PROTECTIVE EFFECT OF SODIUM L-MALATE, AN ACTIVE CONSTITUENT ISOLATED FROM ANGELICAE-RADIX, ON CIS-DIAMINEDICHLOROPLATINUM(II)-INDUCED TOXICSIDE-EFFECT

The effects of ingredients of Shi-Quan-Da-Bu-Tang (Juzen-taiho-to) on the nephrotoxicity and bone marrow toxicity caused by i.p. administrat ion of 3 mg/kg cis-diamminedichloroplatinum (II) (CDDP) 9 times (on da ys 3, 4, 5, 6, 7, 8, 10, 11, 12) were examined in ddY mice s.c. inocul ated with sarcoma 180 (S-180) cells on day 1. Angelicae Radix showed t he strongest protective effect against the toxicity among the ingredie nts. The ED(50) of a water extract of Angelicae Radix was 17.8 mg/kg f or nephrotoxicity (indicated by an increase in blood urea nitrogen) an d 59.4 mg/kg for bone marrow toxicity (indicated by a decrease in whit e blood cell count), when it was administered perorally (p.o.) on days 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15. The water extract did not e xert any significant effect on the antitumor activity of CDDP. Bioassa y-directed fractionation of the water extract resulted in isolation of a constituent having protective effects against the toxicity: sodium L-malate, C4H4Na2O5, was found to exhibit protective effects against b oth nephrotoxicity (ED(50): 0.4 mg/kg, p.o.) and bone marrow toxicity (ED(50): 1.8 mg/kg, p.o.), without reducing the antitumor activity of CDDP. These findings indicate that Angelicae Radix and its constituent sodium L-malate could provide significant protection against CDDP-ind uced nephrotoxicity and bone marrow toxicity without reducing the anti tumor activity.