The proposed studies represent an integrated program consisting of basic research interfaced with concurrent clinical trials of differentiating agents in the treatment of hematologic malignancies. The proposal is comprised of 4 interrelated areas. The basic studies encompass two areas that will monitor changes in expression of cell surface antigens and proto-oncogenes during differentiation. Each of these approaches is now applicable to clinical samples. The basic approaches will be used to monitor differentiation of leukemic blasts transplanted into cyclosporine-treated mice. The fourth area of emphasis will be clinical investigation. In addition to ongoing studies with low-dose cytosine arabinoside and 13-cis-retinoic acid, protocols are being developed for the study of interferon-gamma, hexamethylene bisacetamide, N-methylformamide and 1,25(OH)2D3. Combination trials will be directed by preclinical findings. The available resources will thus allow us to integrate molecular biology, immunology and in vivo pharmacology with clinical trials.
The specific aims are: 1) to monitor expression of cell surface differentiation antigens, self-renewal capacity and cytogenetics of leukemic blast progenitors following treatment with differentiating agents; 2) to monitor proto-oncogene expression as a measure of in vitro and in vivo differentiation of leukemic blasts and leukemic progenitor cells; 3) to determine the effects of differentiating agents alone and in combination on induction of leukemic blasts using an in vivo model; 4) to perform clinical trials with differentiating agents in which outcome is correlated with cell surface differentiation antigens, proto-oncogene expression and differentiation of blasts in vitro and in the in vivo model. These approaches, taken together, should provide new and relevant information regarding the induction of differentiation as clinical therapy.
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