alone produced no significant increase in survival time. Irradiation alone produced 27.5 days with 27.9% ILS (P<0.001) and the combined treatment resulted in 32.0 days with 48.8% ILS. The median survival time of the combined treatment was significantly longer than that of irradiation alone (P<0.001). The third series assessed the schedule dependency of the combined treatment effect using D-74. The single dose of cis-DDP (5 mg/kg) on Day 10 produced no significant increase. Irradiation alone (1, 500 rads) on Day 10 resulted in 26.0 days with 26.8% ILS (P<0.001). The combined treatment group receiving cis-DDP 24 hours or 1 hour prior to irradiation on Day 10 showed a significant increase in the median survival time of 29 days with 41.4% ILS or 30 days with 46.3% ILS and the median survival time of the combined treatment was significantly longer than that of irradiation alone (P=0.040, P=0.008). Also a significant increase of the median survival time was observed when cis-DDP was administered 6 hours after irradiation (29 days with 41.4% ILS) (P=0.024). In conclusion, cis-DDP alone showed a significant direct increase in the survival time on F-98 glioma but not on D-74 glioma. Cis-DDP has a significant radiation enhancement effect which was demonstrated by using three different drug/irradiation schedules. There was no particular timing for the enhancement effect between cis-DDP and irradiation.

Experimental Study in a Rat Brain Tumor by Combined Treatment with cis-DDP and Irradiation