Overexpression of
P-glycoprotein (P-gp) has been implicated as the mechanism of multidrug resistance (MDR) in a number of human
cancers, including
carcinoma of the breast. We conducted a clinical trial to determine whether the P-gp inhibitor,
trifluoperazine, could sensitize patients with refractory
breast cancer to
vinblastine chemotherapy. Adult patients with histologically confirmed, refractory, advanced
breast cancer were treated with
vinblastine at a dose of 1.7 mg/m2 per day by continuous infusion for five consecutive days. Patients who did not respond after two cycles were subsequently treated with
vinblastine plus
trifluoperazine at a dose of 8 mg twice daily during the five days of
chemotherapy. In patients from whom
tumor samples were available, the expression of P-gp was determined by immunocytochemistry. Of 35 patients enrolled, 30 were evaluable, 2 of whom (7%) achieved a partial response to
vinblastine alone. Among the 16 patients treated with
vinblastine plus
trifluoperazine there was one response (6%) which lasted 16 weeks.
Tumor samples were available from 16 patients, and 14 (87%) were immunoreactive for P-pg. P_pg expression was detected both in the patient who responded to
vinblastine plus
trifluoperazine and in one of the two patients who responded to
vinblastine alone. Continuous-infusion
vinblastine demonstrated limited activity in this study. Furthermore,
trifluoperazine did not effectively reverse established resistance to
vinblastine. This failure may be related the presence of multiple mechanisms of drug resistance in the heavily pretreated population, or because ineffective concentrations of the modulator were achieved in vivo. Future studies should evaluate more effective modulators, and attempt to reverse MDR earlier in the course of treatment, before other forms of resistance can develop.