Efficacy of two-route chemotherapy using cis-diamminedichloroplatinum(II) and its antidote, sodium thiosulfate, in combination with angiotensin II in a rat limb tumor

Abstract

We combined the angiotensin II (AT-II)-induced hypertension method with "two-route chemotherapy" (TRC), using cis-diamminedichloroplatinum(II) (CDDP) and its antidote, sodium thiosulfate (STS). The efficacy of the modified TRC was evaluated in rats bearing a limb tumor (transitional cell carcinoma). Immediately after infusing CDDP (15 mg/kg) and AT-II (15 micrograms/kg) via the femoral artery for 5 min, 1580 mg/kg STS (200-fold molar ratio to 15 mg/kg of CDDP) were administered i.v. for a further 5 min. Other treatments were as follows: 5 mg/kg of CDDP mixed or not mixed with 15 micrograms/kg of AT-II were given intraarterially (i.a.); 5 mg/kg of CDDP alone were injected i.v.; CDDP (15 mg/kg, i.a.) and STS (1580 mg/kg, i.v.) were simultaneously administered, without AT-II (conventional TRC). The antitumor effects of the modified TRC, evaluated by regression of tumor growth and extended life span, were superior to the other treatments. On the other hand, nephrotoxicity, loss of body weight, and leukopenia, seen in the rats given TRC with AT-II, occurred less than or at the same rate as in rats given other treatments. Thus, the TRC with AT-II was the most effective treatment given to rats bearing a regionally confined tumor. The feasibility of clinical application of modified TRC using i.a. CDDP plus AT-II and i.v. STS is discussed.