Essentially all chemotherapeutic drugs commonly used in the treatment of cancer, as well as radiation, have been shown to ultimately kill tumor cells by triggering a form of cell death called """"""""apoptosis"""""""". Consequently, alterations in the regulation of cellular genes that control the apoptotic cell death process can play an important role in determining he relative chemosensitivity and resistance of tumors. Members of the Bcl-2 family of proteins are critical regulators of apoptosis, with some functioning as blockers of apoptosis (Bcl-2, Bcl-XL, Mcl-1) and others acting o promote cell death (Bax, Bcl-Xs, and Bad). Elevations in Bcl-2 expression have been associated with chemoresistance in several settings. Furthermore, recently we have shown that alterations in the expression of other members of this gene family such as Bcl-XL and Bax can occur in drug-resistant cancers, in the absence of changes in Bcl-2. We therefore propose to compare the relative levels of Bcl-2, Bcl-X, Mcl-1, Bax, and other members of the Bcl-2 family in AMLs, using antibodies which we have raised. These results will be correlated with response rates, remission duration, and overall survival. Comparisons will be made at the time of diagnosis and again at relapse, thus determining whether alterations in Bcl-2 family gene expression occur in association with progression of a chemoresistant phenotype. Bcl-2 family protein levels will also be correlated with cytogenetic data in an effort to seek an explanation for the differential clinical behavior of AMLs in the favorable (inv 16 and 8;21) and unfavorable (monosomy 5 and 7, 5q-, and trisomy 8) prognostic groups. Finally, biological response modifiers, including cytokines and retinoids, will be employed in an attempt to identify methods for altering the ratios of anti-and pro-apoptotic Bcl-2 family proteins and thus rendering AML cells more sensitive to chemotherapy.
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