PRECLINICAL STUDIES OF WATER-INSOLUBLE CAMPTOTHECIN CONGENERS - CYTOTOXICITY, DEVELOPMENT OF RESISTANCE, AND COMBINATION TREATMENTS

Water-insoluble camptothecin (CPT) congeners are rapidly establishing themselves as promising anticancer drugs, In vitro, they have exhibite d: (a) insensitivity to elevated levels of P-glycoprotein that confers multidrug resistance; (b) selective killing of malignant cells traver sing the S-phase of the cell cycle, while leaving viable normal cells, which either are arrested at the S-G(2) boundary or continue to divid e; (c) no cross-resistance with several other anticancer drugs; and (a ) potentiation or enhancement of cytotoxicity when appropriately used in combination with tumor necrosis factor, ionizing radiation, and hyp erthermia. In addition, development of cell resistance to water-insolu ble CPT congeners irt vitro is accompanied by increased sensitivity to other anticancer drugs. Furthermore, water-insoluble CPT congeners ha ve exhibited an unprecedented activity against a wide variety of human tumors xenografted in nude mice by inhibiting growth and inducing reg ression of carcinomas of the lung, breast, ovary, colon, stomach, panc reas, and prostate, as well as malignant melanoma, lymphoma, and leuke mia. More importantly, oral administration of the water-insoluble CPT congeners in clinical studies with cancer patients makes other route(s ) of administration unnecessary.