Anticancer benefits of early versus late use of rapamycin in a rat model of urothelial carcinoma.

BACKGROUND: We previously reported both in vivo and in vitro effects of rapamycin on urothelial carcinoma. Clinically, the use of rapamycin could not completely prevent the recurrence of urothelial carcinoma. Therefore, we designed this study to compare the difference of efficacy between early and late use of rapamycin in a rat model of urothelial carcinoma. METHODS: The rat model of urothelial carcinoma was induced by adding 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to the drinking water for up to 20 weeks in male Fisher-344 rats. Rapamycin was fed orally from the 1st day, 5th week, 9th week, 13th week, and 17th week. The antitumor effects of different periods of rapamycin treatment were assessed grossly and microscopically. RESULTS: Papillary tumors of urinary bladder were successfully induced in the BBN group. Simultaneous use of rapamycin and BBN from the 1st day of treatment significantly reduced the tumor growth in urinary bladder: 80% of the rats had no tumor and 20% had low-grade tumors. Adding rapamycin from the 5th week was associated with more tumor growth: 20% of the rats had no tumors, 20% had low-grade tumors, and 60% had high-grade tumors. Moreover, in the groups with rapamycin treatment from the 9th week, 13th week, and 17th week, all rats developed high-grade papillary tumors in urinary bladder, as did the control group that received no rapamycin. CONCLUSIONS: The study results suggest that the anticancer effect of rapamycin on urothelial carcinoma is stage dependent. Early use of rapamycin provides better anticancer effect, whereas late use of rapamycin fails to inhibit the cancer growth.

Reduced variability of tacrolimus trough level in once-daily tacrolimus-based Taiwanese kidney transplant recipients with high-expressive genotype of cytochrome P450 3A5.

BACKGROUND: Our previous study results indicated that conversion from twice-daily Prograf to once-daily Advagraf associated with lower variability of tacrolimus blood trough level. Some factors, such as frequency of interaction by food exposure, expression of cytochrome P450 3A5 genetic polymorphism, and other interactions of unknown factors, could be the reasons for the change of variability. We aimed to clarify the impact of cytochrome P450 3A5 genetic polymorphism on the variability of tacrolimus blood trough level in Taiwanese kidney transplant recipients. METHODS: We collected blood samples from kidney transplant recipients to prepare DNA and then performed single-nucleotide polymorphism genotyping by using the restriction fragment length polymorphism. RESULTS: We found that 79 (52.7%) of 150 kidney transplant recipients had the low-expressive genotype (CYP3A5*3/*3), whereas the other 71 (47.3%) kidney transplant recipients had high-expressive genotype (CYP3A5*1/*1 and CYP3A5*1/*3). The prevalence of high-expressive genotype is higher than previous reports from western countries. Compared with the patients with high-expressive genotype, the average dose-normalized trough level of tacrolimus was significantly higher in patients with low-expressive genotype. Interestingly, when patients converted from twice-daily Prograf to once-daily Advagraf, the percent coefficient of variation of tacrolimus trough level was significantly decreased in patients with high-expressive genotype. CONCLUSION: This study suggested that there is a potential benefit for kidney transplant recipients with cytochrome P450 3A5 high-expressive genotype (*1/*1 or *1/*3) to convert from Prograf to once-daily Advagraf.