Abstract
We tested the in vitro inhibitory activities of three 2',3'-dideoxynucleosides and two inhibitors of viral binding in combinations against the infectivity and cytopathic effect of human immunodeficiency virus type 1. 3'-Azido-2',3'-dideoxythymidine, 2',3'-dideoxyinosine, or 2',3'-dideoxycytidine, combined with recombinant soluble CD4 (sCD4), brought about synergistic antiretroviral activity without toxicity at clinically achievable concentrations. Combinations of 2',3'-dideoxynucleosides plus dextran sulfate exerted similar synergistic antiviral effects without concomitant increases in toxicities. When sCD4 and dextran sulfate were combined, apparent antagonism was observed. We confirmed that no combination of sCD4 plus 3'-azido-2',3'-dideoxythymidine, 2',3'-dideoxyinosine, or 2',3'-dideoxycytidine significantly increased the inhibitory effect on colony formation of human myeloid-monocytic bone marrow cells in vitro at the concentrations used in this study. These data might have clinical relevance for the treatment of patients infected with human immunodeficiency virus.
Full text
PDF






Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Baba M., Pauwels R., Balzarini J., Arnout J., Desmyter J., De Clercq E. Mechanism of inhibitory effect of dextran sulfate and heparin on replication of human immunodeficiency virus in vitro. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6132–6136. doi: 10.1073/pnas.85.16.6132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chou T. C. Derivation and properties of Michaelis-Menten type and Hill type equations for reference ligands. J Theor Biol. 1976 Jul 7;59(2):253–276. doi: 10.1016/0022-5193(76)90169-7. [DOI] [PubMed] [Google Scholar]
- Chou T. C., Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55. doi: 10.1016/0065-2571(84)90007-4. [DOI] [PubMed] [Google Scholar]
- Dahlberg J. E., Mitsuya H., Blam S. B., Broder S., Aaronson S. A. Broad spectrum antiretroviral activity of 2',3'-dideoxynucleosides. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2469–2473. doi: 10.1073/pnas.84.8.2469. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dainiak N., Worthington M., Riordan M. A., Kreczko S., Goldman L. 3'-Azido-3'-deoxythymidine (AZT) inhibits proliferation in vitro of human haematopoietic progenitor cells. Br J Haematol. 1988 Jul;69(3):299–304. doi: 10.1111/j.1365-2141.1988.tb02366.x. [DOI] [PubMed] [Google Scholar]
- De Clercq E. Perspectives for the chemotherapy of AIDS. Anticancer Res. 1987 Sep-Oct;7(5B):1023–1038. [PubMed] [Google Scholar]
- Deen K. C., McDougal J. S., Inacker R., Folena-Wasserman G., Arthos J., Rosenberg J., Maddon P. J., Axel R., Sweet R. W. A soluble form of CD4 (T4) protein inhibits AIDS virus infection. Nature. 1988 Jan 7;331(6151):82–84. doi: 10.1038/331082a0. [DOI] [PubMed] [Google Scholar]
- Fine R. L., Koizumi S., Curt G. A., Chabner B. A. Effect of calcium channel blockers on human CFU-GM with cytotoxic drugs. J Clin Oncol. 1987 Mar;5(3):489–495. doi: 10.1200/JCO.1987.5.3.489. [DOI] [PubMed] [Google Scholar]
- Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
- Fisher R. A., Bertonis J. M., Meier W., Johnson V. A., Costopoulos D. S., Liu T., Tizard R., Walker B. D., Hirsch M. S., Schooley R. T. HIV infection is blocked in vitro by recombinant soluble CD4. Nature. 1988 Jan 7;331(6151):76–78. doi: 10.1038/331076a0. [DOI] [PubMed] [Google Scholar]
- Hartshorn K. L., Vogt M. W., Chou T. C., Blumberg R. S., Byington R., Schooley R. T., Hirsch M. S. Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant alpha A interferon. Antimicrob Agents Chemother. 1987 Feb;31(2):168–172. doi: 10.1128/aac.31.2.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hayashi S., Phadtare S., Zemlicka J., Matsukura M., Mitsuya H., Broder S. Adenallene and cytallene: acyclic-nucleoside analogues that inhibit replication and cytopathic effect of human immunodeficiency virus in vitro. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6127–6131. doi: 10.1073/pnas.85.16.6127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hirsch M. S., Kaplan J. C. Treatment of human immunodeficiency virus infections. Antimicrob Agents Chemother. 1987 Jun;31(6):839–843. doi: 10.1128/aac.31.6.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hussey R. E., Richardson N. E., Kowalski M., Brown N. R., Chang H. C., Siliciano R. F., Dorfman T., Walker B., Sodroski J., Reinherz E. L. A soluble CD4 protein selectively inhibits HIV replication and syncytium formation. Nature. 1988 Jan 7;331(6151):78–81. doi: 10.1038/331078a0. [DOI] [PubMed] [Google Scholar]
- Johnson M., Caiazzo T., Molina J. M., Donahue R., Groopman J. Inhibition of bone marrow myelopoiesis and erythropoiesis in vitro by anti-retroviral nucleoside derivatives. Br J Haematol. 1988 Oct;70(2):137–141. doi: 10.1111/j.1365-2141.1988.tb02454.x. [DOI] [PubMed] [Google Scholar]
- Johnson V. A., Barlow M. A., Chou T. C., Fisher R. A., Walker B. D., Hirsch M. S., Schooley R. T. Synergistic inhibition of human immunodeficiency virus type 1 (HIV-1) replication in vitro by recombinant soluble CD4 and 3'-azido-3'-deoxythymidine. J Infect Dis. 1989 May;159(5):837–844. doi: 10.1093/infdis/159.5.837. [DOI] [PubMed] [Google Scholar]
- Kubota K., Mizoguchi H., Miura Y., Suda T., Takaku F. A new technique for the cytochemical examination of human hemopoietic cells grown in agar gel. Exp Hematol. 1980 Mar;8(3):339–344. [PubMed] [Google Scholar]
- Larder B. A., Darby G., Richman D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. doi: 10.1126/science.2467383. [DOI] [PubMed] [Google Scholar]
- Marsh J. C. The effects of cancer chemotherapeutic agents on normal hematopoietic precursor cells: a review. Cancer Res. 1976 Jun;36(6):1853–1882. [PubMed] [Google Scholar]
- Merigan T. C., Skowron G., Bozzette S. A., Richman D., Uttamchandani R., Fischl M., Schooley R., Hirsch M., Soo W., Pettinelli C. Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections. A phase I and II study. Ann Intern Med. 1989 Feb 1;110(3):189–194. doi: 10.7326/0003-4819-110-3-189. [DOI] [PubMed] [Google Scholar]
- Mitsuya H., Broder S. Inhibition of infectivity and replication of HIV-2 and SIV in helper T-cells by 2',3'-dideoxynucleosides in vitro. AIDS Res Hum Retroviruses. 1988 Apr;4(2):107–113. doi: 10.1089/aid.1988.4.107. [DOI] [PubMed] [Google Scholar]
- Mitsuya H., Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1911–1915. doi: 10.1073/pnas.83.6.1911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mitsuya H., Broder S. Strategies for antiviral therapy in AIDS. 1987 Feb 26-Mar 4Nature. 325(6107):773–778. doi: 10.1038/325773a0. [DOI] [PubMed] [Google Scholar]
- Mitsuya H., Weinhold K. J., Furman P. A., St Clair M. H., Lehrman S. N., Gallo R. C., Bolognesi D., Barry D. W., Broder S. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7096–7100. doi: 10.1073/pnas.82.20.7096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pike B. L., Robinson W. A. Human bone marrow colony growth in agar-gel. J Cell Physiol. 1970 Aug;76(1):77–84. doi: 10.1002/jcp.1040760111. [DOI] [PubMed] [Google Scholar]
- Richman D. D., Fischl M. A., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Hirsch M. S. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):192–197. doi: 10.1056/NEJM198707233170402. [DOI] [PubMed] [Google Scholar]
- Smith D. H., Byrn R. A., Marsters S. A., Gregory T., Groopman J. E., Capon D. J. Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen. Science. 1987 Dec 18;238(4834):1704–1707. doi: 10.1126/science.3500514. [DOI] [PubMed] [Google Scholar]
- Sommadossi J. P., Carlisle R. Toxicity of 3'-azido-3'-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoietic progenitor cells in vitro. Antimicrob Agents Chemother. 1987 Mar;31(3):452–454. doi: 10.1128/aac.31.3.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Traunecker A., Lüke W., Karjalainen K. Soluble CD4 molecules neutralize human immunodeficiency virus type 1. Nature. 1988 Jan 7;331(6151):84–86. doi: 10.1038/331084a0. [DOI] [PubMed] [Google Scholar]
- Ueno R., Kuno S. Dextran sulphate, a potent anti-HIV agent in vitro having synergism with zidovudine. Lancet. 1987 Jun 13;1(8546):1379–1379. doi: 10.1016/s0140-6736(87)90681-7. [DOI] [PubMed] [Google Scholar]
- Yarchoan R., Berg G., Brouwers P., Fischl M. A., Spitzer A. R., Wichman A., Grafman J., Thomas R. V., Safai B., Brunetti A. Response of human-immunodeficiency-virus-associated neurological disease to 3'-azido-3'-deoxythymidine. Lancet. 1987 Jan 17;1(8525):132–135. doi: 10.1016/s0140-6736(87)91968-4. [DOI] [PubMed] [Google Scholar]
- Yarchoan R., Klecker R. W., Weinhold K. J., Markham P. D., Lyerly H. K., Durack D. T., Gelmann E., Lehrman S. N., Blum R. M., Barry D. W. Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet. 1986 Mar 15;1(8481):575–580. doi: 10.1016/s0140-6736(86)92808-4. [DOI] [PubMed] [Google Scholar]
- Yarchoan R., Mitsuya H., Thomas R. V., Pluda J. M., Hartman N. R., Perno C. F., Marczyk K. S., Allain J. P., Johns D. G., Broder S. In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. Science. 1989 Jul 28;245(4916):412–415. doi: 10.1126/science.2502840. [DOI] [PubMed] [Google Scholar]
- Yarchoan R., Perno C. F., Thomas R. V., Klecker R. W., Allain J. P., Wills R. J., McAtee N., Fischl M. A., Dubinsky R., McNeely M. C. Phase I studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet. 1988 Jan 16;1(8577):76–81. doi: 10.1016/s0140-6736(88)90283-8. [DOI] [PubMed] [Google Scholar]