Effect of 5-iodo-2'-deoxyuridine on the biosynthesis of phosphorylated derivatives of thymidine

Abstract

A study was made of the effect of 5-iodo-2'-deoxyuridine (IUDR) on the formation and utilization of phosphorylated derivatives of thymidine, as well as on the formation of DNA-thymidine, in various murine and human neoplastic tissues. The decreased incorporation, in the presence of IUDR, of the incorporation of 14C-formate and 3H-thymidine into DNA-thymine is a reflection of an inhibition of the utilization of thymidine, thymidylic acid or thymidine triphosphate, presumably by IUDR or the corresponding phosphorylated derivatives of IUDR. It is to be noted that the specific metabolic site primarily affected in the various tissues studied is a characteristic of the individual tissue. Thus, DNA-polymerase was primarily inhibited in murine Ehrlich ascites carcinoma and in human chronic granulocytic and acute monocytic leukemias, whereas studies with murine L5178Y leukemia cells, using 3H-thymidine and 14C-formate showed a prime blockade of thymidine kinase and thymidylic acid kinase, respectively. Confirmation of the inhibition of thymidine kinase was obtained with a cell-free extract of the L5178Y cells ; however, with normal calf thymus, thymidylic acid kinase, but not thymidine kinase, was inhibited primarily. The apparent resistance to IUDR of the Walker carcinosarcoma 256 of the rat, in vivo, as well as of a patient with acute mono-cytic leukemia, could be explained by an inadequate dosage regimen, since marked inhibition of the biosynthesis of DNA by these tissues could be demonstrated in vitro.