Indiana University Medical Center researchers, led by Dr. Christopher Sweeney, have demonstrated that selective apoptotic antineoplastic drugs (SAANDs) possess antiangiogenic properties that inhibit vascular endothelial cell proliferation and new blood vessel formation. This anti-cancer activity is in addition to the drugs' ability to trigger apoptosis, or programmed cell death, selectively in cancer cells. In laboratory assays, the researchers tested two of Cell Pathways' SAANDs, exisulind (Aptosyn) and a second-generation compound, CP461.
Both drugs, which are currently in human clinical cancer trials, inhibited the proliferation of human umbilical venous endothelial cells (HUVECs) and the formation of capillaries in a dose-dependant manner, even in the presence of vascular growth stimulating factors. Moreover the two SAANDs inhibited capillary formation at substantially lower doses than were required to inhibit endothelial cell proliferation. The findings were reported at the "Angiogenesis in Cancer" meeting of the American Association for Cancer Research (AACR) in Traverse City, MI.
"Drugs that halt tumor growth by preventing them from forming new blood vessels have been a promising avenue of research for the discovery of anticancer agents," said Dr. Christopher Sweeney. "However, the antiproliferative effects of some compounds, like the taxanes, are inhibited in the presence of growth stimulators such as vascular endothelial growth factor (VEGF) and bovine fibroblast growth factor (bFGF). In contrast, when tested in cell culture assays of capillary formation and HUVEC proliferation, exisulind and CP461 both demonstrated antiangiogenic activity that was not overruled by these vascular growth stimulating factors."
CP461 inhibits new blood vessel formation at submicromolar concentrations, values well below blood levels already achieved by this drug in phase I clinical trials. Current research is ongoing to determine if the antiangiogenic effect of CP461 involves cyclic GMP (cGMP)-based mechanisms similar to those responsible for the drug's pro-apoptotic activity.
In the proliferation assay, the researchers first incubated HUVECs for 48 hours and exposed them to varying concentrations of exisulind and CP461, both with and without the growth stimulators VEGF and bFGF. They then measured the viability of the cells. The researchers found that exisulind inhibited proliferation of the HUVECs by 50 percent (IC50) at 1000 micromolar concentrations, both in the presence of and without growth stimulating factors. With and without stimulation, the IC50 of CP461 for HUVEC proliferation was 20 micromolar.
In the capillary formation assay, the researchers evaluated the ability of stimulated HUVECs to form capillaries from microcarrier beads placed in a fibrin clot. The IC50 of exisulind and CP461 in the capillary formation assay was 437 micromolar and 0.5 micromolar, respectively. Exisulind and CP461 are the first members of a new class of potential therapeutic agents called selective apoptotic antineoplastic drugs, or SAANDs, discovered and under development by Cell Pathways. The company and its collaborators have previously shown the ability of SAANDs to trigger apoptosis in abnormal cells in over 50 different tumor cell lines, as well as in animal models of a variety of human cancers.