Effects of mannitol or furosemide diuresis on cis-dichlorodiammineplatinum(II) antitumor activity and toxicity to host-renewing cell populations in rats.

against COOP4-induced impairment of renal function in mats.At the same time, plasma clearance and urinary excme tion of platinum were essentially unaltered by diuretic administration. If plasma and urine platinum disposition reflects the disposition of the cytotoxic form(s) of COOP, then the above findings suggest that diuretic administration should result in decreased renal toxicity of COOP without alteration of drug toxicity to host renewing cell populations (bone marrow, and gastrointestinal tract) and without alter ation in the antitumom activity of the drug. We therefore investigated effects of diuretics on the gastrointestinal and hematopoietic toxicity and antitumom activity of COOP and found this view to be incorrect. This paper provides evi dence that the osmotic diuretic, mannitol, protects matbone marrow and gastrointestinal cell renewal systems without lowering the antitumom effect of COOP towards one expemi mental leukemia. Ward et a!. (14) showed that although fumosemide pro tected rat kidneys against the functional impairment caused by COOP, the diuretic did not decrease the acute lethal toxicity of the platinum compound. We confirmed this finding, but we also observed that coadministration of mannitol allowed rats to survive a lethal dose of COOP (Ref. 9 and this publication). The acute lethal toxicity of COOP involves damage to several systems, including the kidney, proliferating cells of the gastrointestinal mucosa, and he matopoietic and lymphoid tissues (7, 13). Since furosemide and mannitol protect renal function from COOP toxicity to a similar degree (10), it seemed possible that the enhanced survival of mannitol-treated rats was due to an interaction at sites of COOP toxicity other than the kidney. Although gastrointestinal toxicity due to inhibition of crypt cell proliferative activity is not a major clinical problem with COOP, we noted that the acute toxic response to COOP in rats resembles the gastrointestinal radiation syndrome in many respects (1). We considered, therefore, that survival of mannitol-treated ratsmightrelatetodecreasedtoxicity in this organ system. Hagemann et a!. (4) have stressed the importance of the relationship of the timing of recovery of proliferative activity to animal survival in the gastrointestinal radiation syndrome. Therefore, we followed the course of inhibition and recovery of ONA synthesis in the small intestine of mats given a sublethal dose of COOP and compared this pattern to that observed in rats given a lethal dose of the platinum compound either alone or in combi nation with furosemide or mannitol. We next examined the effects of the 2 diuretics on the toxicity of COOP to †̃kema