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. 1993 Jun;92(3):455–459. doi: 10.1111/j.1365-2249.1993.tb03420.x

In vitro immunotoxicity of +/- 2'-deoxy-3'-thiacytidine, a new anti-HIV agent.

G Lisignoli 1, M C Monaco 1, A Degrassi 1, S Toneguzzi 1, E Ricchi 1, P Costigliola 1, A Facchini 1
PMCID: PMC1554772  PMID: 8390335

Abstract

The present study compares the in vitro effect of (+/-)-2'-deoxy-3'-thiacytidine (BCH 189) a new synthetic anti-HIV-1 dideoxynucleoside, with 3'-azido-3'-deoxythymidine (AZT) on the immune function of lymphocytes from 10 normal and 12 HIV-1+ patients (CDC II and III). The effect of different doses of BCH 189 and AZT was analysed in vitro on: (i) T cell proliferation after stimulation with concanavalin A (Con A) or anti-CD3 MoAb; (ii) B cell proliferation and immunoglobulin production after stimulation with pokeweed mitogen (PWM); (iii) cytokine production (IL-2, IL-6, GM-CSF, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) from lymphocytes stimulated with anti-CD3 MoAb or phytohaemagglutinin (PHA). BCH 189 inhibited the proliferation of B and T lymphocytes from normal and HIV+ subjects less than AZT; even if lymphocytes from HIV+ (CDC III) subjects produced higher levels of IL-6 and TNF-alpha, neither BCH 189 nor AZT molecule interfered with cytokine release. Immunoglobulin production from B lymphocytes was inhibited only by a high concentration (50 microM) of BCH 189 or AZT. These results show that BCH 189 affects lymphocyte proliferation in vitro less than AZT, and support its use in clinical trials in HIV-infected patients.

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Selected References

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  1. Amadori A., Zamarchi R., Veronese M. L., Panozzo M., Barelli A., Borri A., Sironi M., Colotta F., Mantovani A., Chieco-Bianchi L. B cell activation during HIV-1 infection. II. Cell-to-cell interactions and cytokine requirement. J Immunol. 1991 Jan 1;146(1):57–62. [PubMed] [Google Scholar]
  2. Borzì R. M., Dal Monte P., Honorati M. C., Facchini A. IgG subclass distribution of anti-HBs antibodies following vaccination with cDNA HBsAg. J Immunol Methods. 1992 Jan 21;146(1):17–23. doi: 10.1016/0022-1759(92)90043-s. [DOI] [PubMed] [Google Scholar]
  3. Breen E. C., Rezai A. R., Nakajima K., Beall G. N., Mitsuyasu R. T., Hirano T., Kishimoto T., Martinez-Maza O. Infection with HIV is associated with elevated IL-6 levels and production. J Immunol. 1990 Jan 15;144(2):480–484. [PubMed] [Google Scholar]
  4. Broder S., Mitsuya H., Yarchoan R., Pavlakis G. N. NIH conference. Antiretroviral therapy in AIDS. Ann Intern Med. 1990 Oct 15;113(8):604–618. doi: 10.7326/0003-4819-113-8-604. [DOI] [PubMed] [Google Scholar]
  5. Chen C. H., Cheng Y. C. Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2',3'-dideoxycytidine. J Biol Chem. 1989 Jul 15;264(20):11934–11937. [PubMed] [Google Scholar]
  6. Chen C. H., Vazquez-Padua M., Cheng Y. C. Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol. 1991 May;39(5):625–628. [PubMed] [Google Scholar]
  7. Coates J. A., Cammack N., Jenkinson H. J., Jowett A. J., Jowett M. I., Pearson B. A., Penn C. R., Rouse P. L., Viner K. C., Cameron J. M. (-)-2'-deoxy-3'-thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro. Antimicrob Agents Chemother. 1992 Apr;36(4):733–739. doi: 10.1128/aac.36.4.733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coates J. A., Cammack N., Jenkinson H. J., Mutton I. M., Pearson B. A., Storer R., Cameron J. M., Penn C. R. The separated enantiomers of 2'-deoxy-3'-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro. Antimicrob Agents Chemother. 1992 Jan;36(1):202–205. doi: 10.1128/aac.36.1.202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hart G. J., Orr D. C., Penn C. R., Figueiredo H. T., Gray N. M., Boehme R. E., Cameron J. M. Effects of (-)-2'-deoxy-3'-thiacytidine (3TC) 5'-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerases alpha, beta, and gamma. Antimicrob Agents Chemother. 1992 Aug;36(8):1688–1694. doi: 10.1128/aac.36.8.1688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Honda M., Kitamura K., Mizutani Y., Oishi M., Arai M., Okura T., Igarahi K., Yasukawa K., Hirano T., Kishimoto T. Quantitative analysis of serum IL-6 and its correlation with increased levels of serum IL-2R in HIV-induced diseases. J Immunol. 1990 Dec 15;145(12):4059–4064. [PubMed] [Google Scholar]
  11. Mitsuya H., Yarchoan R., Kageyama S., Broder S. Targeted therapy of human immunodeficiency virus-related disease. FASEB J. 1991 Jul;5(10):2369–2381. doi: 10.1096/fasebj.5.10.1712326. [DOI] [PubMed] [Google Scholar]
  12. Nakajima K., Martínez-Maza O., Hirano T., Breen E. C., Nishanian P. G., Salazar-Gonzalez J. F., Fahey J. L., Kishimoto T. Induction of IL-6 (B cell stimulatory factor-2/IFN-beta 2) production by HIV. J Immunol. 1989 Jan 15;142(2):531–536. [PubMed] [Google Scholar]
  13. Rooke R., Parniak M. A., Tremblay M., Soudeyns H., Li X. G., Gao Q., Yao X. J., Wainberg M. A. Biological comparison of wild-type and zidovudine-resistant isolates of human immunodeficiency virus type 1 from the same subjects: susceptibility and resistance to other drugs. Antimicrob Agents Chemother. 1991 May;35(5):988–991. doi: 10.1128/aac.35.5.988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Soudeyns H., Yao X. I., Gao Q., Belleau B., Kraus J. L., Nguyen-Ba N., Spira B., Wainberg M. A. Anti-human immunodeficiency virus type 1 activity and in vitro toxicity of 2'-deoxy-3'-thiacytidine (BCH-189), a novel heterocyclic nucleoside analog. Antimicrob Agents Chemother. 1991 Jul;35(7):1386–1390. doi: 10.1128/aac.35.7.1386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Vyakarnam A., Matear P., Meager A., Kelly G., Stanley B., Weller I., Beverley P. Altered production of tumour necrosis factors alpha and beta and interferon gamma by HIV-infected individuals. Clin Exp Immunol. 1991 Apr;84(1):109–115. doi: 10.1111/j.1365-2249.1991.tb08132.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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