Therapeutic efficacy of two-route chemotherapy using cis-diamminedichloroplatinum(II) and its antidote, sodium thiosulfate, combined with the angiotensin-II-induced hypertension method in a rat uterine tumor.

To enhance the therapeutic effect of conventional TRC using intra-arterial (i.a.) DDP plus simultaneous i.v. STS, we combined the AT-II-induced hypertension method with TRC and evaluated its efficacy for a rat uterine tumor, using the simulation of intra-arterial chemotherapy for human uterine tumors. During interruption of arterial blood flow by vascular manipulations, DDP plus AT-II were injected for 10 min through the abdominal aorta in the direction of the uterus. Then STS was administered i.v. for a further 5 min and all the arterial restrictions were released. This modified TRC using AT-II showed a much higher anti-tumor effect than that seen in conventional TRC without AT-II and was free from DDP-induced renal damage. On the other hand, severe nephrotoxicity was unavoidable in the rats given the delayed i.v. administration of STS to i.a. DDP alone. The feasibility of post-administration of STS without obvious nephrotoxicity in modified TRC was explained by transient inhibition of DDP delivery to the kidney during the AT-II-induced hypertension. The loss of body weight and the decrease in the number of leukocytes after this therapy were tolerable. Modified TRC showed a higher anti-tumor effect and a lower nephrotoxicity compared with other treatments, as follows: DDP i.a. with or without AT-II; i.v. infusion of DDP alone. Such a superior anti-tumor effect of modified TRC consists of the following 2 factors: (i) the post-administration of STS leading to the delayed neutralization of DDP at the tumor site; (ii) the selective enhancement of DDP delivery to the tumor tissue during AT-II-induced hypertension.