Arnold D. Welch

Biochemical and pharmacological studies with 1-β-d-arabinofuranosylcytosine in man

Abstract Cytosine arabinoside, labeled with tritium, was administered to five patients with far-advanced neoplasms. The analog was rapidly deaminated to uracil arabinoside; the latter accounted for between 86 and 96 per cent of the radioactivity excreted in the urine. Incorporation of tritium-labeled cytidine into DNA by suspensions of human leukemic leukocytes was inhibited in the presence of cytosine arabinoside. Although administration of cytosine arabinoside at therapeutic levels depressed the ability of leukemic leukocytes to incorporate cytidine into DNA in vitro , there was no correlation between the degree and duration of this effect and the clinical response to the drug. Tritium-labeled cytosine arabinoside entered human leukemic leukocytes very rapidly when incubated with the cells in vitro ; there was a small but significant incorporation of the analog into both DNA and RNA.

Effect of the deoxyriboside of 6-azathymine (azathymidine) on the biosynthesis of deoxyribonucleic acid by bone marrow and neoplastic cells (in vitro).

Abstract Incorporation in vitro of radioactive formate into the bases of the DNA of rabbit bone marrow and Ehrlich ascites tumor cells was related predominantly to the formation of thymine. Thymine deoxyriboside by dilution, and 6-azathymine deoxyriboside and Aminopterin by inhibition, caused a marked decreased in the utilization of formate for the biosynthesis of DNA-thymine. Deoxyuridine and deoxycytidine each may serve as an acceptor of formate-carbon for the biosynthesis (of the methyl group) of DNA-thymine. Certain implications of these findings are discussed.

Immunosuppression by pyrimidine nucleoside analogs.

Abstract Pyrimidine nucleoside analogs have been examined in mice for their ability to suppress the primary immune response to the intraperitoneal injection of sheep erythrocytes. 5-Fluorodeoxyuridine was more effective than the corresponding 5-bromo-compound, while 5-iododeoxyuridine was essentially inactive in practical dosage levels. In all cases, the drugs were more effective when given intraperitoneally than subcutaneously, and this observation applied also to 6-mercaptopurine and to azathioprine. Cytosine arabinoside was the most potent agent tested, and its immuno-suppressive effects could be inhibited by the concurrent administration of deoxycytidine. The combination of chloramphenicol with 6-azauridine exhibited potentiation of the weak immunosuppressive activity exerted by 6-azauridine, while no such activity was demonstrated by chloramphenicol under the conditions of the experiments.

The mode of interruption of pregnancy by 6-azauridine in mice and rats

Abstract Mice and rats were treated, during different stages of pregnancy, with 6-azauridine (AzUR), an inhibitor of pyrimidine synthesis de novo . Pregnancy and the effects of AzUR were observed and confirmed at the time of laparotomy, and gross and histological studies were performed on the products of conception. AzUR, given in doses of 2–4 g/kg to mice and of 4–6 g/kg to rats, was highly embryotoxic primarily during the period from day 5 to day 10 of pregnancy; subsequent to embryonic deaths, the necrotic embryos and placentas were resorbed in utero . When AzUR was administered before day 4, embryotoxicity was not observed, while after day 10 exposure to the drug often resulted in the premature delivery of either sick or dead progeny. The high toxicity of AzUR between day 5 and day 10 of pregnancy suggests that, during this phase of embryogenesis, certain tissues of the developing organism are critically dependent upon the biosynthesis of pyrimidines de novo . It is postulated that, during the first half of pregnancy the biosynthesis of pyrimidines is blocked by AzUR, except when the drug cannot reach the implanted ovum via the maternal blood stream, i.e. prior to implantation and during the very early stage of implantation. During the second half of pregnancy, it is suggested that the fetuses are probably not totally dependent upon the availability of pyrimidines formed de novo ; nevertheless, effects of AzUR are still encountered, because adequate doses of it may cause either the premature delivery of fetuses with decreased viability or the expulsion of dead fetuses.