INDUCTION OF DRUG-RESISTANT BLADDER-CARCINOMA CELLS IN-VITRO - IMPACTON POLYCHEMOTHERAPY WITH CISPLATIN, METHOTREXATE AND VINBLASTINE (CMV)

Residual tumor, tumor progression or relapse after chemotherapy of pat ients with advanced or metastasized transitional cell carcinoma of the bladder (TCCB) are suggested to reflect intrinsic drug resistance of cancer cells, or the development of chemotherapy-resistant tumor cell populations. The present study aimed to establish drug-resistant subcu lture cell lines from human TCCB, selected for anticancer drugs, admin istered in the cisplatin, methotrexate and vinblastine (CMV) polychemo therapy protocol. Tumor cells from chemonaive cell lines of human TCCB (HT1376, TCCSUP) have been exposed to progressively increasing concen trations of cis-diamminedichloroplatinum (II) (CDDP), methotrexate (MT X), vinblastine (VBL) or etoposide (VP16). The resulting drug-resistan t subculture cell lines (HT1376-CDDP, HT1376-MTX, HT1376-VBL, HT1376-V P, TCCSUP-CDDP, TCCSUP-MTX, TCCSUP-VBL, TCCSUP-VP) were analyzed with regard to the achieved resistance factor (RF) for the inductive antica ncer agent, the acquisition of cross-resistance, DNA content, cell cyc le distribution and cellular morphology. Parental HT1376 cells were in trinsically less sensitive to all anticancer drugs (1.7-50x), compared with TCCSUP cells. Relative resistance against the inductive anticanc er agents was similar for the final drug-resistant subculture cell lin es of both parental cell lines concerning CDDP and VP-16 (RF: 4-5x), b ut were reciprocal for MTX and VBL, respectively. MTX led to much stro nger resistance(RF > 200) than the other drugs (RF < 10). Pleiotropic cross-resistances were observed in six out of eight (75%) drug-resista nt subculture cell lines. Highest RF (50-500x) and frequency of cross- resistance (five of six cell lines) occured for MTX, and the least fro m exposure to CDDP (one of six cell lines). Overall, the results corro borated the central role of CDDP against urothelial carcinoma whereas repetitive applications of MTX appeared to be a doubtful strategy. Mor eover, the experiments provide the largest panel so far of drug-resist ant cell lines of human TCCB. They represent an appropriate tool for b asic research on drug-resistance mechanisms, for the development and s creening of future anticancer drugs or to elaborate strategies to over come drug resistance for those patients who ultimately fail to respond to standard chemotherapy.