Diethyldithiocarbamate modulation of murine bone marrow toxicity induced by cis-diammine(cyclobutanedicarboxylato)platinum (II).
Diethyldithiocarbamate (DDTC) has been shown to ameliorate the myelosuppression induced by the platinum cancer chemotherapeutic drugs in mice. Optimal drug scheduling for DDTC and cis-diammine(cyclobutanedicarboxylato)platinum(II) (CBDCA) has been determined in C57BL/6 x DBA/2 F1 mice, using the pluripotent stem cell assay to assess hematological toxicity. DDTC, at doses of 0.3 to 300 mg/kg given 3 h after 60 mg/kg CBDCA, tripled the number of proliferating spleen colony-forming units compared to treatment with CBDCA alone. No significant difference in efficacy was noted among these doses. DDTC, at the lowest myeloprotective dose (0.3 mg/kg), was most active when administered from 1 to 3 h after CBDCA. The combination of DDTC with CBDCA in vivo did not alter the clonogenic survival of L1210 cells compared to CBDCA alone. CBDCA depressed both bone marrow and tumor cell DNA synthesis. DDTC given 3 h after CBDCA hastened the recovery of DNA synthesis only in marrow cells; the addition of DDTC to CBDCA did not alter DNA synthesis in tumor cells. DDTC alone did not significantly affect DNA synthesis in either normal or tumor cells. These results suggest that the mechanism of DDTC myeloprotection involves stimulation of bone marrow cell proliferation and that the selectivity of DDTC is based upon the absence of stimulation in tumor cells.
Schmalbach
T K
TK
Department of Pharmacology, University of Rochester School of Medicine and Dentistry, New York 14642.
Borch
R F
RF
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D016190:Carboplatin; D002453:Cell Cycle / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004050:Ditiocarb / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D009944:Organoplatinum Compounds / Q000633:toxicity*
D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D004247:DNA; D004050:Ditiocarb; D016190:Carboplatin