Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine

Purpose: Expression of P-glycoprotein (Pgp), which confers the multidrug re sistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at dose s required to achieve adequate cellular concentration. Toremifene is able t o reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo t oremifene is tightly bound to serum proteins, in particular the acute phase protein alpha(1)-acid glycoprotein (AAG), which may limit tissue availabil ity. In this phase I-II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo. Methods: Twenty-seven patients wi th metastatic RCC received escalating doses of oral toremifene for 3 days e very 2 weeks in combination with vinblastine 6 mg/m(2) i.v. on day 3 of eac h cycle. The serum concentration of toremifene, its metabolites and AAG wer e measured and the effect of patients' serum on inhibition of Pgp in vitro was determined. Results: Twenty-six patients were evaluable for response. E ight patients (31%) had stable disease and 18 patients (69%) progressive di sease. The mean serum concentration of toremifene at 780 mg daily for 3 day s was 7.82 mu M [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses M DR, was 5.13 mu M (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre -treatment AAG concentration was above that known to block the effects of t oremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123. Conclusions: We have shown that short course, high-dose toremifene in comb ination with vinblastine is generally well tolerated and that the concentra tion of toremifene required to reverse MDR in vitro is achievable in vivo.