Contrasting cytotoxicity kinetics of 5-azacytidine and dihydro-5-azacytidine hydrochloride in L1210 leukemia in mice.
For a comparison of the kinetics of the cytotoxicity of dihydro-5-azacytidine hydrochloride (DHAzaCR) and 5-azacytidine (AzaCR) in L1210 leukemia, the spleen colony assay was used to determine the surviving fraction of normal hematopoietic colony-forming units (NCFU) and leukemia colony-forming units (LCFU). Increasing doses of DHAzaCR above 1 mg per mouse enhanced cytotoxicity to LCFU but not to NCFU. The NCFU dose-survival curve showed a plateau with DHAzaCR, such that increasing the dose from 1 to 80 mg per mouse produced no further decrease in NCFU survival. In contrast, AzaCR produced a biphasic dose-NCFU survival curve without a plateau. Although DHAzaCR produced less cytotoxicity on a milligram basis than did AzaCR, both DHAzaCR and AzaCR elicited a biphasic dose-survival curve for LCFU. An infusion of DHAzaCR was less cytotoxic than was a similar dose of DHAzaCR administered as an iv bolus. Although high doses of AzaCR administered as an iv bolus. Although high doses of AzaCR delayed LCFU repopulation, both low and high doses of DHAzaCR were associated with prompt LCFU repopulation. Confirming this prompt repopulation of LCFU, there was a good correlation between the increase in life-span of mice with leukemia predicted by LCFU data following DHAzaCR treatment, compared to the discrepancy between predicted survival and observed survival following AzaCR. Therefore, the kinetics of cytotoxicity of DHAzaCR differ from those of AzaCR.
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000633:toxicity; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007700:Kinetics; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000188:drug therapy*; D008297:Male; D051379:Mice; D013154:Spleen / Q000187:drug effects / Q000473:pathology
C013938:5,6-dihydro-5-azacytidine; D001374:Azacitidine