Impact of SLCO1B1 521T > C variant on leucovorin rescue and risk of relapse in childhood acute lymphoblastic leukemia treated with high-dose methotrexate.

BACKGROUND: Recent studies suggest that SLCO1B1 c.521T > C variant decreases the clearance of methotrexate (MTX) and elevates its plasma concentration, hence leucovorin doses may need to be adjusted. However, high leucovorin doses may affect the cure rate in childhood acute lymphoblastic leukemia (ALL). Hitherto neither the appropriate dose of leucovorin in carriers of SLCO1B1 c.521T > C variant nor the impact of SLCO1B1 polymorphism on the risk of ALL relapse has been clarified. PROCEDURE: A double-blind and controlled study was conducted in 136 children with ALL. They were genotyped for rs4149056 single nucleotide polymorphism into wild-type group and variant group, and received MTX at 3-5 g/m(2) . Plasma concentration MTX and its metabolite were determined by HPLC. The toxicity of MTX, dose of leucovorin and 5-year relapse rate of ALL were recorded. RESULTS: Compared with wild-type group, area under the concentration time curve of MTX increased by 4.2-fold and peripheral clearance rate decreased significantly in variant group. Patients carrying rs4149056 C allele endured a remarkable longer time above the MTX safety threshold and suffered from a higher frequency of toxicity, so 2.2-fold leucovorin was given. However, no association was found between SLCO1B1 c.521T > C variant and the relapse risk in five years. CONCLUSIONS: The SLCO1B1 c.521T > C variant was an important determinant of MTX disposition and their carriers were exposed to increased intensity and time of MTX. An appropriate leucovorin dose raise in variant group was beneficial to reducing the serious toxicity. The c.521T > C variant wasn't associated with the risk of ALL relapse.

Protective effects of neferine on amiodarone-induced pulmonary fibrosis in mice.

The effects of neferine, a bisbenzylisoquinline alkaloid extracted from the Chinese traditional medicine seed embryo of Nelumbo nucifera Gaertn, on amiodarone-induced pulmonary fibrosis in mice were evaluated. Adult Kunming mice were induced to develop pulmonary fibrosis through intratracheal instillation of amiodarone (6.25 mg/kg) on the 1st, 3rd and 5th day. Mice were treated orally with saline, neferine (20 mg/kg), prednisolone (15 mg/kg), pirfenidone (100 mg/kg) twice a day after the third amiodarone instillation. On Day 21, all the lung tissues were collected for hydroxyproline measurement and the histological examination by hematoxylin-eosin and Masson staining. All the blood sample were collected for surfactant protein-D (SP-D) levels assay, Th1/Th2 balance valuation, CD4+CD25+ regulatory T cells (Tregs) analysis by Enzyme-linked immunosorbent assay and flow cytometry. Our data showed that neferine significantly restored the significant reductions in body weights, the increased levels of lung index and hydroxyproline, the abnormal histological findings, the serum SP-D increase, the Th1/Th2 imbalance by decreasing IL-4 and increasing IFN-γ levels and the increases in the population of CD4+CD25+ Tregs associated with amiodarone instillation in mice. Similar changes were also observed in the prednisolone or pirfenidone treated mice. In conclusion, these results indicated that neferine possessed a significant inhibitory effect on amiodarone-induced pulmonary fibrosis, probably due to its properties of anti-inflammation, SP-D inhibition and restoring increased CD4+CD25+ Tregs which may modulate Th1/Th2 imbalance by suppressing Th2 response (from Th2 polarity toward a Th1 dominant response).