Abstract--The preclinical pharmacology, antitumor activity and toxicity of seven of the more important amino acid analogs, with antineoplastic activity, is discussed in this review. Three of these compounds are antagonists of L-glutamine: acivicin, DON and azaserine; and two are analogs of L-aspartic acid: PALA and L-alanosine. All five of these antimetabolites interrupt cellular nucleotide synthesis and thereby halt the formation of DNA and/or RNA in the tumor cell. The remaining two compounds, buthionine sulfoximine and difluoromethylornithine, are inhibitors of glutathione and polyamine synthesis, respectively, with limited intrinsic antitumor activity; however, because of their powerful biochemical actions and their low systemic toxicities, they are being evaluated as chemotherapeutic adjuncts to or modulators of other more toxic antineoplastic agents.
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Because of the probable role of HIV-infected monocyte/macrophages in the pathogenesis and progression of AIDS, it is essential that antiretroviral therapy address viral replication in cells of this lineage. Several dideoxynucleosides have been shown to have potent in vitro and, in the case of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC), in vivo activity against HIV. However, because these compounds must be phosphorylated (activated) in target cells, and because monocyte/macrophages may have levels of kinases that differ from those in lymphocytes, we investigated the capacity of these drugs to suppress HIV replication in monocyte/macrophages using HIV-1/HTLV-IIIBa-L (a monocytotropic isolate). In the present study, we observed that HTLV-IIIBa-L replication in fresh human peripheral blood monocyte/macrophages was suppressed by each of three dideoxynucleosides: 3'-azido-2',3'-dideoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), and 2',3'-dideoxyadenosine (ddA). Similar results were observed in 5-d-cultured monocyte/macrophages, although higher concentrations of the drugs were required. We then studied the metabolism of AZT and ddC in such cells. The phosphorylation of ddC to a triphosphate moiety was somewhat decreased in monocyte/macrophages as compared with H9 T cells. On the other hand, the phosphorylation of AZT in monocyte/macrophages was markedly decreased to 25% or less of the level in T cells. However, when we examined the level of the normal endogenous 2'-deoxynucleoside triphosphate pools, which compete with 2',3'-dideoxynucleoside triphosphate for viral reverse transcriptase, we found that the level of 2'-deoxycytidine-triphosphate (dCTP) was six- to eightfold reduced, and that of 2'-deoxythymidine-triphosphate (dTTP) was only a small fraction of that found in T cell lines. These results suggest that the ratio of dideoxynucleoside triphosphate to normal deoxynucleoside triphosphate is a crucial factor in determining the antiviral activity of dideoxynucleosides in HIV target cells, and that the lower levels of dTTP may account for the antiretroviral activity of AZT in the face of inefficient phosphorylation of this compound.
The effects of 3'-azido-3'-deoxythymidine (AZT) and three of its intracellular metabolites, azido-thymidine mono-, di-, and triphosphates, on the human immunodeficiency virus type 1 Integrase have been determined. AZT mono-, di-, and triphosphate have an IC50 for integration between 110 and 150 FM, whereas AZT does not inhibit the integrase. The inhibition by AZT monophosphate can be partially reversed by coincubation with either thymidine monophosphate or 2',3'-ddeoxythymldine monophosphate, suggesting that either of these monophosphates can bind to the integrase but that the azido group at the 3' position could be responsible for the inhibition. Integrase inhibition is associated with reduced enzyme-DNA binding but does not appear to be competitive with respect to the DNA substrate. Inhibition of an integrase deletion mutant containing only amino acids 50-212 suggests that these nucleotides bind in the catalytic core. Concentrations up to 1 mM AZT monophosphate can accumulate in vivo, indicating that integrase inhibition may contribute to the antiviral effects of AZT. The increasing incidence of AZT-resistant virus strains may, therefore, be associated with mutations not only in the reverse transcriptase but also in the human immundeficiency virus integrase. Finally, these observations suggest that additional strategies for antiviral drug development could be based upon nucleotide analogs as inhibitors of human immunodeficiency virus integrase.The first clinically approved drug in the treatment ofAIDS was 3'-azido-3'-deoxythymidine (AZT). This thymidine analog is converted to AZT monophosphate (AZTMP), diphosphate (AZTDP), and triphosphate (AZTTP) by thymidine, thymidylate, and nucleoside diphosphate kinases, respectively (1). The antiretroviral effect of AZT is attributed to AZTTP, which interferes with viral DNA replication by two mechanisms (2). (i) It can competitively inhibit the human immunodeficiency virus (HIV) reverse transcriptase against normal dTTP for DNA polymerization; and (ii) it can act as a chain terminator of the nascent viral DNA chain. The major limitation to AZT therapy is bone marrow suppression, leading to anemia or neutropenia (3). The most likely mechanism for AZT-induced toxicity could be incorporation ofAZT into newly synthesized host (i.e., nonviral) DNA and inhibition of strand elongation due to chain termination (4).Studies on the cellular metabolism ofAZT have shown that AZTMP accumulates in vivo because it is a competitive substrate inhibitor of thymidylate kinase that converts AZ-
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