Second International Congress Drug Therapy in HIV Infection 18-22 November 1994 Glasgow, UK

INHIBITION OF ANGIOGENESIS AS A POTENTIAL THERAPEUTIC STRATEGY FOR THE TREATMENT OF AIDS-ASSOCIATED KAPOSI'S SARCOMA (KS)

James M. Pluda, M.D., Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, USA
6130 Executive Plaza, EPN Room 715, Rockville, MD, USA 20852

Int Cong Drug Therapy HIV 1994 Nov 18-22;2:Abstract No. 13.3
AIDS 1994, Vol. 8 (Suppl. 4);S11

KS is the most frequently occurring neoplasm in the setting of HIV infection. Histopathologically, KS is characterized by the presence of capillary slits, and clinically the lesions are extremely vascular and prone to spontaneous bleeding, particularly when viscerally located. There is evidence that angiogenesis may be intimately involved in the pathogenesis of KS. A number of angiogenic cytokines, including basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) have been found to be secreted by KS-derived spindle cells in vitro in an autocrine and paracrine manner. Combinations of these cytokines may yield greater effects that each alone. For example, there is evidence of in vitro synergistic angiogenic activity between bFGF and VEGF. In addition, vascular cells have been shown to assume a spindle-shaped morphology in vitro when exposed to inflammatory cytokines secreted by stimulate immune cells, cytokines that are increased in HIV-infected patients. These spindle-shaped vascular cells are then responsive to the in vitro mitogenic effect of the HIV tat gene product (Tat), which may be released by HIV-infected cells. Finally, a novel human oncogene isolated from KS tissue that encodes a growth factor similar to bFGF (K-fgf), when transfected Into human cells, can result in the constitutive production of bFGF capable of autocrine growth stimulation. Therefore, it appears that angiogenesis and the production of angiogenic peptides may be one of the central pathogenic mechanism associate with the development of KS. It thus seems reasonable to explore the clinical use of agents that inhibit angiogenesis, either through a mechanism that involves inhibition of the activity of angiogenic peptides, or by interfering with another step in the process of angiogenesis, for the treatment of KS. There currently are three antiangiogenesis agents in Phase I clinical trials for patients with AIDS-associated KS: the fumagillin analogue TNP-470 (AGM-1470); the platelet α-granule product platelet factor-4 (PF4); and a sulfated polysaccharide-peptidopolyglycan derived from an Arthrobacter species bacteria cell wall (SP.PG, DS-4152).

Presenting author: James M. Pluda, M.D.

1994-11-18
13.3

Originally published in AIDS Volume 8, Supplement 4 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701

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