The long term goal of this proposal is to develop a new class of angiogenesis inhibitors for suppressing the growth of solid tumors. The new drugs consist of a non-anticoagulating derivative of heparin, which binds to capillary endothelial cells, coupled to a steroid (tetrahydro S, tetrahydrocortisone, tetrahydrocortisol or cortisol) which suppresses endothelial cell division. The rationale was that the heparin derivative should concentrate the steroid on the endothelial cell surface and enhance its angiostatic effects. An acid labile bond is used to form the conjugate so that the steroid can be released within the endosomes and lysosomes of the endothelial cells. The concept, thus far, appears to be valid. The conjugates potently inhibit DNA synthesis and migration of vascular endothelial cells in vitro, retard the vascularization of sponges implanted into mice, and when administered to mice bearing solid subcutaneous lung tumors or to rats bearing 9L gliomas, they significantly reduce or abolish tumor growth. In all of these assays, equivalent treatments with a mixture of the heparin derivative and the steroid were less effective. This proposal has six specific aims which are directed at understanding how the new drugs inhibit angiogenesis and at refining them for clinical use.
The first aim i s to study the binding, endocytosis and intracellular breakdown of HAH- steroid conjugates by vascular endothelial cells and the interaction of the released steroid with intracellular steroid receptors.
The second aim i s to study the effects of the conjugates on the synthesis and dissolution of extracellular matrix components by endothelial cells.
The third aim i s to determine the cell- type specificity of the conjugates and the basis for the apparent lack of activity on non-endothelial cells.
The fourth aim i s to determine whether the anti-tumor effects observed in vivo are consistent with an effect of the conjugates on tumor angiogenesis. The fifth aim is to evaluate the anti-tumor effects of the conjugates in mouse and human tumor models that parallel human malignant disease. The sixth aim is to determine the pharmacokinetics, biodistribution and immunogenicity of the conjugates. If good anti-tumor effects are obtained at doses giving acceptable toxicity, this information will be used to support an IND application to enable Phase I trials to be initiated in patients with solid tumors.
| Gottstein, C; Wels, W; Ober, B et al. (2001) Generation and characterization of recombinant vascular targeting agents from hybridoma cell lines. Biotechniques 30:190-4, 196, 198 passim |
| Huang, X; Molema, G; King, S et al. (1997) Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 275:547-50 |
| Derbyshire, E J; Yang, Y C; Li, S et al. (1996) Heparin-steroid conjugates lacking glucocorticoid or mineralocorticoid activities inhibit the proliferation of vascular endothelial cells. Biochim Biophys Acta 1310:86-96 |
| Derbyshire, E J; Comin, G A; Yang, Y C et al. (1995) Anti-tumor and anti-angiogenic effects in mice of heparin conjugated to angiostatic steroids. Int J Cancer 63:694-701 |
