Disease relevance of A-5021

• They were selected either because they are already approved for clinical use in the treatment of herpesvirus infections (acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir, brivudin, foscarnet and cidofovir) or have demonstrated marked activity against herpesviruses (lobucavir, H2G, A-5021, D/L-cyclohexenyl G and S2242) [1].
• We demonstrated that A-5021 had potent cytotoxic activity equal to that of GCV against the retroviral vector-mediated HSV-TK gene-transduced lung cancer cell lines [2].
• The bone marrow toxicity of A-5021 and GCV was studied by colony formation assay in both rodent and human bone marrow specimens [2].
• Avoidance of bone marrow suppression using A-5021 as a nucleoside analog for retrovirus-mediated herpes simplex virus type I thymidine kinase gene therapy [2].
• The new guanosine analogues (i.e. A-5021 and D- and L-cyclohexenyl G) were found to be particularly active against those viruses (HSV-1, HSV-2, VZV) that encode for a specific thymidine kinase (TK), suggesting that their antiviral activity (at least partially) depends on phosphorylation by the virus-induced TK [3].

High impact information on A-5021

• In contrast, A-5021 did not exhibit an inhibitory effect on bone marrow progenitor cells and colony formation (the 50% inhibitory concentration of the colony-forming units in culture = >100 microg/mL in human bone marrow specimens and >66 microg/mL in rodent bone marrow specimens) [2].
• Exogenously added guanosine reversed this potentiating effect, suggesting that a depletion of the endogenous dGTP pools enhanced the inhibitory effect of the 5'-triphosphate metabolite of A-5021 on the viral DNA polymerase [4].

Analytical, diagnostic and therapeutic context of A-5021

• These results indicate that A-5021 has potent cytotoxic activity as a nucleoside analog for gene therapy using HSV-TK gene, and can be used much more safely than GCV [2].

References