Inhibition of human prostate cancer proliferation in vitro and in a mouse model by a compound synthesized to block Ca2+ entry

Accelerated Ca2+ entry may be one component of the pathway regulating the p roliferative phenotype of some types of cancer, Thus, a pharmacological age nt with the ability to retard Ca2+ influx in susceptible cancers might inhi bit proliferation of them by a cytostatic mechanism rather than by inducing cytotoxicity, We have developed a chemical synthetic scheme that has produ ced a small library of novel compounds that block Ca2+ entry induced by occ upancy of the P2 receptor in two prostate cancer cell lines and inhibit pro liferation of these cells in vitro. One of the agents, named TH-1177, was u sed to treat severe combined immunodeficient mice inoculated with the human prostate cancer line PC-3, Although the doses used and treatment schedule were chosen arbitrarily, treatment extended the mean life span of mice bear ing tumors by up to 38%, Treatment of mice without cancer at doses 18 times that used in mice with tumors was not associated with any obvious toxicity , either grossly or on histological examination. These results suggest that novel cytostatic agents with efficacy against human prostate cancer cells can be developed by chemical synthesis of agents directed at the Ca2+ entry pathway.