Phosphonium-Taxol Conjugates as Antitumor Drugs
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AbstractTaxol is a promising new cancer agent. We will determine whether phosphonium-ion conjugates of taxol would be more effective in a patient-like animal model. It has recently been demonstrated that taxol inhibits the metastatic spread of a PC-3 human prostate tumor cell subline in a SCID (severe combined immunodeficiency) model and processes associated with metastasis (attachment, migration, protease secretion) in vitro. Phosphonium salts are antineoplastic agents that are selectively concentrated in many carcinoma cells relative to untransformed cells and have anticarcinoma activity in animal models due to abnormally high transmembrane potentials of the tumors. We propose the development of taxol-phosphonium conjugates that will be more potent, selective and water-soluble than taxol. These conjugates will consist of triarylalkylphosphonium groups attached through ester linkages to the 2'- or 7- positions of taxol. The overall lipophilicity, weak acidity, and delocalized positive charge of these conjugates will serve to impart greater selectivity and potency due to the high transmembrane potentials of prostate carcinoma cells, in addition to greater water solubility. Two taxol-phosphonium conjugates will be chosen for in vivo metastatic studies on the basis of their potency against PC-3 cell proliferation in vitro, their low toxicity against untransformed cells, their stability in water and mouse serum, and the tolerance of mice to their intraperitoneal administration. Antimetastatic activity will be determined against PC-3 xenografts using the prostate carcinoma MetaMouse model, an orthotopic transplantation model whereby intact human prostate PC-3 tissue is transplanted to the nude-mouse prostate and the resulting tumor grows locally in the prostate and metastasizes, and thereby mimics the clinical properties of human prostate carcinomas (Fu, X., Herrera, H. and Hoffman, R.M. Int. J. Cancer, 52: 987-990, 1992).
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