Effect of angiostatin on 1,2-dimethylhydrazine-induced colon cancer in mice

Abstract

Antiangiogenic therapy is supposed to be an attractive approach for antitumor treatment. Human plasminogen-derived angiostatin K1-3 is one of the most potent antiangiogenic agents known currently. However, it is unclear whether angiostatin has got protective effects on colon cancer. So we investigated the protective effects of angiostatin on 1,2-dimethylhydrazine (DMH)-induced colon cancer in mice. Thirty Balb/C male mice, weighing 25-30g and 8 weeks of age, were used. Twenty of the mice were treated with DMH subcutaneously (20mg/kg) once a week for 12 weeks. Six mice died during the DMH injection and surviving mice were divided into two groups (7 mice in DMH and 7 mice in DMH+angiostatin groups). In the angiostatin group, 6 weeks after the last DMH injection the animals were first treated with angiostatin (20g/mouse) intraperitoneally and then subcutaneously every 48h (5g/mouse) throughout a period of 12 weeks. The animals were killed after 30 weeks for histopathological examination. When we look at the distribution of lesions in the colon, they mainly occurred in the distal colon. The incidence of mean colonic lesions in a tumor-bearing mouse was 9.85 +/- 4.91 in those treated with DMH and 8.71 +/- 3.49 in those treated with angiostatin. The incidence of colon tumors was not significantly affected by low dose of angiostatin, and we noticed that the number of lesions decreased by 12% in DMH+angiostatin group compared to the number of the lesions in DMH group, but this decrease was not statistically significant (p>0.05). The administration period of angiostatin corresponds to the precancerous period and the reduction in the number of lesions could be important for the protective function of angiostatin in DMH+angiostain group. We assume that therapeutic effects of angiostatin are related to its doses, route of administration, frequency and administration period. In addition, we believe that combination of high doses of angiostatin with radiation, gene therapy or chemotherapy might be successful in proper tumor model.