DRUG-RESISTANCE CONFERRED BY MDR1 EXPRESSION IN SPHEROIDS FORMED BY GLIOBLASTOMA CELL-LINES

Three-dimensional cell cultures (spheroids) provide an in vitro approx imation of solid tumors in vivo. Some mechanisms of dug resistance wer e reported to differ in their effects on monolayer and spheroid cells. We have compared the effect of the expression of P-glycoprotein (Pgp) , the MDR1 gene product, on vinblastine resistance in two glioblastoma lines, U87 and U251, grown as either monolayers or spheroids. U87 cel ls form spheroids spontaneously and the spheroids continue to grow, wh ile U251 cells form spheroids only when plated over agarose and do not proliferate in spheroids. U87 cells are equally resistant to vinblast ine in monolayer and in spheroids, while U251 cells are 4.5 rimes more resistant in spheroids than in monolayers. The distribution of a fluo rescent vinblastine derivative in cells of spheroids was more heteroge neous than in monolayers MDR1-expressing U87 cells increased their res istance 9-fold in monolayer and 50-fold in spheroids, while MDR1 trans duction of U251 cells made them 20-fold more resistant in monolayer an d 160-fold more resistant in spheroids. MDR1 expression in both cell l ines decreased the accumulation of H-3-vinblastine and fluorescent vin blastine derivative. These results indicate that MDR1 is more efficien t in conferring drug resistance in spheroids than in monolayer cells.