Studies completed during the tenure of the expiring grant have demonstrated that the ability of DNA-specific anticancer agents to induce the differentiation of human myeloblastic leukemia (ML-1) cells depends upon the presence of natural differentiation- inducing factors. They have also shown that a myb oncogene- product, p75, controls the expression of some proliferation- related transcription. The research plan proposed is designed to expand on these topics by examining the mechanism by which ML- 1 specific growth-(GF) and differentiation factors (DF), in conjunction with pertinent oncogene (c-myb, c-myc, c-fos) products cause the expression of the cellular proliferation and differentiation programs. Specific GF and DF are to be characterized, and their cell receptors and intracellular targets are to be determined. Changes in oncogene expression during GF- and DF-initiated growth or differentiation are to be assessed, and the identity of p75 and of the mRNAs that are expressed in its presence are to be determined. Finally, the therapeutic potential that derives from the GF- and DF-mediated control of tumor growth and differentiation is to be examined, by using molecularly cloned DF for treating ML-1 leukemia cells in the nude mouse model, in the presence and absence of DNA-specific antineoplastic agents. As part of this examination, methods are to be developed for detecting the levels of DF in vivo. The proposed evaluation of the dynamic interactions that exist between GF, DF and antineoplastic drugs, and the effect these have on the molecular processes involved in growth and differentiation, should provide new insights useful for the more rational and effective use of these drugs and for the application of natural growth and differentiation factors in cancer therapy.
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