Carcinogenicity and haemoglobin synthesis induction by cytidine analogues.
We investigated 5-azacytidine and five of its analogues for: (1) carcinogenicity, in the male Fischer rat; (2) toxicities using changes in rat weights in vivo and a cytotoxicity assay in vitro; and (3) haemoglobin gene expression, using minor haemoglobin synthesis in sheep, mice and rats. 5-Azacytidine was found to be a complete carcinogen. It increased the incidence of testicular tumours as well as non-testicular tumours in rats treated for 12 months. 5-Azacytidine also had hepatic tumour promoting properties and was able to induce transplacental carcinogenesis when administered to pregnant rats on day 21 of timed pregnancies. None of the other 5 analogues that were tested appeared to be carcinogenic in small experiments. All the analogues which are known to have hypomethylating activity were found to be cytotoxic in vitro; the most potent being 5-azacytidine. As judged by decreased rat weight compared to untreated controls, the fluorinated cytidine analogues and 5'-deoxyazacytidine were more toxic than 5-azacytidine. Altered haemoglobin synthesis was seen in rats and DBA/2J mice, but not in sheep. In mice, where the clearest haemoglobin changes were noted, an increase in minor haemoglobin synthesis was found using both high and low doses of 5-azacytidine, and with 5,6-dihydro-5-azacytidine and 5-aza-2'-deoxycytidine. These last two analogues appear to be relatively non-toxic, noncarcinogenic in these experiments, and retain haemoglobin activating properties with a potency similar to that of 5-azacytidine.
Carr
B I
BI
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA.
Rahbar
S
S
Asmeron
Y
Y
Riggs
A
A
Winberg
C D
CD
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006454:Hemoglobins / Q000096:biosynthesis*; D007984:Leydig Cell Tumor / Q000139:chemically induced; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344; D012756:Sheep; D013736:Testicular Neoplasms / Q000139:chemically induced
D006454:Hemoglobins; D001374:Azacitidine