Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for...
Reexamination Certificate
2001-07-23
2004-03-16
Caputa, Anthony C. (Department: 1642)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
C436S064000, C435S006120
Reexamination Certificate
active
06706506
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to a method of determining the presence or absence of cancer or a precancerous condition in epithelial cells, i.e., epithelial cell carcinomas or precancerous epithelium.
BACKGROUND OF THE INVENTION
Retinoids
Retinoids (vitamin A and its metabolites) can act as chemopreventive and/or chemotherapeutic agents for several types of cancer (Bertram et al., Cancer Res. 1987, 47:3012-3031.; Moon et al., In Sporn, M. B., Roberts, A. B. and Goodman, D. S. (ed.)
The Retinoids: Biology, Chemistry and Medicine,
1994, Raven Press, New York, pp. 573-596; Hong et al. In Sporn, M. B., Roberts, A. B. and Goodman, D. S. (ed.)
The Retinoids: Biology, Chemistry, and Medicine,
1994, Raven Press, New York, pp. 597-630; Hong et al., Science 1997, 278:1073-1077. Retinoids exert major effects on the growth and differentiation of normal, premalignant, and malignant epithelial cells both in vitro and in vivo (Gudas et al., In Sporn, M. B., Roberts, A. B. and Goodman, D. S. (ed.)
The Retinoids: Biology, Chemistry, and Medicine,
1994, Raven Press, New York, pp. 443-520). Retinol can be metabolized to retinyl esters and to various structurally related compounds, such as retinoic acid (RA), retinaldehyde, 4-oxoretinol, 14-hydroxy-4-14-retroretinol (14-HRR), and anhydroretinol in many cell types (Blaner et al., In Sporn, M. B., Roberts, A. B. and Goodman, D. S. (ed.)
The Retinoids: Biology, Chemistry, and Medicine,
1994, Raven Press, New York, pp. 229-256; Kurlandsky et al., J. Biol. Chem. 1994, 269:32821-32827; Achkar et al., Proc. Natl. Acad. Sci. USA 1996, 93:4879-4884; Lane et al., Proc. Natl. Acad. Sci. USA 1999, 96:13524-13529; Buck et al., Science 1991, 254:1654-1656; Buck et al, J. Exp. Med. 1993, 178:675-680). While retinoic acid in particular has been demonstrated by many researchers to be useful in the prevention and treatment of cancer in humans (Hong et al., Retinoids in Oncology 1993, Marcel Dekker, New York; Warrell Jr., et al., N. Engl. J. Med 1991, 324:1385-1393), more recently other retinoids such as anhydroretinol have been shown to prevent cancer in animal models (Shealy et al., Oncol. Rep. 1998, 5:857-860).
Retinyl esters are the major metabolites of retinol in some normal cells and tissues, whereas there are data that other cell types are not capable of esterifying retinol. For example, human keratinocytes (Randolph et al. J. Biol. Chem. 1993, 268:9198-9205; Törma et al., J. Invest. Dermatol. 1990, 94:132-138; Kurlandsky et al., J. Biol. Chem. 1996, 271:15346-15352; Guo et al., Cancer Res. 1998, 58:166-176; Creek et al. J. Nutr. 1993, 123:356-361; Randolph et al. J. Invest. Dermatol. 1996, 106:168-175), human intestinal Caco-2 cells (Quick et al, Biochemistry 1990, 29:11116-11123.) cultured tracheal epithelial cells (Bhat et al., Biochim. Biophys. Acta 1987, 922:18-27), retinal pigment epithelial cells (Das et al., Biochem J. 1988, 259:459-465; Barry et al., J. Biol. Chem. 1989, 264:9231-9238; Saari et al., J. Biol. Chem. 1989, 264:8636-8640), liver (Ong et al., J. Biol. Chem. 1988, 263:5789-5796; Yost et al., J. Biol. Chem. 1988, 263:18693-18701; Blomhoff et al., J. Biol. Chem. 1985, 260:13560-13565; Matsuura et al., J. Nutr. 1997, 127:218-224; Shimada et al. Arch. Biochem. Biophys. 1997, 344:220-227), and mammary epithelial cells (Ross et al., J. Lipid Res. 1982, 23:133-144; Bhat et al., Cancer Res. 1989, 49:139-144; Chen et al. Cancer Res. 1997, 57:4642-4651) exhibit a high level of retinol esterification activity. Two enzyme activities can catalyze retinyl ester synthesis: acyl CoA:retinol acyltransferase (ARAT) and lecithin:retinol acyltransferase (LRAT). The enzyme activities can be distinguished from each other by substrate preferences and differential sensitivities to various inhibitors (Ong et al., J. Biol. Chem. 1988, 263:5789-5796; Yost et al., J. Biol. Chem. 1988, 263:18693-18701; Herr et al. J. Nutr. Biochem. 1991, 503-511). LRAT employs the acyl group at the sn1 position of membrane phospholipid (Herr et al. J. Nutr. Biochem. 1991, 503-511) as an acyl donor, whereas ARAT utilizes acyl CoA (Ross et al., Methods Enzymol. 1990, 189:442-445). ARAT catalyzes esterification of free retinol (Ong et al., J. Biol. Chem. 1988, 263:5789-5796; Yost et al., J. Biol. Chem. 1988, 263:18693-18701; Herr et al. J. Nutr. Biochem. 1991, 503-511; Ong, et al., Nutr. Rev. 1994, 52:S24-S31), while LRAT can utilize both free retinol and retinol bound to the cellular retinol binding protein I as a substrate (Saari et al., Vision Res. 1984, 24:1595-1603). However, it was shown that elevation of the cellular retinol binding protein (CRBP-I) did not enhance retinyl ester storage in transgenic animals (Troen et al., J. Nutr. 1996, 126:2709-2719). An LRAT partial cDNA was recently cloned from human retinal pigment epithelium cells. This cDNA hybridizes to a major RNA transcript of approximately 5.0 kb and minor transcripts of 2.2.-2.5 kb in several tissues, including the testis and liver (Ruiz, et al., J. Biol. Chem. 1999, 274:3834-3841). The ARAT gene has not yet been cloned.
The hydrolysis of retinyl esters also can occur in hepatic cells and in other types of epithelial cells (Cooper, et al, J. Nutr. 1987, 117:2066-2071; Blaner, et al., FEBS Lett. 1990, 274: 89-92; Harrison et al., J. Biol. Chem. 1989, 264:17142-14147; Ghosh, et al. Lipids 1990, 25:221-225; Ritter et al., Biochim. Biophys. Acta 1996, 1291: 228-236; Schlinder, et al, Eur. J. Biochem. 1998, 251:863-873.) Recently, a neutral, bile salt-independent retinyl ester hydrolase (NREH) was purified (Sun, et al. ES-2. J. Biol. Chem. 1997, 272:24488-24493), and a hepatic, bile salt dependent retinyl ester hydrolase was cloned and shown to be identical to pancreatic carboxylester lipase (Chen et al., Proc. Soc. Exp. Biol. Med. 1997, 215:186-191). The retinyl ester hydrolase(s) which are responsible for retinyl ester hydrolysis in many extra-hepatic tissues have not been well characterized, though retinyl ester hydrolases have been described in tissues and cell types in addition to liver. In the retinal pigment epithelium (RPE), all-trans retinyl esters are substrates for an isomerohydrolase which converts the esters into 11-cis retinol; 11-cis retinol is then oxidized and converted to 11-cis retinaldehyde, the chromophore for rhodopsin and cone pigments (Bernstein et al., Proc. Natl. Acad. Sci. USA 1987, 84:1849-1853; Deigner et al., Science 1989, 244:968-971). In adipocytes, there is evidence that retinyl esters can be hydrolyzed by a cyclic AMP dependent enzyme-like hormone sensitive lipase (Wei et al., J. Biol. Chem. 1997, 272:14159-14165).
In contrast to normal epithelial cells, there are some reports that in normal human fibroblasts retinol, although readily taken up by the fibroblasts, is not metabolized to either retinoic acid or retinyl esters (Rundhaug et al., Cancer Res. 1987, 47:5637-5643; Randolph et al., J. Invest. Dermatol. 1998, 111:478-484). In another study, it was reported that cultured human dermal fibroblasts, treated with retinol, metabolized retinol to retinoic acid and retinyl esters (Bailly et al., Exp. Dermatol. 1998, 7:27-34). Little information is available concerning retinol metabolism in normal human endothelial cells. It was previously reported that isolated endothelial cells from the liver contained very low levels of retinoids (Blomhoff et al., J. Biol. Chem. 1985, 260:13560-13565). However, retinoids can influence endothelial cell growth, gene expression, and morphology (Braunhut et al., Microvasc. Res. 1991, 41:47-62; Kooistra et al., J. Biochem. 1995, 232:425-432; Braunhut et al., J. Biol. Chem. 1994, 269:13472-13479; Spencer-Green et al., Clin. Immunol. Immunopath. 1994, 72:53-61; Thompson et al., Eur. J. Biochem. 1991, 203:627-632).
While the functions of retinyl esters are not fully understood, it is believed that retinyl esters act as a storage form for retinol both in the liver and in many other tissues in the body. Interestingly, carcinoma cells of the breast, oral cavity, and skin are deficient in the esterification of retinol (Guo et al., Cancer Re
Gudas Lorraine J.
Guo Xiaojio
Caputa Anthony C.
Cornell Research Foundation Inc.
Darby & Darby
Yaen Christopher
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