Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects.

A microdose study of metformin was conducted to investigate the predictability of drug-drug interactions at the therapeutic dose (ThD). Healthy subjects received a microdose (100 µg) or ThD (250 mg) of metformin orally, with or without a potent and competitive multidrug and toxin extrusion (MATE) inhibitor, pyrimethamine (50 mg, p.o.), in a crossover fashion. Pyrimethamine significantly reduced the renal clearance of metformin by 23 and 35% at the microdose and ThD, respectively. At ThD, but not at microdose, it caused significant increases in the maximum concentration (C(max)) and area under the plasma concentration-time curve (AUC) of metformin (142 and 139% of control values, respectively). Human canalicular membrane vesicles showed pyrimethamine-inhibitable metformin uptake. Pyrimethamine did not affect plasma lactate/pyruvate after ThD of metformin but significantly reduced the renal clearance of creatinine, thereby causing elevation of plasma creatinine level. This microdose study quantitatively predicted a drug-drug interaction involving the renal clearance of metformin at ThD by pyrimethamine. Pyrimethamine is a useful in vivo inhibitor of MATE proteins.

Interleukin-10 expression and cytotoxic-T-cell response in Epstein-Barr-virus-associated nasopharyngeal carcinoma.

Interleukin-10 (IL-10) is an inhibitory cytokine produced by various cell types. It exhibits strong sequence homology to BCRF-1 (viral IL-10, vIL-10), an open reading frame in the Epstein-Barr-virus (EBV) genome. Using in situ hybridization (ISH), polymerase chain reaction (PCR) and immunohistochemistry, we checked 41 cases of nasopharyngeal carcinoma (NPC), to study the presence of EBV in the tumor cells, as well as to clarify the relationship between IL-10 expression of the tumor cells and the response of cytotoxic T cells. IL-10 expression was studied by immunohistochemistry; as a result, 29 of 41 cases expressed EBER-1 RNA of EBV by ISH. In addition, 19 of the 29 with EBV and 9 of 12 without EBV cases expressed IL-10 in the tumor cells. The number of cytotoxic T cells increased in the tumor tissue, and the increase in the intratumoral stroma was stronger than in the remaining normal epithelia. The number of cytotoxic T cells also significantly increased in the cases with EBV. On the other hand, in the IL-10-positive series, the number of cytotoxic T cells decreased significantly more than in IL-10-negative series. In view of the established inhibitory effects of IL-10, expression of IL-10 may therefore be one of the mechanisms for NPC cells as well as EBV to counter local immune defense. However, we could not conclude whether or not IL-10 expression was directly induced by EBV.

Spindle cell carcinoma of the breast: a case report and an immunohistochemical study including p53 and Ki-67 expression.

A rare case of spindle cell carcinoma (SpCC) of the breast occurring in a 51-year-old Japanese woman is reported. A firm and well-circumscribed tumor, measuring 9 x 8.5 x 8.5 cm, was located on the upper lateral region of the right breast. Microscopically, the tumor consisted of sheets of both malignant spindle cells and poorly differentiated ductal carcinoma containing squamoid islands with gradual transition to the spindle cell component. The immunocytochemical expression of epithelial markers was recognized in the spindle cells, as well as in the carcinomatous cells. Moreover, the spindle cell component expressed vimentin, alpha-smooth muscle actin and S-100 protein. Ultrastructurally, in addition to the features of adenocarcinoma, squamous or myoepithelial differentiation was confirmed in the spindle cell component. These findings thus suggest an epithelial origin with squamous differentiation and myoepithelial participation in the genesis of SpCC. In a comparative study, the expression of p53 protein and Ki-67 as a proliferation marker in each component of this tumor was also investigated. The mean p53 labeling index (LI) in both the carcinomatous and spindle cell area was similar, however the mean MIB-1 LI in the spindle cell area was significantly higher than that in the carcinomatous area. The results indicate that p53 overexpression is involved in the tumorigenesis of both components in the SpCC, and the spindle cell component shows a higher degree of proliferative activity than the carcinomatous component.