EVALUATION OF MULTIPLE-DRUG RESISTANCE IN HUMAN BLADDER-CANCER CELL-LINES

We evaluated multidrug resistance (MDR) in human bladder cancer cell l ines UM-UC-2, UM-UC-6, UM-UC-9 and the UM-UC-6dox subline induced to d oxorubicin resistance by in vitro doxorubicin exposure. We compared th e profile of multidrug resistance in these cell lines with that of the UM-UC-3 human renal cancer cell line. Of these cell lines, UM-UC-2 wa s most sensitive to both doxorubicin and etoposide, while UM-UC-6, UM- UC-9 and UM-UC-3 showed 1.5-, 2.1-, and 5.4-fold more resistance to do xorubicin than UM-UC-2 cells. These cell lines were also more resistan t to etoposide than UM-UC-2. Addition of verapamil at 10 muM. reduced the doxorubicin resistance in UM-UC-6 and UM-UC-6dox cells, but UM-UC- 9 cells showed little change in doxorubicin sensitivity in the presenc e of verapamil. In a model of intravesical (short-term) treatment vera pamil increased the doxorubicin sensitivity of UM-UC-6dox but not that of UM-UC-6 cells. This effect in UM-UC-6dox cells was enhanced by con tinuously treating with verapamil after doxorubicin had been removed. Western blot analysis with rabbit anti-human P-glycoprotein polyclonal antibody demonstrated a distinct increase in P-glycoprotein in the re sistant cell lines as compared with UM-UC-2. P-glycoprotein expression was roughly proportional to the degree of resistance to both doxorubi cin and etoposide, but did not always correlate with the effect of ver apamil on decreasing doxorubicin resistance. These results suggest tha t multidrug resistance is an important phenomenon in bladder cancer an d that more than one pathway of multidrug resistance may be present in human bladder cancer cell lines.