EFFECTS OF TUBULIN-INHIBITING AGENTS IN HUMAN LUNG AND BREAST-CANCER CELL-LINES WITH DIFFERENT MULTIDRUG-RESISTANCE PHENOTYPES

Drug sensitivity was studied for the tubulin inhibitors taxol, taxoter e, rhizoxin and for doxorubucin and cisplatin, in human lung and breas t cancer cell lines, including drug-selected cell lines, overexpressin g the membrane transporter P-glycoprotein (Pgp) or the multidrug resis tance protein (MRP). All tubulin-inhibiting agents were more potent th an doxorubicin and cisplatin in all cell lines. In the drug resistance -selected cell lines (doxorubicin or mitoxantrone resistant) there was cross-resistance between the tubulin inhibitors and the selecting age nt; however, MRP overexpressing cells were relatively less resistant t o taxanes than the Pgp overexpressing cells. Polymerization of microtu bules after exposure to taxol was observed in drug sensitive cell line s, but not in resistant cell lines, even at high taxol concentrations and after long exposure times. In the Pgp overexpressing cell lines, s teady accumulation of C-14-taxol was defective and could be reverted b y verapamil. MRP overexpressing cells did not have a significant accum ulation defect of taxol, compared to the parental cell lines, and vera pamil did not have any effect. These data confirm that the Pgp overexp ression is an important mechanism of resistance to taxanes and rhizoxi n in human lung and breast tumor cells. However, the presence of mecha nims other than transport defects may play an important role in non-Pg p expressing cells, and these may include an altered function of tubul ins.