Antitumor effects induced by the combination of TNP-470 as an angiogenesis inhibitor and lentinan as a biological response modifier in a rabbit spontaneous liver metastasis model

Purpose. An angiogenesis inhibitor, TNP-470 (TNP), has shown promising, results in tumor dormancy therapy, and we have been studying its antitumor effects using a rabbit spontaneous liver metastasis model. However, because inhibition was observed only at the step of micrometastasis, we examined the effects of combining TNP in the same model with a nonspecific immunopotentiator, lentinan (LNT), as a biological response modifier. Methods. The model was established by the inoculation of VX-2 tumors into the colon, and colectomy was subsequently performed, including the primary tumor. Combination (TNP + LNT) effects were evaluated in terms of the number and volume of metastatic nodules, microvessel density (MVD), expression of proliferating cell nuclear antigen (PCNA), and apoptosis, using immunohistochemical staining with anti-CD31, anti-PCNA monoclonal antibody, and the TUNEL (in situ nick end-labeling) method, respectively. Results. Angiogenesis was significantly inhibited in the TNP + LNT group, and the apoptotic index was also significantly higher than in the TNP or LNT groups. The positive expression of PCNA in the VX2 cells was reduced in the LNT alone and TNP + LNT groups, but not in the TNP alone group. Conclusion. These findings indicate that TNP-470 and lentinan could prove useful for preventing the development of metachronous liver metastases from colorectal cancers after curative resection.