Abstract
Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) regulate colon cancer growth and metastasis. Previous studies utilizing antibodies against the VEGF receptor (DC101) or EGF receptor (C225) have demonstrated independently that these agents can inhibit tumour growth and induce apoptosis in colon cancer in in vivo and in vitro systems. We hypothesized that simultaneous blockade of the VEGF and EGF receptors would enhance the therapy of colon cancer in a mouse model of peritoneal carcinomatosis. Nude mice were given intraperitoneal injection of KM12L4 human colon cancer cells to generate peritoneal metastases. Mice were then randomized into one of four treatment groups: control, anti-VEGFR (DC101), anti-EGFR (C225), or DC101 and C225. Relative to the control group, treatment with DC101 or with DC101+C225 decreased tumour vascularity, growth, proliferation, formation of ascites and increased apoptosis of both tumour cells and endothelial cells. Although C225 therapy did not change any of the above parameters, C225 combined with DC101 led to a significant decrease in tumour vascularity and increases in tumour cell and endothelial cell apoptosis (vs the DC101 group). These findings suggest that DC101 inhibits angiogenesis, endothelial cell survival, and VEGF-mediated ascites formation in a murine model of colon cancer carcinomatosis. The addition of C225 to DC101 appears to lead to a further decrease in angiogenesis and ascites formation. Combination anti-VEGF and anti-EGFR therapy may represent a novel therapeutic strategy for the management of colon peritoneal carcinomatosis. © 2001 Cancer Research Campaign http://www.bjcancer.com
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References
American Cancer Society (2000) Cancer facts and figures. http://www.cancer.org/statistics/cff2000/selectedcancers.html#col
Aparicio T, Kermorgant S, Dessirier V, Lewin MJ and Lehy T (1999) Matrix metalloproteinase inhibition prevents colon cancer peritoneal carcinomatosis development and prolongs survival in rats. Carcinogenesis 20: 1445–1451
Bruns CJ, Liu W, Davis DW, Shaheen RM, McConkey DJ, Wilson MR, Bucana CD, Hicklin DJ and Ellis LM (2000a) Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases. Cancer 89: 488–499
Bruns CJ, Solorzano CC, Harbison MT, Ozawa S, Tsan R, Fan D, Abbruzzese J, Traxler P, Buchdunger E, Radinsky R and Fidler IJ (2000b) Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 60: 2926–2935
Ciardiello F, Bianco R, Damiano V, De Lorenzo S, Pepe S, De Placido S, Fan Z, Mendelsohn J, Bianco AR and Tortora G (1999) Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res 5: 909–916
Copeland EM, Miller LD and Jones RS (1968) Prognostic factors in carcinoma of the colon and rectum. Am J Surg 116: 875–881
Folkman J (1995) Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis [see comments]. N Engl J Med 333: 1757–1763
Goldstein NI, Prewett M, Zuklys K, Rockwell P and Mendelsohn J (1995) Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1: 1311–1318
Ke L, Qu H, Nagy JA, Eckelhoefer IA, Masse EM, Dvorak AM and Dvorak HF (1996) Vascular targeting of solid and ascites tumours with antibodies to vascular endothelial growth factor. Eur J Cancer 32A: 2467–2473
Liu B, Fang M, Schmidt M, Lu Y, Mendelsohn J and Fan Z (2000) Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. Br J Cancer 82: 1991–1999
Marcus EA, Weber TK, Rodriguez-Bigas MA, Driscoll D, Meropol NJ and Petrelli NJ (1999) Prognostic factors affecting survival in patients with colorectal carcinomatosis. Cancer Invest 17: 249–252
Morikawa K, Walker SM, Jessup JM and Fidler IJ (1988) In vivo selection of highly metastatic cells from surgical specimens of different primary human colon carcinomas implanted into nude mice. Cancer Res 48: 1943–1948
Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ, Radinsky R and Dinney CP (1999) Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 5: 257–265
Prewett M, Huber J, Li Y, Santiago A, O'Connor W, King K, Overholser J, Hooper A, Pytowski B, Witte L, Bohlen P and Hicklin DJ (1999) Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res 59: 5209–5218
Radinsky R Risin, Fan, Dong, Bielenberg, Bucana, Fidler (1995) Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells. Clin Cancer Res 1: 19–31
Senger DR, Connolly DT, Van de Water L, Feder J and Dvorak HF (1990) Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res 50: 1774–1778
Shaheen RM, Davis DW, Liu W, Zebrowski BK, Wilson MR, Bucana CD, McConkey DJ, McMahon G and Ellis LM (1999) Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Cancer Res 59: 5412–5416
Takahashi Y, Kitadai Y, Bucana CD, Cleary KR and Ellis LM (1995) Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 55: 3964–3968
United Kingdom Co-ordinating Committee on Cancer Research (U.K. C. C. C. R) (1998) Guidelines for the welfare of animals in experimental neoplasia. Br J cancer 77: 1–10
Witte L, Hicklin DJ, Zhu Z, Pytowski B, Kotanides H, Rockwell P and Bohlen P (1998) Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev 17: 155–161
Zebrowski BK, Yano S, Liu W, Shaheen RM, Hicklin DJ, Putnam JB Jr and Ellis LM (1999) Vascular endothelial growth factor levels and induction of permeability in malignant pleural effusions. Clin Cancer Res 5: 3364–3368
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Shaheen, R., Ahmad, S., Liu, W. et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 85, 584–589 (2001). https://doi.org/10.1054/bjoc.2001.1936
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DOI: https://doi.org/10.1054/bjoc.2001.1936
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