Diethyldithiocarbamate inhibits scheduled and unscheduled DNA synthesis of rat thymocytes in vitro and in vivo--dose-effect relationships and mechanisms of action.
In vitro as well as in animal models, diethyldithiocarbamate (DDC) modifies the tumoricidal activity of some antineoplastic agents. To gain further information about the mechanism of action of DDC, we measured (i) in vitro and (ii) in vivo changes in DNA synthesis of rat thymocytes. (i) In vitro, the scheduled (SDS) and unscheduled (UDS) incorporation of [3H]thymidine ([3H]dT) into DNA of rat thymic cells were biphasically inhibited in a dose range of 1-1000 micrograms DDC/ml. The UV-induced UDS was totally suppressed by 10 and 100 micrograms DDC/ml. (ii) In vivo, 1-4 h following intraperitoneal administration of 250-1000 mg DDC per kg body wt., SDS and UDS were inhibited up to about 80% in a dose-dependent manner. Nucleoid sedimentation, uptake of [3H]dT into the cells, and the pattern of phosphorylation of the intracellular [3H]dT following DDC treatment did not reveal any differences to the controls. A possible effect of DDC treatment on the ribonucleotide reductase and the DNA polymerase alpha is suggested.
Spath
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Institute of Pharmacology, Toxicology and Pharmacy, Faculty of Veterinary Medicine, University of Munich, F.R.G.
Tempel
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K
D000818:Animals; D004247:DNA / Q000096:biosynthesis*; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004260:DNA Repair / Q000187:drug effects*; D004050:Ditiocarb / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism
D004247:DNA; D004050:Ditiocarb; D012262:Ribonucleoside Diphosphate Reductase; D004257:DNA Polymerase II; D013936:Thymidine