ZIDOVUDINE INDUCES THE EXPRESSION OF CELLULAR-RESISTANCE AFFECTING ITS ANTIVIRAL ACTIVITY

We have previously shown that multidrug-resistant cells expressing the multidrug transporter P-glycoprotein are less sensitive to the antivi ral activity of AZT. Subsequently, we addressed the question whether A ZT itself is able to induce cellular resistance to the drug. Indeed, C EM cells propagated in the presence of increasing concentrations of AZ T become resistant to the antigrowth and antiviral activity of AZT but do not express detectable level of P-glycoprotein. Sensitivity of the se cells to other compounds, such as vinblastine, vincristine, ddI, an d ddC remained unchanged, indicating that, in contrast to P-glycoprote in-positive cells, AZT-induced resistance is specific for AZT. Interes tingly, in AZT-induced resistant cells the intracellular accumulation of AZT and exogenous deoxythymidine, as well as thymidine kinase activ ity, are significantly reduced when compared with the parental cell li ne. Our findings show that AZT itself may directly induce the expressi on of cellular mechanisms leading to the acquisition of specific cellu lar resistance that can affect its antiviral activity.