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Responses to Antiangiogenesis Treatment of Spontaneous Autochthonous Tumors and Their Isografts¹

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 [Y. I., E. d. T., P. H., D. F., R. K. J., H. D. S.], and ImClone Systems Inc., New York, New York 10014 [A. H., J. H., D. J. H.]

Preclinical studies typically use human tumor xenografts or murine tumor isografts.Tumor growth may be accelerated by in vivo passage, thus making these tumors more sensitive to some therapies than the original tumors. In the present study, by comparing the effects of DC101, an antimurine vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody, on spontaneous autochthonous tumors and their early generation transplants, we show that this growth acceleration is diminished by DC101 treatment. Spontaneous autochthonous tumors in aged C3H mice consisted of s.c. sarcomas and adenocarcinomas, and their growth rate was accelerated by in vivo passages. Anti-VEGFR2 treatment decreased vessel density, increased apoptosis, and reduced tumor growth in large (500 mm³) spontaneous autochthonous tumors. Anti-VEGFR2 treatment significantly delayed tumor growth and extended animal survival. Tumor growth acceleration by in vivo passage was diminished by DC101 treatment. To our knowledge, this is the first evaluation of antiangiogenic therapy in a spontaneous autochthonous tumor model, which may more closely resemble human tumors. Additionally, this is the first study to compare treatment response between the parental tumor and its isografts. Although passaged tumors behave differently, it is encouraging that the tumor growth rates under DC101 treatment are comparable among different passage generations.

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