Abstract
The anti-human immunodeficiency virus (HIV) activity and hemopoietic toxicity of zidovudine (AZT) and didanosine (dideoxyinosine;ddI), alone and in combination, were assessed in a variety of cell types. AZT was more potent than ddI as an inhibitor of HIV in vitro. Synergistic inhibition of HIV by the combination of these agents was observed in MT4 cells, peripheral blood lymphocytes, and macrophages. Toxicity assessment in vitro by using progenitor (erythroid and granulocyte-macrophage) colony-forming assays with normal human bone marrow showed ddI to be less toxic than AZT. Addition of inhibitory concentrations of ddI to AZT resulted in additive inhibition of progenitor CFUs. These in vitro findings suggest that combinations of ddI and AZT at appropriately modified doses may provide an enhanced degree of selectivity in anti-HIV chemotherapy.
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- Abraham N. G., Bucher D., Niranjan U., Brown A. C., Lutton J. D., Distenfeld A., Ahmed T., Levere R. D. Microenvironmental toxicity of azidothymidine: partial sparing with hemin. Blood. 1989 Jul;74(1):139–144. [PubMed] [Google Scholar]
- Averett D. R. Anti-HIV compound assessment by two novel high capacity assays. J Virol Methods. 1989 Mar;23(3):263–276. doi: 10.1016/0166-0934(89)90159-6. [DOI] [PubMed] [Google Scholar]
- Baba M., Pauwels R., Balzarini J., Herdewijn P., De Clercq E., Desmyter J. Ribavirin antagonizes inhibitory effects of pyrimidine 2',3'-dideoxynucleosides but enhances inhibitory effects of purine 2',3'-dideoxynucleosides on replication of human immunodeficiency virus in vitro. Antimicrob Agents Chemother. 1987 Oct;31(10):1613–1617. doi: 10.1128/aac.31.10.1613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Berman E., Duigou-Osterndorf R., Krown S. E., Fanucchi M. P., Chou J., Hirsch M. S., Clarkson B. D., Chou T. C. Synergistic cytotoxic effect of azidothymidine and recombinant interferon alpha on normal human bone marrow progenitor cells. Blood. 1989 Sep;74(4):1281–1286. [PubMed] [Google Scholar]
- Bhalla K., Birkhofer M., Grant S., Graham G. The effect of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) on 3'-azido-3'-deoxythymidine (AZT)-mediated biochemical and cytotoxic effects on normal human myeloid progenitor cells. Exp Hematol. 1989 Jan;17(1):17–20. [PubMed] [Google Scholar]
- Bhalla K., Birkhofer M., Li G. R., Grant S., MacLaughlin W., Cole J., Graham G., Volsky D. J. 2'-Deoxycytidine protects normal human bone marrow progenitor cells in vitro against the cytotoxicity of 3'-azido-3'-deoxythymidine with preservation of antiretroviral activity. Blood. 1989 Nov 1;74(6):1923–1928. [PubMed] [Google Scholar]
- Blau I. W., Elstner E., Waechter M., Ihle R., von Janta-Lipinski M., Langen P. Sensitivity of CFU-GM from normal human bone marrow and leukaemic clonogenic cells (CFU-L) from blood of patients with myelogenous leukaemia to 3'-deoxy-3'-fluorothymidine in comparison to 3'-azido-3'-deoxythymidine. Blut. 1989 Nov;59(5):455–457. doi: 10.1007/BF00349067. [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]
- Cooley T. P., Kunches L. M., Saunders C. A., Ritter J. K., Perkins C. J., McLaren C., McCaffrey R. P., Liebman H. A. Once-daily administration of 2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Results of a Phase I trial. N Engl J Med. 1990 May 10;322(19):1340–1345. doi: 10.1056/NEJM199005103221902. [DOI] [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]
- Donahue R. E., Johnson M. M., Zon L. I., Clark S. C., Groopman J. E. Suppression of in vitro haematopoiesis following human immunodeficiency virus infection. Nature. 1987 Mar 12;326(6109):200–203. doi: 10.1038/326200a0. [DOI] [PubMed] [Google Scholar]
- Dornsife R. E., Gasper P. W., Mullins J. I., Hoover E. A. In vitro erythrocytopathic activity of an aplastic anemia-inducing feline retrovirus. Exp Hematol. 1989 Feb;17(2):138–144. [PubMed] [Google Scholar]
- Duggan M. J., Weisenburger D. D., Sun N. C., Purtilo D. T. Bone marrow findings in immunodeficiency syndromes. Hematol Oncol Clin North Am. 1988 Dec;2(4):637–656. [PubMed] [Google Scholar]
- ELION G. B., SINGER S., HITCHINGS G. H. Antagonists of nucleic acid derivatives. VIII. Synergism in combinations of biochemically related antimetabolites. J Biol Chem. 1954 Jun;208(2):477–488. [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]
- Fischl M. A., Richman D. D., Hansen N., Collier A. C., Carey J. T., Para M. F., Hardy W. D., Dolin R., Powderly W. G., Allan J. D. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. A double-blind, placebo-controlled trial. The AIDS Clinical Trials Group. Ann Intern Med. 1990 May 15;112(10):727–737. doi: 10.7326/0003-4819-112-10-727. [DOI] [PubMed] [Google Scholar]
- Folks T. M., Kessler S. W., Orenstein J. M., Justement J. S., Jaffe E. S., Fauci A. S. Infection and replication of HIV-1 in purified progenitor cells of normal human bone marrow. Science. 1988 Nov 11;242(4880):919–922. doi: 10.1126/science.2460922. [DOI] [PubMed] [Google Scholar]
- Ganser A., Greher J., Völkers B., Staszewski S., Hoelzer D. Inhibitory effect of azidothymidine, 2'-3'-dideoxyadenosine, and 2'-3'-dideoxycytidine on in vitro growth of hematopoietic progenitor cells from normal persons and from patients with AIDS. Exp Hematol. 1989 May;17(4):321–325. [PubMed] [Google Scholar]
- Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. doi: 10.1126/science.3014648. [DOI] [PubMed] [Google Scholar]
- Gelmon K., Montaner J. S., Fanning M., Smith J. R., Falutz J., Tsoukas C., Gill J., Wells G., O'Shaughnessy M., Wainberg M. Nature, time course and dose dependence of zidovudine-related side effects: results from the Multicenter Canadian Azidothymidine Trial. AIDS. 1989 Sep;3(9):555–561. doi: 10.1097/00002030-198909000-00001. [DOI] [PubMed] [Google Scholar]
- Gill P. S., Rarick M., Brynes R. K., Causey D., Loureiro C., Levine A. M. Azidothymidine associated with bone marrow failure in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1987 Oct;107(4):502–505. doi: 10.7326/0003-4819-107-4-502. [DOI] [PubMed] [Google Scholar]
- Hammer S. M., Gillis J. M. Synergistic activity of granulocyte-macrophage colony-stimulating factor and 3'-azido-3'-deoxythymidine against human immunodeficiency virus in vitro. Antimicrob Agents Chemother. 1987 Jul;31(7):1046–1050. doi: 10.1128/aac.31.7.1046. [DOI] [PMC free article] [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]
- Harvey R. J. Synergism in the folate pathway. Rev Infect Dis. 1982 Mar-Apr;4(2):255–260. doi: 10.1093/clinids/4.2.255. [DOI] [PubMed] [Google Scholar]
- Hayashi S., Fine R. L., Chou T. C., Currens M. J., Broder S., Mitsuya H. In vitro inhibition of the infectivity and replication of human immunodeficiency virus type 1 by combination of antiretroviral 2',3'-dideoxynucleosides and virus-binding inhibitors. Antimicrob Agents Chemother. 1990 Jan;34(1):82–88. doi: 10.1128/aac.34.1.82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Inoue T., Tsushita K., Itoh T., Ogura M., Hotta T., Saneyoshi M., Yoshida S., Saitoh H., Tomoda Y., Nagai Y. In vitro bone marrow toxicity of nucleoside analogs against human immunodeficiency virus. Antimicrob Agents Chemother. 1989 Apr;33(4):576–579. doi: 10.1128/aac.33.4.576. [DOI] [PMC free article] [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., Walker B. D., Barlow M. A., Paradis T. J., Chou T. C., Hirsch M. S. Synergistic inhibition of human immunodeficiency virus type 1 and type 2 replication in vitro by castanospermine and 3'-azido-3'-deoxythymidine. Antimicrob Agents Chemother. 1989 Jan;33(1):53–57. doi: 10.1128/aac.33.1.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lambert J. S., Seidlin M., Reichman R. C., Plank C. S., Laverty M., Morse G. D., Knupp C., McLaren C., Pettinelli C., Valentine F. T. 2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial. N Engl J Med. 1990 May 10;322(19):1333–1340. doi: 10.1056/NEJM199005103221901. [DOI] [PubMed] [Google Scholar]
- Lunardi-Iskandar Y., Georgoulias V., Bertoli A. M., Augery-Bourget Y., Ammar A., Vittecoq D., Rosenbaum W., Meyer P., Jasmin C. Impaired in-vitro proliferation of hemopoietic precursors in HIV-1-infected subjects. Leuk Res. 1989;13(7):573–581. doi: 10.1016/0145-2126(89)90124-0. [DOI] [PubMed] [Google Scholar]
- Molina J. M., Groopman J. E. Bone marrow toxicity of dideoxyinosine. N Engl J Med. 1989 Nov 23;321(21):1478–1478. doi: 10.1056/NEJM198911233212113. [DOI] [PubMed] [Google Scholar]
- Munch-Petersen B. Azidothymidine inhibits mitogen stimulated growth and DNA-repair in human peripheral lymphocytes. Biochem Biophys Res Commun. 1988 Dec 30;157(3):1369–1375. doi: 10.1016/s0006-291x(88)81026-x. [DOI] [PubMed] [Google Scholar]
- Namiki T. S., Boone D. C., Meyer P. R. A comparison of bone marrow findings in patients with acquired immunodeficiency syndrome (AIDS) and AIDS related conditions. Hematol Oncol. 1987 Apr-Jun;5(2):99–106. doi: 10.1002/hon.2900050204. [DOI] [PubMed] [Google Scholar]
- Nicholson J. K., Cross G. D., Callaway C. S., McDougal J. S. In vitro infection of human monocytes with human T lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). J Immunol. 1986 Jul 1;137(1):323–329. [PubMed] [Google Scholar]
- Perno C. F., Yarchoan R., Cooney D. A., Hartman N. R., Webb D. S., Hao Z., Mitsuya H., Johns D. G., Broder S. Replication of human immunodeficiency virus in monocytes. Granulocyte/macrophage colony-stimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3'-azido-2'3'-dideoxythymidine (AZT) and other dideoxynucleoside congeners of thymidine. J Exp Med. 1989 Mar 1;169(3):933–951. doi: 10.1084/jem.169.3.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Petit A. J., Tersmette M., Terpstra F. G., de Goede R. E., van Lier R. A., Miedema F. Decreased accessory cell function by human monocytic cells after infection with HIV. J Immunol. 1988 Mar 1;140(5):1485–1489. [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]
- Schinazi R. F., Sommadossi J. P., Saalmann V., Cannon D. L., Xie M. Y., Hart G. C., Smith G. A., Hahn E. F. Activities of 3'-azido-3'-deoxythymidine nucleotide dimers in primary lymphocytes infected with human immunodeficiency virus type 1. Antimicrob Agents Chemother. 1990 Jun;34(6):1061–1067. doi: 10.1128/aac.34.6.1061. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schwartz O., Henin Y., Marechal V., Montagnier L. A rapid and simple colorimetric test for the study of anti-HIV agents. AIDS Res Hum Retroviruses. 1988 Dec;4(6):441–448. doi: 10.1089/aid.1988.4.441. [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]
- Sommadossi J. P., Carlisle R., Zhou Z. Cellular pharmacology of 3'-azido-3'-deoxythymidine with evidence of incorporation into DNA of human bone marrow cells. Mol Pharmacol. 1989 Jul;36(1):9–14. [PubMed] [Google Scholar]
- Spector T., Stonehuerner J. G., Biron K. K., Averett D. R. Ribonucleotide reductase induced by varicella zoster virus. Characterization, and potentiation of acyclovir by its inhibition. Biochem Pharmacol. 1987 Dec 15;36(24):4341–4346. doi: 10.1016/0006-2952(87)90682-4. [DOI] [PubMed] [Google Scholar]
- Spivak J. L., Bender B. S., Quinn T. C. Hematologic abnormalities in the acquired immune deficiency syndrome. Am J Med. 1984 Aug;77(2):224–228. doi: 10.1016/0002-9343(84)90695-8. [DOI] [PubMed] [Google Scholar]
- Stella C. C., Ganser A., Hoelzer D. Defective in vitro growth of the hemopoietic progenitor cells in the acquired immunodeficiency syndrome. J Clin Invest. 1987 Aug;80(2):286–293. doi: 10.1172/JCI113071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sun N. C., Shapshak P., Lachant N. A., Hsu M. Y., Sieger L., Schmid P., Beall G., Imagawa D. T. Bone marrow examination in patients with AIDS and AIDS-related complex (ARC). Morphologic and in situ hybridization studies. Am J Clin Pathol. 1989 Nov;92(5):589–594. doi: 10.1093/ajcp/92.5.589. [DOI] [PubMed] [Google Scholar]
- Surbone A., Yarchoan R., McAtee N., Blum M. R., Maha M., Allain J. P., Thomas R. V., Mitsuya H., Lehrman S. N., Leuther M. Treatment of the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex with a regimen of 3'-azido-2',3'-dideoxythymidine (azidothymidine or zidovudine) and acyclovir. A pilot study. Ann Intern Med. 1988 Apr;108(4):534–540. doi: 10.7326/0003-4819-108-4-534. [DOI] [PubMed] [Google Scholar]
- Szebeni J., Wahl S. M., Popovic M., Wahl L. M., Gartner S., Fine R. L., Skaleric U., Friedmann R. M., Weinstein J. N. Dipyridamole potentiates the inhibition by 3'-azido-3'-deoxythymidine and other dideoxynucleosides of human immunodeficiency virus replication in monocyte-macrophages. Proc Natl Acad Sci U S A. 1989 May;86(10):3842–3846. doi: 10.1073/pnas.86.10.3842. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vogt M. W., Hartshorn K. L., Furman P. A., Chou T. C., Fyfe J. A., Coleman L. A., Crumpacker C., Schooley R. T., Hirsch M. S. Ribavirin antagonizes the effect of azidothymidine on HIV replication. Science. 1987 Mar 13;235(4794):1376–1379. doi: 10.1126/science.2435003. [DOI] [PubMed] [Google Scholar]
- Walker R. E., Parker R. I., Kovacs J. A., Masur H., Lane H. C., Carleton S., Kirk L. E., Gralnick H. R., Fauci A. S. Anemia and erythropoiesis in patients with the acquired immunodeficiency syndrome (AIDS) and Kaposi sarcoma treated with zidovudine. Ann Intern Med. 1988 Mar;108(3):372–376. doi: 10.7326/0003-4819-108-3-372. [DOI] [PubMed] [Google Scholar]
- Yarchoan R., Mitsuya H., Myers C. E., Broder S. Clinical pharmacology of 3'-azido-2',3'-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med. 1989 Sep 14;321(11):726–738. doi: 10.1056/NEJM198909143211106. [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]
- Zon L. I., Arkin C., Groopman J. E. Haematologic manifestations of the human immune deficiency virus (HIV). Br J Haematol. 1987 Jun;66(2):251–256. doi: 10.1111/j.1365-2141.1987.tb01307.x. [DOI] [PubMed] [Google Scholar]