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Abstract
3$\sp\prime$-azido-3$\sp\prime$-deoxythymidine (AZT) is the first approved drug for treatment of AIDS. Its major dose-limiting toxicity is myelosuppression. Elucidation of the underlying mechanism(s) of this toxicity is important for the development of new anti-HIV nucleoside analogs and combination therapies. The cellular pharmacology of three structurally related 2$\sp\prime$,3$\sp\prime$-dideoxynucleoside analogs, AZT, 3$\sp\prime$-azido-2$\sp\prime$,3$\sp\prime$-dideoxyuridine (AzdU), and 2$\sp\prime$,3$\sp\prime$-didehydro-2$\sp\prime$,3$\sp\prime$-dideoxythymidine (D4T) has been studied to gain insights into the interaction of these compounds with human host cells.
The studies were performed in human bone marrow (BM) cells and human peripheral blood mononuclear (PBM) cells and demonstrated the following: AZT-5$\sp\prime$-monophosphate was the predominant metabolite of AZT; AZT only caused a transient decline of intracellular dTTP level; most importantly, AZT was incorporated into host cellular DNA; this incorporation correlated to a certain degree with its in vitro hematopoietic toxicity. AzdU was phosphorylated to its 5$\sp\prime$-mono- and 5$\sp\prime$-di-phosphates in both BM and PBM cells, whereas AzdU-5$\sp\prime$-triphosphate was only found in PBM cells; AzdU-diphosphohexose derivatives were discovered in both cell systems, probably being formed from AzdU-TP; no incorporation of AzdU into DNA was observed. D4T-5$\sp\prime$-triphosphate was the predominant metabolite of D4T in both BM cells and mitogen-stimulated PBM cells; D4T was incorporated into cellular DNA but was excised upon removal of the drug from the medium.
In conclusion, the three compounds studied have different intracellular metabolic profiles; incorporation of AZT into cellular DNA appears important for its cytotoxicity while the depletion of intracellular dNTPs may not be critical; the unique metabolic pathways of AzdU in BM and PBM cells are important for the lack of bone marrow toxicity of AzdU and may also play a role in the mechanism of action of this agent; and excision of D4T from DNA may partially explain the lack of toxicity of D4T to BM cells.
