ANTITUMOR ACTIVE ETHER PHOSPHOLIPIDS

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Chemotherapy continues to play a key role in the control of neoplastic diseases. Development of chemical agents with potent and selective anticancer activity holds the promise particularly for the treatment of those malignancies (such as leukemia) where alternative interventions are ineffective or impractical. One of the most exciting new developments in this area has been the discovery that a group of synthetic ether phospholipids were shown effective in directly and selectively destroying cells from numerous human leukemias and solid tumors in vitro, a number of allogeneic and syngeneic mouse tumor-growths in vivo, and in inhibiting the development of metastases of lewis lung carcinoma in syngeneic mice. Furthermore, phase I clinical studies reported well-documented objective response in patients with solid tumors, including bronchogeneic carcinomas and with acute myeloid leukemia. As the therapeutic levels were found to be nontoxic to normal cells, it was suggested that the use of synthetic ether phospholipids could present a new approach to human neoplastic therapy. Development of ether phospholipids with highly potent and selective tumor cytotoxicity is the main objective of this research project. We will design structural modified phospholipid compounds that will be developed on the basis of experimentally determined requirements for antitumor potency and selectivity. The synthesis will be accomplished using the methods recently developed in our laboratory. The synthetic compounds will be tested in a number of collaborative studies. Potency and selectivity will be determined following 3H-thymidine uptake and the release of cytosolic LDH, and by enumeration of viable cells of normal vs. cancerous origin. Immunological tests will assess the extent of macrophage activation and monocyte differentiation induction. 14C-serotonin release will be used to measure platelet activation, spontaneous hypertensive rats will be used to determine antihypertensive activity.