In vitro and in vivo studies of a promising antileukemic thymidine analogue, 5-hydroxymethyl-2' deoxyuridine.
The toxicity and metabolism of a thymidine analogue, 5-hydroxymethyl-2'-deoxyuridine (5HmdUrd) were studied with human leukemia cells (HL-60) and with human platelets. 3 X 10(-5) M 5HmdUrd caused a 50% inhibition in the proliferation of HL-60 cells. The compound was hydrolyzed to 5-hydroxymethyluracil (5HmUra) by the enzyme thymidine phosphorylase (EC 2.4.2.4) present in leukemia cells; this catabolic product was non-toxic. The catabolism of 5HmdUrd by human platelet thymidine phosphorylase could be inhibited by 6-aminothymine. The toxicity of 5HmdUrd was effectively reversed by deoxycytidine and 5HmdUrd increased the incorporation of deoxycytidine into dCTP and DNA several fold. The two latter phenomena are explicable in terms of a feedback action to ribonucleotide reductase, resulting in deoxycytidylate starvation, which is a known effect of excess thymidine. We report here also our preliminary observations that 5HmdUrd is active against mouse leukemia in vivo.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism; D002460:Cell Line; D003841:Deoxycytidine / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D007939:Leukemia L1210 / Q000188:drug therapy; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D003841:Deoxycytidine; C018080:5-hydroxymethyl-2'-deoxyuridine; D013936:Thymidine