Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-10-25
2001-04-17
Priebe, Scott D. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S04400A, C536S023500, C435S320100, C435S440000, C435S455000, C435S475000, C435S476000, C435S375000
Reexamination Certificate
active
06218372
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides methods for treating or preventing restenosis and cancer in vivo by administration of a composition comprising an expression vector containing a gene encoding p21and a pharmaceutical carrier.
DISCUSSION OF THE BACKGROUND
The identification of cell cycle regulatory proteins has been greatly facilitated by studies of mutant yeast strains with abnormalities related to cell proliferation. Among the gene products defined in yeast is Far 1 (1), whose mammalian homologue, p21, alters the activity of cyclin-dependent kinases and is implicated in cell cycle progression and senescence (2-13). p21, also known as WAF1, CIP1 or SDI1 (11,12,14,15), is a downstream target of the p53 tumor suppressor gene and has thus been implicated indirectly in malignant transformation (15-18). Induction of p53 in response to DNA damage results in G1 checkpoint arrest (16-19), at which point DNA repair is accomplished prior to DNA replication in S phase. Consistent with its presumed role as a downstream effector for p53 , p21 has been shown to inhibit proliferating cell nuclear antigen (PCNA) dependent DNA replication but not DNA repair in vitro (20).
Zhang et al, Genes & Development (1994) 8:1750) studied p21 in vitro. As p21 functions as a kinase inhibitor, it had been predicted that normal cells should contain virtually no active cyclin kinases. By demonstrating that p21-containing cyclin kinases exist in both active and inactive states, Zhang et al rationalized that p21 was involved in controlling cell cycle progression in normal cells. Zhang et al found that in fibroblasts transformed with a variety of tumor viral oncoproteins, cyclin kinases exist in a binary state [cylcin/CDK]; whereas in normal fibroblasts multiple cyclin kinases exist in quaternary complexes containing p21 [cyclin/CDK/ proliferating cell nuclear antigen (PCNA)/p21]. Active complexes contain a single p21 molecule. In contrast inactive complexes possess multiple p21 subunits. Although changes in p21 stoichiometry were sufficient to account for the conversion of active to inactive complexes in vitro, Zhang et al believed that “association of cyclin knases with p21 must be intertwined with other modes of regulation in vivo.” Zhang et al noted that “it is not known what effect association with noninhibitory levels of p21 might have on the function of these CDK-modifying enzymes in vivo.”
WO 94/09135 describes methods and diagnostic kits for diagnosing transformation of a cell, involving detection of the subunit components of cyclin complexes. In particular, the method pertains to the interaction of cyclins, PCNA, CDKs and low molecular weight polypeptides such as p21, p19 and p16.
Despite the evidence of cyclin kinase inhibitory activity in vitro, the role of p21 in tumor formation and its ability to reverse the malignant phenotype in vivo has not been defined.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide methods for treating and preventing cancer (tumor formation) in vivo.
A second object of the present invention is to provide methods for treating and preventing restenosis in vivo.
A third object of the present invention is to provide methods to induce antitumor effects in cells through induction of terminal differentiation. This method is useful for altering expression of cell surface proteins which might potentially facilitate immune recognition of tumors or causing the secretion of factors which might secondarily inhibit cell growth.
The present inventors have now determined the role of the p21 cyclin-dependent kinase inhibitor on tumor cell growth and restenosis. p21 is induced by p53 (6,7,15-18) and has thus been implicated as a downstream effector of p53 tumor suppression (23). The present inventors provide the first direct demonstration that p21 expression is sufficient to produce these tumor and restenosis suppressor effects in vivo. p21 expression was also found to facilitate transcriptional activation by NF-&kgr;B providing a mechanism whereby p21 can directly influence the expression of genes, such as adhesion molecules, associated with differentiation. The suppression of tumor growth and restenosis as well as the induction of the differentiated phenotype arises from altered patterns of gene expression, mediated in part by NF-kB, resulting from p21 induced transcriptional regulation leading to terminal differentiation and growth arrest. Previous attempts to induce antitumor effects through induction of terminal differentiation have involved the use of cytotoxic drugs or hormones (25-28) which have had variable success in achieving this effect.
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Nabel Elizabeth G.
Nabel Gary J.
Yang Zhi-yong
Brinks Hofer Gilson & Lione
Paras, Jr. Peter
Priebe Scott D.
The Trustees of the University of Michigan
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