Wakao Sato

Reversal of multidrug resistance by a novel quinoline derivative, MS-209

MS-209, a novel quinoline derivative, was examined for its reversing effect on multidrug-resistant tumor cells. MS-209 at 1–10 μM completely reversed resistance against vincristine (VCR) in vitro in multidrug-resistant variants of mouse leukemia P388 cells (VCR-resistant P388/VCR and Adriamycin (ADM)-resistant P388/ADM) and human leukemia K562 cells (VCR-resistant K562/VCR and ADM-resistant K562/ADM). MS-209 at 1–10 μM also completely reversed resistance against ADM in vitro in P388/VCR cells, K562/VCR cells, and K562/ADM cells. In ADM-resistant P388 (P388/ADM) cells, however, ADM resistance was only partially reversed at the MS-209 concentrations tested. MS-209 enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. When MS-209 was given p.o. at 80 mg/kg twice a day (total dose, 160 mg/kg per day) with 100 μg/kg VCR, a treated/control (T/C) value of 155% was obtained. MS-209 also enhanced the chemotherapeutic effect of ADM in P388/ADM-bearing mice. The most prominent effects were obtained when MS-209 was given with 2 mg/kg ADM, yielding T/C values of 150%–194% for the combined treatment at an MS-209 dose of 200–450 mg/kg. MS-209 inhibited [3H]-azidopine photolabeling of P-glycoprotein efficiently. Furthermore, the accumulation of ADM in K562/ADM cells was increased more eficiently by MS-209 than by verapamil. These results indicate that MS-209, like verapamil, directly interacts with P-glycoprotein and inhibits the active efflux of antitumor agents, thus overcoming multidrug resistance in vitro and in vivo.

Dofequidar Fumarate (MS-209) in Combination With Cyclophosphamide, Doxorubicin, and Fluorouracil for Patients With Advanced or Recurrent Breast Cancer

PURPOSE To evaluate the efficacy and tolerability of dofequidar plus cyclophosphamide, doxorubicin, and fluorouracil (CAF) therapy in comparison with CAF alone, in patients with advanced or recurrent breast cancer. Dofequidar is a novel, orally active quinoline derivative that reverses multidrug resistance. PATIENTS AND METHODS In this randomized, double-blind, placebo-controlled trial, patients were treated with six cycles of CAF therapy: 28 days/cycle, with doxorubicin (25 mg/m2) and fluorouracil (500 mg/m2) administered on days 1 and 8 and cyclophosphamide (100 mg orally [PO]) administered on day 1 through 14. Patients received dofequidar (900 mg PO) 30 minutes before each dose of doxorubicin. Primary end point was overall response rate (ORR; partial or complete response). In total, 221 patients were assessable. RESULTS ORR was 42.6% for CAF compared with 53.1% for dofequidar + CAF, a 24.6% relative improvement and 10.5% absolute increase (P = .077). There was a trend for prolonged progression-free survival (PFS; median 241 days for CAF v 366 days for dofequidar + CAF; P = .145). In retrospectively defined subgroups, significant improvement in PFS in favor of dofequidar was observed in patients who were premenopausal, had no prior therapy, and were stage IV at diagnosis with an intact primary tumor. Except for neutropenia and leukopenia, there was no statistically significant excess of grade 3/4 adverse events compared with CAF. Treatment with dofequidar did not affect the plasma concentration of doxorubicin. CONCLUSION Dofequidar + CAF was well tolerated and is suggested to have efficacy in patients who had not received prior therapy.

Relationship between multidrug resistant gene expression and multidrug resistant-reversing effect of MS-209 in various tumor cells

MS-209 is a novel quinoline compound which can overcome multidrug resistance (MDR) both in vitro and in vivo, while having a low level of side effects, and is now being evaluated in a clinical phase II study. Reverse transcription-polymerase chain reaction (RT-PCR) was used to quantitative the expression levels ofMDR genes in various mouse and human tumor cell lines. TheMDR gene and the βactin gene, as the internal reference standard, were coamplified separately, and the relative expression of theMDR gene was represented by the MDR/β actin ratio. The in vitro MDR-reversing effect of MS-209 was then compared with theMDR gene expression (MDR/β actin ratio). We found a significant correlation between these two parameters. Moreover, a significant correlation was also observed between the level of expression of theMDR1 gene and that of P-glycoprotein in human cell lines. Therefore, the efficacy of MS-209 seems to specifically depend on the level ofMDR gene expression (P-glycoprotein). From these observations, it is suggested that RT-PCR assays ofMDR1 gene in tumor biopsy specimens might be an effective means to predict the response of tumor cells to combination therapy with MS-209.