Angiogenin antagonists prevent tumor growth in vivo.

Abstract

A noncytotoxic neutralizing monoclonal antibody (mAb), 26-2F, to human angiogenin (Ang), a potent inducer of neovascularization, has been reported to prevent or delay the establishment of HT-29 human tumor xenografts in athymic mice. In the present study the tumor model was modified to increase sensitivity to Ang antagonists to facilitate further investigations and comparisons of their capacity to inhibit tumor growth. An increase in the percentage of tumor-free mice from 10-25% to 65% is observed in this modified model after treatment with mAb 26-2F. An additional neutralizing mAb, 36u, that interacts with a different epitope on Ang similarly prevents the appearance of tumors, both alone and in combination with mAb 26-2F. In those tumors that develop in mice treated with these agents, the number of vascular elements is reduced. Actin, an Ang antagonist that unlike the mAbs binds both human and mouse Ang, also prevents the establishment of tumors while exhibiting no toxic effects at daily doses > 50 times the molar amount of circulating mouse Ang. Ang antagonists also inhibit the appearance of tumors derived from two other Ang-secreting human tumor cell lines--i.e., A549 lung adenocarcinoma and HT-1080 fibrosarcoma. These results demonstrate that inhibition of the action of Ang is an effective therapeutic approach for the treatment of malignant disease.

Inhibition of prostate carcinoma establishment and metastatic growth in mice by an antiangiogenin monoclonal antibody

“…These results extend previous findings in which angiogenin antagonists, including MAb 26-2F, exerted similar antitumor effects in preclinical models of human colon, lung and fibrosarcoma tumors. 12,13 Our results also showed that the efficacy of MAb 26-2F was significantly improved when it was combined with 2 cytotoxic agents whose activity was minimal when administered without antibody. Further, we demonstrated a profound effect of MAb 26-2F in preventing the formation of regional iliac lymph node metastasis arising from a primary tumor rapidly growing in the prostate of a mouse.…”

“…Using antagonists of its activities, we have previously reported that angiogenin plays a crucial role in the subcutaneous (s.c.) growth of human colon, lung and fibrosarcoma tumors in athymic mice, presumably acting at an early stage of tumor development. 12,13 In our work, we extend these studies and show that the neutralizing antiangiogenin monoclonal antibody (MAb) 26-2F similarly inhibits the s.c. establishment of androgen-independent human PC-3 prostate tumor cells in, on average, 40% of the treated mice. Since it has been reported that therapies that combine antiangiogenic treatment with cytotoxic drugs have in some instances resulted in increased efficacy against tumors in mice, experiments of this type were performed in the above PC-3 model system using MAb 26-2F in conjunction with cisplatin and suramin, 2 drugs that have been employed clinically for treating advanced prostate cancer.…”

“…This extent of protection for prostatic carcinoma is comparable to that achieved with MAb 26-2F treatments of other histologic types of human tumors. 12,13 In comparison with the above treatment protocol, decreasing the dose of MAb 26-2F to 15 g/day resulted in fewer tumor-free mice on day 49 (17% tumor-free mice, n ϭ 18, p ϭ 0.318), whereas increasing the dose to 180 g for the first 2 weeks (and then continuing with the 60 g/dose regimen) did not increase the number of tumor-free mice (39%, n ϭ 18, p ϭ 0.634). When MAb 26-2F treatment was administered after primary tumors were established and palpable, no effect on their growth rates was discernable (data not shown).…”

Biological and Structural Features of Murine Angiogenin-4, an Angiogenic Protein,

“…A constituent of normal plasma (6) and milk (7), it is secreted by a wide variety of normal cells (3,8) including those of the placenta (9,10). It has received much attention because of its involvement in the growth of tumors (11)(12)(13)(14)(15). Its expression level is elevated in pancreatic and several other types of cancers (15).…”

Selective abolition of pancreatic RNase binding to its inhibitor protein

“…Monoclonal antibodies and an antisense oligonucleotide against ANG have proved to be highly effective against several types of cancer in athymic mice (23,24), and clinical studies have shown an association between ANG and cancer (e.g., refs. 25 and 26).…”