Effective anti-angiogenic therapy of established tumors in mice by naked anti-human endoglin (CD105) antibody: differences in growth rate and therapeutic response between tumors growing at different sites.

ABSTRACT

We investigated anti-angiogenic/vascular targeting therapy of established tumors in immunocompetent mice using an anti-human endoglin (EDG; CD105) monoclonal antibody (mAb) SN6j. SN6j weakly cross-reacted with murine endothelial cells but reacted neither with colon-26 murine colon carcinoma cells nor with 4T1 murine mammary carcinoma cells. Systemic administration of naked (unconjugated) SN6j showed significant growth suppression of established tumors of colon-26 and 4T1 cells in immunocompetent BALB/c mice (P<0.05). Moreover, the overall survival rate of SN6j-treated mice was significantly higher than that of control IgG-treated mice (P<0.01). During these studies, we found that two different types of tumor formed in BALB/c and immunodeficient SCID mice when three different types of tumor cells (colon-26, 4T1 and MCF-7 human breast cancer cells) were inoculated subcutaneously. One type of tumor grew in the skin-side tissue (i.e., epidermis, corium, or subcutis), and mainly invaded into the corium and epidermis. The other type grew in the muscle-side tissue (i.e., fascia, muscle, or peritoneum/pleura). We termed the former SS tumors and the latter MS tumors. MS tumors grew faster than SS tumors. This differential growth of MS and SS tumors was observed in three different animal models, i.e., colon-26 tumors and 4T1 tumors in BALB/c mice, and MCF-7 tumors in SCID mice. In the therapeutic study of colon-26 and 4T1 tumors with SN6j, MS tumors were less responsive to therapy than SS tumors although SN6j showed significant antitumor efficacy against both tumors (P<0.05). The results show that antitumor therapy can yield different therapeutic outcomes depending on the tumor growth sites even for the same tumor. A differential survival between mice with the two types of tumor was also observed when mice were untreated (P<0.01).