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Biotech / Medical : OXIGENE INC. (OXGN) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (214)	6/2/2001 1:07:24 PM
From: scaram(o)uche	Respond to of 273

Ann Thorac Surg 2001 May;71(5):1657-65 Combretastatin A-4 prodrug inhibits growth of human non-small cell lung cancer in a murine xenotransplant model. Boehle AS, Sipos B, Kliche U, Kalthoff H, Dohrmann P. Department for General Surgery and Thoracic Surgery, Christian-Albrechts-University, Kiel, Germany. boehle@surgery.uni-kiel.de BACKGROUND: Combretastatin A-4 prodrug (CA-4PD) has been identified as a potent antivascular agent in various rodent tumor models. The aim of this study was to investigate the effect of CA-4PD on human non-small cell lung cancer (NSCLC). METHODS: Cytostatic and cytotoxic effects of CA-4PD on selected NSCLC cells, Colo-699 and KNS-62, were studied in vitro. After subcutaneous xenotransplantation the effect of systemically administrated CA-4PD on tumor growth was investigated in vivo. A newly established orthotopic xenotransplant model was employed to estimate prolongation of survival after intrapulmonary tumor induction with secondary metastatic disease. RESULTS: In vitro, CA-4PD displayed a time and dose dependent antiproliferative effect on human lung cancer cells. In vivo, CA-4PD significantly delayed growth of subcutaneously induced lung cancer. This growth delay was translated into a prolongation of survival in the metastasizing orthotopic xenotransplant model. CONCLUSIONS: In vitro CA-4PD inhibits proliferation of NSCLC cells, most likely by disruption of microtubule assembly. In vivo, systemic treatment inhibits growth of subcutaneously xenotransplanted tumors by an antivascular effect. In the case of metastasizing human lung cancer this translated into a prolongation of survival. Clin Cancer Res 2001 Apr;7(4):1052-60 Combretastatin a4 prodrug study of effect on the growth and the microvasculature of colorectal liver metastases in a murine model. Malcontenti-Wilson C, Muralidharan V, Skinner S, Christophi C, Sherris D, O'Brien PE. Monash University Department of Surgery, Alfred Hospital, Province Prahran, Melbourne 3181, Australia [C. M-W., V. M., S. S., C. C., P. E. O'B.], and OXiGENE, Inc., Boston, Massachusetts 02116 [D. S.]. Combretastatin A4P (CA4P) is a prodrug that, in active form, binds to tubulin microtubules of capillary endothelial cells. Studies to date indicate it has significant activity as a specific tumor vascular targeting agent. The goals were to assess the effects of CA4P on tumor growth and microvasculature of colorectal liver metastases in the mouse model, using stereological and histological methods to measure tumor growth, and vascular corrosion casting and laser doppler flowmetry to assess effect on the microvasculature. Continuous s.c. infusion of CA4P produced a major reduction in tumor growth. The percentage of the liver occupied by metastases decreased from 20.55 +/- 13.3% in controls to 7.46 +/- 5.99% in treated animals (P = 0.03). Ultrastructural study of tumor microvasculature after a single dose of CA4P revealed marked effects 1 h after treatment. There was loss of patent microvessels at the normal liver-tumor interface. Central microvascular density was reduced, with constriction and tapering of vessels. CA4P appeared to cause no damage to normal liver tissue or vasculature. Tumor blood flow decreased from 37.6 +/- 13.9% in controls to 24.4 +/- 6.1% in tumors >5 mm in diameter, 1 h after treatment with CA4P (P < 0.03). Quantitative histology of tissue at 6 and 24 h after CA4P treatment showed a significant increase in tumor necrosis (48.7 +/- 21% and 55.5 +/- 19% compared with controls, 20.6 +/- 8%; P = 0.01). Continuous infusion with CA4P causes marked reduction in tumor volume. A single dose of CA4P causes major changes of the tumor microvasculature, reduction of tumor blood flow, and increase in tumor necrosis. CA4P has a potential role in the management of patients with liver metastases.