This is a resubmission of a application which focuses on the cyclin kinase inhibitors (CKIs) as novel potential targets for cancer therapy. While the paradigm, until quite recently, has been that these proteins act solely as inhibitors of cell growth, our recent published work showing that the CKI p21 Wafl/Cipl has, under some conditions and with some cell types, permissive effects on vascular smooth muscle (VSM) cell growth, has led us to propose this class of molecules as novel potential targets in cancer chemotherapy. Since the first submission of this application, we have obtained new data further validating this molecule as such a target. Furthermore, we have more new (and, we modestly believe, very exciting) data providing evidence that inhibition of p21 by our simple antisense oligodeoxynucleotide (oligo) transfection technique leads to marked inhibition of tumor angiogenesis, as well as tumor growth, in an in vivo animal model of mammary cancer. The excitement which we hope to generate in this research is, in part, due to the ease of administration, the lack of toxicity, the absence of phenotypic changes in p21 knockouts (suggesting redundancy in signaling of p21 as an effector of the tumor suppressor p53), and the possibility for whole animal application of this novel antisense oligo technique against a novel target molecule for treatment of a devastating human disease. This resubmission has been modified, in response to the critiques received from the last submission, by the removal of many of the mechanistic experiments and a narrowing of the focus of the work to a single CKI, p21, concerning which we have the most data. Significantly more preliminary data is provided in this resubmission supporting our hypothesis, and we now propose to examine in some detail the exciting possibility that we have discovered an antiangiogenic molecule that is acting upon the VSM cell scaffolding in tumor angiogenic vessels.
The Specific Aims are (1) to determine optimal by which the antisense CKI oligos are growth inhibitory, apoptosis-promoting, or anti-angiogenic; (2) to determine the effect of p21 antisense oligos locally on tumor cell growth and systemically in a mouse injected with metastatic tumor cells; and (3) to begin to study the mechanism of the anti-angiogenic effect of antisense p21 oligos. We believe that completion of the experiments in this application will fully validate the use of antisense oligos to p21 in the field of mammalian cancer and will lead not only to adequate data to submit a fundable R01 application, but, more importantly, to further animal, and ultimately human, trials of p21 inhibition as a viable treatment adjunct in human cancer.
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