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Chemical Compound Review

AZT-ddC     [(2S,5R)-5-(4-amino-2-oxo- pyrimidin-1...

Synonyms: AC1LATVI
 
 
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Disease relevance of AZT-ddC

  • Resistance of HIV-1 reverse transcriptase (RT) to nucleoside analogs (e.g. AZT, ddC and 3TC) is conferred by various amino acid substitutions or combinations thereof on the RT molecule [1].
  • This severe in vitro toxicity of ddC and the synergistic toxicity of AZT-ddC combinations on hemopoietic progenitor cells should be considered when the two drugs are administered in concurrent or alternating regimens [2].
  • The HIV protease inhibitors (PI) represent a promising alternative to the reverse transcriptase (RT) inhibitors (AZT, ddC, ddI) hitherto used with limited success for HIV chemotherapy [3].
  • No serious side effects have been observed with either combination therapy (AZT/ddC or AZT/ddI) although not surprisingly, patients receiving ddI were more likely to suffer gastrointestinal side effects and those receiving ddC were more likely to suffer from peripheral neuropathy [4].
 

High impact information on AZT-ddC

  • Only one strain obtained after AZT/ddC therapy showed reduced susceptibility to ddC in addition to AZT and had previously unreported amino acid substitutions in the viral polymerase-encoding pol region, whereas three other strains had one or more of the five previously reported AZT-related mutations [5].
  • In particular, the EC50 of AZT, ddC, and ddI in M/M is 2- to 100-fold lower than that found in lymphocytes [6].
  • In this study, we assessed the in vitro antiviral efficacy of two gene therapy strategies (trans-dominant RevM10, Gag antisense RNA) in combination with clinically relevant RT (AZT, ddC) or PR (indinavir) inhibitors [7].
  • Similarly, IDV/AZT, IDV/ddC and IDV/AZT/ddC combinations does not strenghten the modulation of TNF-alpha, IFN-gamma and IL-4 induced by AZT, ddC and AZT/ddC [8].
  • In clinical studies, AZT/ddI in combination, tended to have a more positive effect on CD4 cell count than the AZT/ddC combination, although the difference was statistically significant only when baseline CD4 count was greater than 100 cells/mm3 [4].
 

Anatomical context of AZT-ddC

  • The rate of occurrence of typical microvascular retinopathy with cotton-wool exudates was lower in patients receiving combination treatment than in those given monotherapy [10 patients (26%) receiving AZT/ddC vs 23 patients (56%) given AZT; P < or = 0.01, chi-square test] [9].
 

Analytical, diagnostic and therapeutic context of AZT-ddC

References

  1. Endogenous reverse transcriptase assays reveal synergy between combinations of the M184V and other drug resistance-conferring mutations in interactions with nucleoside analog triphosphates. Quan, Y., Gu, Z., Li, X., Liang, C., Parniak, M.A., Wainberg, M.A. J. Mol. Biol. (1998) [Pubmed]
  2. In vitro synergistic inhibition of human bone marrow hemopoietic progenitor growth by a 3'-azido-3'-deoxy-thymidine, 2',3'-dideoxycytidine combination. Lerza, R., Castello, G., Mela, G.S., Arboscello, E., Cerruti, A., Bogliolo, G., Mencoboni, M., Ballarino, P., Pannacciulli, I. Exp. Hematol. (1997) [Pubmed]
  3. Retroviral proteases: structure, function and inhibition from a non-anticipated viral enzyme to the target of a most promising HIV therapy. von der Helm, K. Biol. Chem. (1996) [Pubmed]
  4. Studies of zidovudine in combination with didanosine and zalcitabine. Jablonowski, H. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. (1995) [Pubmed]
  5. Changes in drug sensitivity of human immunodeficiency virus type 1 during therapy with azidothymidine, dideoxycytidine, and dideoxyinosine: an in vitro comparative study. Shirasaka, T., Yarchoan, R., O'Brien, M.C., Husson, R.N., Anderson, B.D., Kojima, E., Shimada, T., Broder, S., Mitsuya, H. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  6. Inhibition of replication of HIV in primary monocyte/macrophages by different antiviral drugs and comparative efficacy in lymphocytes. Aquaro, S., Perno, C.F., Balestra, E., Balzarini, J., Cenci, A., Francesconi, M., Panti, S., Serra, F., Villani, N., Caliò, R. J. Leukoc. Biol. (1997) [Pubmed]
  7. Antiviral potency of drug-gene therapy combinations against human immunodeficiency virus type 1. Junker, U., Baker, J., Kalfoglou, C.S., Veres, G., Kaneshima, H., Böhnlein, E. AIDS Res. Hum. Retroviruses (1997) [Pubmed]
  8. Effect of indinavir used alone or in double or triple combination with AZT and ddC on human immune functions. Mattioli, B., Giordani, L., Quaranta, M.G., Viora, M. Life Sci. (2004) [Pubmed]
  9. Cytomegalovirus retinitis under combination therapy with zidovudine and dideoxycytidine in advanced human immunodeficiency virus infection. Kaulen, P., Pham, D.T., Baranowski, E., Wollensak, J. German journal of ophthalmology. (1993) [Pubmed]
  10. Antiviral effects of 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, and 2',3'-dideoxyadenosine against simian acquired immunodeficiency syndrome-associated type D retrovirus in vitro. Tsai, C.C., Follis, K.E., Benveniste, R.E. AIDS Res. Hum. Retroviruses (1988) [Pubmed]
 
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