Phosphorothioate homo-oligodeoxynucleotides were found to be potent inhibitors of herpes lvus type 2 (HSV-2) but less potent for HSV-1 in cell culture studies. Oligomers with longer chain lengths were more active against HSV-2 than those with shorter ones. Of all the compounds examined, the 28-mer phosphorothioate homo-oligodeoxynucleotides were the strongest inhibitors of HSV-2. The degree of inhibition was relited to the base moiety on the order of deoxycytidiie = thymidine > deoxyadenosine. The inhibition of HSV-2 growth by S-dC23 was dose dependent with a 90% inhibitory dose of 1 FLM. At 50 FM, S-dC2 inhibited HeLa S3 cell growth by less than 10%. The anti-HSV-2 activity was time and schedule dependent. The oligomer wu most inhibitory to viral growth when present during the 1-h viral adso*ption period, and this effect could -be enhanced by continuous drug exposure after the adsorption period. S-dC23 was also an effective inhibitor of two HSV-2 drug-resistant mutants: a phosphonoformate-reistant mutant that induces an altered DNA polymerase and a 9-(1,3-dihydroxy-2-propoxymethyl)guanine-resistant mutant that does not induce the viral thymidine kinase. In drug combination studies, phosphonoformate was shown to potentiate the action of S4C2 against HSV-2 growth. In condusion, because of their potency and selectivity, phosphorothioate homo-oligedeoxynucleotides are a promising new class of anti-HSV agents.

3'-Azido-3'-deoxythymidine (AZT) is currently used in the treatment of patients with the acquired immunodeficiency syndrome (AIDS); this often, however, results in hematological toxicity. Although the mechanism of toxicity is not clear, it is thought to result in part from incorporation of AZT into DNA, which causes chain termination. In order to investigate the mechanism of AZT toxicity, the relationship between the presence of AZT in DNA of K562 cells, a chronic myelogenous leukemia cell line, and growth inhibition was examined. No growth inhibition was evident at less than 50 microM AZT, although incorporation of AZT into DNA was detected at 10 and 20 microM. This suggested that the presence of AZT in DNA was not sufficient to inhibit cell growth. Removal of AZT from the medium resulted in the removal of AZT from DNA of the cells, indicative of a cellular repair mechanism. Cellular DNA polymerases alpha, beta, gamma, and delta from human leukemic cells were inhibited by AZT trisphosphate to different degrees, polymerase alpha being the least potently inhibited. Furthermore, an enzyme with exonucleolytic activity, capable of removing AZT and dideoxycytidine from the correspondingly terminated DNA (in vitro), was obtained from these cells. In summary, AZT was incorporated into DNA at levels that were not toxic, and it could be removed by an exonuclease, which might play a key role in the susceptibility of cells to AZT.

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