INDUCTION OF BROAD DRUG-RESISTANCE IN SMALL-CELL LUNG-CANCER CELLS AND ITS REVERSAL BY PACLITAXEL

The H82 ''variant'' and the H69 ''classic'' small cell lung cancer (SC LC) cell lines were treated with low levels of epirubicin (69 and 14 n M) which caused little cell death but produced the H82/E8 and H69/E8 e xtended-multidrug resistant sublines. Both were resistant to drugs ass ociated with multidrug resistance (MDR), and to chlorambucil (9.5- and 5.6-fold, respectively) and cisplatin (2.3- and 8.5-fold, respectivel y). There was increased expression of the multidrug resistance-associa ted protein (MRP1) in the H82/E8 subline while P-glycoprotein expressi on was not detected in any cells or sublines. Treatment of the H82 cel ls for 1 hr with 69 nM epirubicin increased MRP1-mRNA expression withi n 4 hr and this was associated with an increase in the resistance to e pirubicin, chlorambucil, cisplatin and paclitaxel. Further, a 1 hr tre atment with non cytotoxic doses of chlorambucil (2.5 mu M), cisplatin (1.3 mu M) or paclitaxel (13 nM), drugs not normally associated with M RP1-mediated MDR, also increased MRP1-mRNA expression in the H82 cells with paclitaxel causing the highest increase (4.5-fold). For chloramb ucil treatment, this increased MRP1-mRNA expression was accompanied by increased drug resistance while paclitaxel treatment had no effect on drug resistance in the H82 cells. For the drug resistant H82/E8 subli ne, these drug treatments had no effect on the MRP1-mRNA expression an d little effect on increasing the subline drug resistance. However, pr etreatment with paclitaxel sensitised the H82/E8 subline to chlorambuc il and cisplatin returning the subline to the sensitivity of the H82 c ell line. We conclude that treatment with low levels of MDR and non-MD R drugs can induce extended-multidrug resistance in SCLC cells, a proc ess that probably involves the co-ordinate upregulation of MRP1 and ot her resistance mechanisms. The results also suggest paclitaxel may hav e a role as a response modifier in the treatment of refractory SCLC. ( C) 1998 Wiley-Liss, Inc.