Clinical Cancer Research, Vol 4, Issue 5 1331-1336, Copyright © 1998 by American Association for Cancer Research

ARTICLES

Antiangiogenic chemotherapeutic agents: characterization in comparison to their tumor growth inhibition in human renal cell carcinoma models

M Schirner, J Hoffmann, A Menrad and MR Schneider
Research Laboratories of Schering AG, Berlin, Germany. michael.schirner@schering.de

The mechanism of action of anticancer chemotherapeutic agents is mainly thought to be due to a direct inhibition of tumor cell proliferation. The enhanced endothelial cell proliferation rate in tumor specimens raised the question of whether therapeutic effects of chemotherapeutic agents might be at least partially attributed to inhibition of tumor angiogenesis. In the present study, we investigated the potential effects of chemotherapeutic agents on human renal carcinoma angiogenesis with the alginate implantation model in mice. For the first time, we also compared results from the angiogenesis model with the inhibitory effects on growth of s.c. xenografts in nude mice. Vincristine and bleomycin exerted strong inhibition of tumor angiogenesis in both carcinoma lines close to the level of the standard antiangiogenic agent O-chloroacetyl-carbamyl-fumagillol (AGM-1470; T/C 22%). Adriamycin reduced angiogenesis of Caki-2 cells (T/C 33%) but had no effect on Caki-1 angiogenesis (T/C 137%). Etoposide and 5-fluorouracil reduced Caki-1 tumor angiogenesis but had no effect on Caki-2. Despite antiangiogenic effects in both carcinoma lines, vincristine, bleomycin, and AGM-1470 significantly reduced only the growth of fast-growing Caki-1 s.c. xenografts but not the slow-growing Caki-2. Antivascular effects by bleomycin and AGM-1470 were also shown by a decrease of microvessel density in nude mouse xenografts. Our findings suggest that chemotherapeutic agents may exert inhibition of tumor angiogenesis, which could be exploitable by combination therapy of fast-growing tumors. The resistance of the slow-growing Caki-2 carcinoma against acute angiogenesis inhibition indicates a need for well-tolerated angiogenesis inhibitors. Our results also suggest the use of fast-growing s.c. xenografts for demonstrating growth inhibition by antiangiogenic compounds. Further characterization of antiangiogenic compounds considered for clinical application should, however, have its focus on slow-growing tumors, which are not accessible for most therapeutic strategies.

This article has been cited by other articles:

				C. Sarkar, D. Chakroborty, U. R. Chowdhury, P. S. Dasgupta, and S. Basu Dopamine Increases the Efficacy of Anticancer Drugs in Breast and Colon Cancer Preclinical Models Clin. Cancer Res., April 15, 2008; 14(8): 2502 - 2510. [Abstract] [Full Text] [PDF]

				G. Kaur, D. Belotti, A. M. Burger, K. Fisher-Nielson, P. Borsotti, E. Riccardi, J. Thillainathan, M. Hollingshead, E. A. Sausville, and R. Giavazzi Antiangiogenic Properties of 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin: An Orally Bioavailable Heat Shock Protein 90 Modulator Clin. Cancer Res., July 15, 2004; 10(14): 4813 - 4821. [Abstract] [Full Text] [PDF]

				T. WALTHER, A. MENRAD, H.-D. ORZECHOWSKI, G. SIEMEISTER, M. PAUL, and M. SCHIRNER Differential regulation of in vivo angiogenesis by angiotensin II receptors FASEB J, November 1, 2003; 17(14): 2061 - 2067. [Abstract] [Full Text] [PDF]

				E. A. Ojo-Amaize, E. J. Nchekwube, H. B. Cottam, R. Bai, P. Verdier-Pinard, V. N. Kakkanaiah, J. A. Varner, L. Leoni, J. I. Okogun, A. A. Adesomoju, et al. Hypoestoxide, a Natural Nonmutagenic Diterpenoid with Antiangiogenic and Antitumor Activity: Possible Mechanisms of Action Cancer Res., July 15, 2002; 62(14): 4007 - 4014. [Abstract] [Full Text] [PDF]

				S. Sleijfer Bleomycin-Induced Pneumonitis Chest, August 1, 2001; 120(2): 617 - 624. [Abstract] [Full Text] [PDF]

				K. D. Miller, C. J. Sweeney, and G. W. Sledge Jr Redefining the Target: Chemotherapeutics as Antiangiogenics J. Clin. Oncol., February 15, 2001; 19(4): 1195 - 1206. [Abstract] [Full Text] [PDF]

				T. Padro, S. Ruiz, R. Bieker, H. Burger, M. Steins, J. Kienast, T. Buchner, W. E. Berdel, and R. M. Mesters Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia Blood, April 15, 2000; 95(8): 2637 - 2644. [Abstract] [Full Text] [PDF]