This program project focuses on the determinants of response and resistance to cancer chemotherapy of patients with acute nonlymphocytic leukemia (ANLL) and solid tumors. Determinants of response to cytosine arabinoside (Ara-C) including high dose Ara- C and related antimetabolites will be evaluated in patients receiving this drug for the teatment of ANLL. Aspects of sensitivity and resistance to anthracyclines, particularly daunorubicin, and related agents will be evaluated in the same patients. Pharmacokinetic parameters will be examined, cellular metabolism will be investigated, and the extent of DNA damage in leukemic cells will be evaluated by newer techniques. Methods of ovrcoming resistance to antimetabolites, both in solid tumors and in leukemia will focus on the fluorinated pyrimidines, with specific reference to approaches to the metabolic modulation of antimetabolites intracellularly to improve their antitumor selecivity and therapeutic index. Pleotropic multidrug resistance (PMR) will also be examined. Human tumors will be explored for the presence of P-glycoprotein, and this will be correlated with response to chemotherapy. Enzyme activities related to glutathione metabolism will also be examined as a possible determinant of drug resistance. On the basis of delineation of the mechanism involved, specific studies to circumvent each type of drug resistance will also be carried out. The effect of hepatic injury on the pharmacokinetics and metabolism anthracyclines as a determinant of toxicity and response will be evaluated both in a animal model and in human drug trials. Methods of disaggregating solid tumors will be refined to provide a well characterized tumor cell population of high viability and biochemical integrity for the studies being carried out in a number of the projects. Biomathematical support will be provided for the whole program. A characteristic of this program project will be the close integration of laboratory and clinical stuidies with verification of laboratory studies in the clinic and development of concepts for further laboratory exploration from biochemcial and pharmacologic observations made in patients.
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