SYNERGISTIC CYTOTOXICITY OF BCL-2 ANTISENSE OLIGODEOXYNUCLEOTIDES ANDETOPOSIDE, DOXORUBICIN AND CISPLATIN ON SMALL-CELL LUNG-CANCER CELL-LINES

Expression of Bcl-2 is life-sustaining for small-cell lung cancer cell s and associated with drug resistance. In the present study, the inter actions between the bcl-2 antisense oligodeoxynucleotide 2009 and the chemotherapeutic agents etoposide, doxorubicin and cisplatin were inve stigated on small-cell lung cancer cell lines to search for synergisti c combinations. The cell lines NCI-H69, SW2 and NCI-H82 express high. intermediate-high and low basal levels of Bcl-2, respectively, which a re inversely correlated with the sensitivities of the cell lines to tr eatment with oligodeoxynucleotide 2009 and the chemotherapeutic agents alone. Moreover, differences were found in the responsiveness of the cell lines to treatment with combinations of oligodeoxynucleotide 2009 and the chemotherapeutic agents. In the cell lines NCI-H69 and SW2, a ll combinations resulted in synergistic cytotoxicity. In NCI-H69 cells , maximum synergy with a combination index of 0.2 was achieved with th e combination of oligodeoxynucleotide 2009 and etoposide. In SW2 cells , the combination of oligodeoxynucleotide 2009 and doxorubicin was the most effective (combination index = 0.5). In the cell line NCI-H82, w hich expresses a low basal level of Bcl-2, most of the combinations we re slightly antagonistic. Our data suggest the use of oligodeoxynucleo tide 2009 in combination with chemotherapy for the treatment of small- cell lung cancer that overexpresses Bcl-2.