An abundance of evidence has emerged which suggests that the induction of apoptosis is a critical mechanistic determinant of successful tumor eradication by antineoplastic therapies. This evidence derives largely from studies of cell cycle regulation and the identification of key modulators of cell growth and death. The most commonly aberrant gene in human cancer is p53, a factor clearly important for the triggering of apoptosis by many antitumor treatments such as irradiation and certain DNA damaging chemotherapy drugs. We have extensively studied biochemical pathways involved in recognition of DNA damage and p53 dependent events which transmit growth control (or death) signals to the cellular machinery. Through studies of highly defined in vitro generated tumor cells we have demonstrated p53's critical role in mediating apoptosis by the DNA damaging treatments radiation and doxorubicin, both in vitro and in an animal tumor model. We have correlated p53 loss with insensitivity to apoptosis induction and refractory tumor growth cells in vivo. Studies have also identified strategies for restoring apoptosis to p53- tumor cells through non-DNA targeting drugs. Molecular and cellular analyses of cell death in ALL should be highly informative both regarding strategies to optimize therapeutic efficacy and to aid in approaches to minimizing toxicities. This proposal examines whether apoptosis is a prominent mechanism of cell death in ALL, one of the very few human malignancies for which p53 mutations are relatively infrequent at diagnosis (through more common at relapse). We hope to determine whether apoptosis induction, as measured by flow cytometry of ALL cells in vitro, predicts clinical outcome. We will use apoptosis induction as a sensitive indicator of antileukemic efficacy for several alternative dosing strategies designed to minimize undesired toxicities without compromising therapeutic effect. Biochemical determination of the integrity of factors involved in sensing DNA damage and transmitting signals to regulate cell growth and death will be carried out within ALL cells from patients. Through systematic analysis of DNA targeting and non-DNA targeting antileukemic therapies, we hope to identify p53 independent apoptosis inducing gents which might ultimately produce better outcome in p53 mutated leukemias.
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