Angiogenesis, the sprouting of capillaries from pre-existing vessels, is an essential event in many physiologic processes such as reproduction, development and wound healing. Neovascularization is also a key component of many pathologic processes such as inflammation, diabetic and other retinopathies, rheumatoid arthritis, psoriasis, and tumor formation. New vessel formation in both physiologic and pathologic states begins with the activation of endothelial cells in response to an angiogenic stimulus. A number of cytokines and growth factors which activate endothelial cells have been identified and the development of new vessels in pathologic neovascularization can be directly correlated with their expression. For tumor induced angiogenesis, endothelial activation is mediated by a variety of soluble mitogens produced by the tumor cells which act in a paracrine manner via specific receptors on the endothelial cell. Angiogenesis inhibition has become a potential anti-tumor treatment strategy, as avascular tumors would be expected to be incapable of growth and have little metastatic potential. MSI-1256F (squalamine lactate) has been found to be a non-cytotoxic inhibitor of new blood vessel formation as judged by a set of in vitro and in vivo assays. Since angiogenesis is implicated in the growth and maintenance of solid tumors, squalamine is potentially an attractive development candidate in malignancy as well as for disease of blood vessel proliferation such as diabetic retinopathy and macular degeneration which require new blood vessel formation. MSI-1256F inhibits growth of solid tumors by inhibiting the development of a blood supply to the tumor without direct cytotoxicity to tumor cells. This effect appears to be mediated by the blockade of stimulation of endothelial cells by any of multiple mitogens, apparently by modulation of endothelial cell pH, without obvious effect on quiescent endothelial cells or alteration of VEGF production by tumor cells. Therefore, MSI-1256F for injection is considered well suited for targeted therapy of tumors and other diseases characterized by neovascularization. This phase I clinical study is being performed to identify a maximum acceptable tolerated dose for MSI-1256F for injection as a continuous intravenous infusion in patients with solid tumors. The appropriateness of continuous vs. intermittent administration will be revisited after early human pharmacokinetic data are evaluated. Squalamine lactate, a natural aminosterol originally isolated from the dogfish shark Squalus acanthicus, has been shown to be an antiangiogenic agent that limits tumor growth in vivo. A phase I study was initiated to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics of Squalamine lactate when given as a 120-hour continuous intravenous (i.v.) infusion to patients with advanced incurable cancer, and also to obtain information on prolonged (>120-hour) i.v. infusions in patients who have tolerated 120-hour infusions. Doses of 120-hour infusions were escalated until DLT was encountered. Once a patient experienced DLT, treatment was carried out at a dose one dose-level below that at which DLT occurred; if this dose was well tolerated, then the duration of infusion was prolonged from 10 up to a maximum of 30 days.
NIH ExPorter
NIH ExPorter