Azidothymidine resistance of H9 human T-cell lymphoma cells is associated with decreased sensitivity to antitumor agents and inhibition of apoptosis

Biology of HIV-1 associated neoplasias is modulated by viral and host facto rs. In addition the development of tumors and their response to therapy may be further influenced by long-term treatment of HIV-1 patients with nucleo side analogs such as AZT (3'-azido-3'deoxythymidine), ddI (2',3'-dideoxyino sine), ddC (2',3'-dideoxycytidine), d4T (2',3'-didehydro-2'3'-dideoxythymid ine), and 3TC [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine] alone or in combin ation. As these compounds can trigger mechanisms involved in chemoresistanc e, we tested whether prolonged in vitro treatment of H9 cells (T-cell lymph oma) with AZT alters sensitivity of lymphoma cells to antitumor agents used for AIDS-associated malignancies. H9 cells grown for more than two years i n medium containing 250 mu M AZT developed resistance to the toxic effects of AZT while retaining sensitivity for other nucleoside analogs including d dC or cytosine arabinoside (ARA-C). These cells designated H9(r)AZT(250) we re 2 to 10-fold less sensitive to the toxic effects of antitumor agents, in cluding cisplatin (CDDP), vincristine (VCR), doxorubicin (DOX) and etoposid e (VP-16), when compared with parental H9 cells. The resistance of H9(r)AZT (250) cells to antitumor agents was associated with inhibition of apoptosis as demonstrated by ultrastructural investigations and DNA-fragmentation as say (ELISA). The expression of the antiapoptotic gene bcl-2 was increased i n H9(r)AZT(250) cells while expression of other genes involved in the regul ation of apoptosis such as c-myc, p53 and Fas was not changed. These result s demonstrate that prolonged in vitro treatment of H9 lymphoma cells with A ZT results in the development of resistance to antitumor agents in associat ion with inhibition of apoptosis and increased expression of bcl-2. Therefo re AZT long-term treatment of some HIV-1 patients with malignancies may hav e affected behavior of tumor cells including response to therapy.