Evaluation of potential activity of luseogliflozin on vascular proliferation in the mesenteric lymph node with or without vascular tumors in Sprague-Dawley rats in a carcinogenicity study

Abstract

The incidence of mesenteric lymph node vascular tumors can vary in rats, and appropriate assessment of potential risk of tumorigenicity is needed when the incidence is higher in treated groups than in a control group. In a 2-year rat carcinogenicity study of luseogliflozin, a selective sodium-dependent glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus, there was a slight but statistically significant increase in the total number of hemangiomas and hemangiosarcomas in the mesenteric lymph nodes in males at a high-dose. As part of the risk assessment for luseogliflozin, its effect on the vascular proliferation potential in the mesenteric lymph nodes was examined in a rat carcinogenicity study by performing an image analysis using specimens with double immunohistochemical staining for PCNA and CD34 in control and high-dose males. In addition, immunohistochemical staining for VEGF was performed to detect enhanced angiogenesis. In the high-dose males that did not have a hemangioma/hemangiosarcoma, neither an increased number of PCNA/CD34-positive cells nor changes in the expression pattern of VEGF was observed. On the other hand, in the high-dose males that had a hemangioma/hemangiosarcoma, the number of PCNA-positive cells was increased in the tumor areas, and the number in the hemangioma/hemangiosarcoma was approximately one-half of that in the hemangiosarcoma in the control male. In conclusion, no potential change leading to vascular proliferation/tumors was detected in the mesenteric lymph nodes of high-dose males receiving luseogliflozin.

Morphological analysis of patchy thickening and reddish discoloration of active hair growth areas in the skin of New Zealand White rabbits

“…The sections were stained with hematoxylin and eosin (H&E) and the following immunohistochemical methods. For the detection of cell proliferation, endothelial cells, and collagen type 1 (most prominent structural component of the dermis), monoclonal mouse anti-proliferating cell nuclear antigen (PCNA) antibody (M0879, 0.163 μg/ml, 1:2000, Dako, Glostrup, Denmark), monoclonal mouse anti-CD31 antibody (NB600-562, antibody concentration unknown, 1:10, Novus Biologicals., Littleton, CO, USA), and polyclonal goat anti-collagen type 1 antibody (1310-01, 5 μg/ml, 1:80, Southern Biotechnology Associates, Inc., Birmingham, AL, USA) were used 9 , 10 . Immunohistochemical staining with anti-PCNA and anti-collagen type 1 was performed using a Ventana HX system Discovery (Roche Diagnostics K.K., Tokyo, Japan).…”

Metastatic hemangiosarcoma of the liver in a young rat

“…There are only a few case reports 8 , 9 on young rats. Although the spleen is reported to be the most frequent site of the primary lesion in rats 7 , the tongue 8 , pancreas 10 , lung 11 , and mesenteric lymph node 12 have also been reported as sites of primary lesions. Metastasis is often present 1 , and cases of distant metastasis have also been reported 8 , 9 .…”