Interferons (IFN) and retinoids are powerful biological response modifiers. Although they are effective growth inhibitors of certain transformed cells, both these agents have limited efficacy as single agents against several tumors. However, they strongly inhibit the growth of certain tumor cells when used in combination. In this proposal we have presented substantial evidence for the synergistic inhibition of a variety of breast and other tumors both in vitro and in vivo by IFN-beta+retinoic acid (RA) combination. This combination also regresses the growth of established tumors. Furthermore, antitumor action of IFN+RA was independent of type, etiology, species origin and estrogen receptor status of the breast tumors. Thus, this combination has potential use for the therapy of human cancers. More importantly, in several breast carcinoma cells, death was induced by the combination at pharmacologically achievable doses. Death was observed in a variety of breast tumor cell lines only when co-treated with these agents. Preliminary attempts did not suggest a role for known gene products in the observed cell death. Therefore, we hypothesize that IFN+RA combination employs either novel or hitherto unimplicated gene products for inducing cell death. In the light of this data, it becomes important to understand the changes in gene expression that lead to growth suppression. We propose to investigate the basis for tumor cell death caused by certain biological agents. We will employ a powerful antisense knock out strategy to identify the gene products that mediate cell death. This method will directly identify the gene products of either IFN or retinoid pathway or jointly induced products that are essential for tumor cell death. It also circumvents conventional approaches in which evidence is limited to correlation with effect. In contrast, our screening approach will directly demonstrate the biological function. We will clone and characterize some of these death associated genes. Our studies have multiple implications for cancer biology and therapy. The cloned gene products may :i) represent novel tumor suppressors, ii) serve as markers for disease status and therapeutic response, iii) play a role in death of other cancer types, iv) be useful in gene therapy, and v) participate the cell death pathways induced by other biological response modifiers.
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