Zidovudine Induces Resistance to Antineoplastic Agents and Alterations in Apoptosis in T-Cell Lymphoma Cells

Abstract

Prolonged treatment of leukemic cell lines with antiretroviral agents such as nucleoside analogues may result in the development of cell resistance against antiviral agents. We tested whether prolonged treatment of H9 cells (T-cell lymphoma cell line) with 3′-azido-3′-deoxythymidine (AZT) interferes with sensitivity to antitumor agents commonly used for treatment of AIDS-associated malignancies. H9 cells grown for more than 2 years in medium containing 250 µM of AZT were at least 100-fold less sensitive to cytotoxic effects of AZT than parental H9 cell line. These cells designated H9^rAZT²⁵⁰ were 5- to 20-fold less sensitive to toxic effects of antitumor agents including cisplatin (CP), vincristine (VIN), doxorubicin (DOX) and etoposide (VP-16). The resistance to these drugs was associated with inhibition of apoptosis as demonstrated by the terminal deoxynucleotidyl transferase-mediated nicked-end labelling (TUNEL) assay and DNA fragmentation assay. The expression of genes involved in regulation of apoptosis such bd-2 was enhanced in H9^rAZT ²⁵⁰ cells. The results demonstrate that prolonged treatment of tumor cells with AZT may result in the development of resistance to antineoplastic agents due to the inhibition of apoptosis.