Systemic chemotherapy in tumor-bearing rats using high-dose cis-diamminedichloroplatinum(II) with low nephrotoxicity in combination with angiotensin II and sodium thiosulfate.

Systemic chemotherapy using high-dose DDP and its antidote, STS, was combined with the AT-II-induced hypertension method and evaluated for efficacy against s.c. tumors in rats. After i.v. infusion of DDP plus AT-II for 5 min, STS was administered i.v. over a further 5 min. The rats treated with this combination chemotherapy showed normal levels of BUN and serum creatinine 4 days after the treatment, although most rats given i.v. STS after DDP without AT-II showed severe nephrotoxicity. The absence of obvious nephrotoxicity in AT-II-combined chemotherapy using i.v. DDP plus post-administered STS can be explained by a transient inhibition of DDP-delivery to the kidney during the AT-II-induced hypertension. The anti-tumor effect of this modified therapy, evaluated by inhibition of tumor growth, was superior to other treatments, as follows: concomitant i.v. administrations of DDP and STS; i.v. DDP, with or without AT-II. The improvement in anti-tumor effect of this combination therapy is explained by the delayed neutralization of active DDP by STS at the tumor site and the selective enhancement of DDP delivery to the tumor tissue, as produced by AT-II. Thus, systemic chemotherapy using high-dose DDP induced no obvious nephrotoxicity and improved the anti-cancer effect in the case of concomitant administration of DDP plus AT-II and the time-delayed injection of STS.