EFFECTS OF C-MYC ONCOGENE MODULATION ON DRUG-RESISTANCE IN HUMAN SMALL-CELL LUNG-CARCINOMA CELL-LINES

Small cell lung carcinoma (SCLC) is characterized by rapid development of resistance to drugs, such as cis-diamminedichloroplatinum(II) (cDD P) and anthracyclines. The molecular basis for resistance to cDDP and adriamycin (Adr) is poorly understood. One of the genetic alterations observed in SCLC, which is correlated with poor prognosis, is amplific ation and overexpression of c-myc oncogene. Therefore, activation of t he c-myc oncogene might form a basis for resistance. The relationship between c-myc and cDDP as well as Adr resistance was analyzed by down- regulation of endogenously expressed c-myc in the human SCLC cell line GLC(4), and its cDDP and Adr resistant sublines (GLC(4)-cDDP and GLC( 4)-Adr). Cells were incubated with an unmodified antisense (AS) oligod eoxynucleotide complementary to the first 5 codons of the c-myc mRNA i n serum free culture medium. Pre-incubation with 15 mu M AS c-myc, red uced c-myc protein expression and induced 30-35% growth inhibition in all 3 cell lines. It resulted in increased cDDP sensitivity in GLC(4)- cDDP but not affect Adr sensitivity in all lines. The effect of AS c-m yc pretreatment in cDDP resistance was not mediated by changes in cell cycle distribution. These findings suggest that c-myc plays a role in cDDP resistance by effects other than those on cell cycle distributio n.