Modification of the bone marrow toxicity of cis-diamminedichloroplatinum(II) in mice by diethyldithiocarbamate.
It has been shown that cis-platinum-induced nephrotoxicity in rats can be inhibited by diethyldithiocarbamate (DDC). We report here the bone marrow protective properties of DDC in hybrid (C57BL X BALB/c) mice exposed to single and fractionated doses of cis-platinum. Relatively nontoxic doses of DDC afford maximum protection, using that dose of cis-platinum that would result in the death of 50% of the mice within 9 days as an end point (dose-limiting gut toxicity in mice), when injected 0.5 to 2 hr following i.p. cis-platinum treatment. Survivals of colony-forming units in spleen, nucleated bone marrow cells, and peripheral white blood cell were used to assess the bone marrow protective properties of DDC following both single and fractionated doses of cis-platinum. A dose modification factor of 3.2 (based on colony-forming units in spleen survival) was obtained when DDC (1000 mg/kg) was injected into mice 0.5 hr after graded doses of cis-platinum. When fractionated doses of cis-platinum were used (6 mg/kg on Days 0, 10, 20, and 30), the survival of colony-forming units in spleen was markedly enhanced if the animals were rescued with DDC 0.5 hr following each cis-platinum dose. When bone marrow cellularity was measured immediately before and 2 days after each dose of cis-platinum, a similar pattern of depression and recovery was noted whether DDC was present or not; however, the depression was less marked in mice rescued with DDC. When peripheral white blood cell counts were monitored, the nadir and recovery were similar in the presence or absence of DDC; however, recovery occurred sooner in the animals that had received DDC. Our data support the ability of DDC to modify the bone marrow toxicity of cis-platinum in normal mice. Experiments are in progress in tumor-bearing animals exploring the differential protection afforded by DDC between bone marrow and tumor.
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D004050:Ditiocarb / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D007958:Leukocyte Count; D051379:Mice; D008815:Mice, Inbred Strains; D013859:Thiocarbamates / Q000494:pharmacology*
D013859:Thiocarbamates; D004050:Ditiocarb; D002945:Cisplatin