Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-01-07
2002-09-03
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06444658
ABSTRACT:
BACKGROUND OF THE INVENTION
Ovarian cancer is the fourth leading cause of cancer deaths among women in the United States and causes more deaths than all other gynecologic malignancies combined. In the United States, a woman's lifetime risk of developing ovarian cancer is 1 in 70. In 1992, about 21,000 cases of ovarian cancer were reported, and about 13,000 women died from the disease. Chapter 321, Ovarian Cancer,
Harrison's Principles of Internal Medicine
, 13th ed., Isselbacher et al., eds., McGraw-Hill, N.Y. (1994), pages 1853-1858; American Cancer Society Statistics,
Cancer J. Clinicians
, 45:30 (1995). Epithelial ovarian cancer, the most common ovarian cancer, has a distinctive pattern of spread: cancer cells may migrate through the peritoneum to produce multiple metastatic nodules in the visceral and parietal peritoneum and the hemidiaphragms. In addition cancer cells metastasize through the lymphatic and blood vessels to areas such as the liver, lung and brain. Early stage ovarian cancer is often asymptomatic and is detected coincidentally by palpating an ovarian mass on pelvic examination. In premenopausal patients, about 95% of these masses are benign. Even after menopause, 70% of masses are benign but detection of any enlargement requires exploratory surgery. In postmenopausal women with a pelvic mass, a markedly elevated serum CA-125 level of greater than 65 U/ml indicates malignancy with a 96% positive predictive value. Chapter 321, Ovarian Cancer,
Harrison's Principles of Internal Medicine
, supra.
Epithelial ovarian cancer is seldom encountered in women less than 35 years of age. Its incidence increases sharply with advancing age and peaks at ages 75 to 80, with the median age being 60 years. The single most important risk factor for this cancer is a strong family history of breast or ovarian cancer. In families in which ovarian, breast, endometrial or colon cancer can be tracked as an apparent autosomal dominant trait, the risk of this cancer can be as high as 50%. Having a single first-degree relative with ovarian cancer increases a woman's risk by at least three-fold, and having a personal history of breast or colorectal cancer increases the risk of subsequently developing ovarian cancer by two-fold. Chapter 321, Ovarian Cancer,
Harrison's Principles of Internal Medicine
, supra. In addition, those with identifiable genetic mutations in genes such as BRCA1 also have an increased risk. Baker et al., Etiology, Biology, and Epidemiology of Ovarian Cancer,
Seminars in Surgical Oncology
10: 242-248, 1994; Amus et al., Genetic Epidemiology of Epithelial Ovarian Cancer,
Cancer
71: 566-72, 1993; Whitmore, Characteristics Relating To Ovarian Cancer Risk: Implications for Preventing and Detection,
Gynecologie Oncology
55, 515-19, 1994. Oncogenes associated with ovarian cancers include the HER-2
eu (c-erbB-2) gene, which is overexpressed in a third of ovarian cancers, the fins oncogene, and abnormalities in the p53 gene, which are seen in about half of ovarian cancers. A number of environmental factors have also been associated with a higher risk of epithelial ovarian cancer, including a high fat diet and intake of lactose in subjects with relatively low tissue levels of galactose-1-phosphate uridyl transferase.
Previously, there has existed no established pharmaceutical approach to the prevention of ovarian cancer. For all women, especially those at high risk of developing this disease, the only available option has been surgical removal of the ovaries, with all of the attendant risks and subsequent adverse health consequences due to resulting estrogen deficiency.
Of interest to the present invention is the disclosure of co-owned and copending U.S. patent application Ser. No. 08/713,834 filed Sep. 13, 1996 entitled “Prevention of Ovarian Cancer by Administration of Progestin Products” the disclosure of which is hereby incorporated by reference. This application discloses a method for preventing the development of epithelial ovarian cancer by administering progestin products, either alone or in combination with other agents, such as estrogen products. Specifically, a method is described for preventing ovarian cancer comprising administering to a female subject an amount of progestin product effective to increase apoptosis in ovarian epithelial cells of the female subject. Apoptosis is one of the most important mechanisms used for the elimination of cells that have sustained DNA damage and which are thus prone to transformation into malignant neoplasms. Thus, increasing apoptosis of ovarial epithelial cells will prevent the transformation of non-neoplastic, including normal and dysplastic, cells into neoplastic cells.
Vitamin D is a fat soluble vitamin which is essential as a positive regulator of calcium homeostasis. In the skin 7-Dehydrocholesterol (pro-Vitamin D
3
) is photolyzed by ultraviolet light to pre-Vitamin D
3
, which spontaneously isomerizes to Vitamin D
3
. Vitamin D
3
(cholecalciferol), the structure of which is set out below, is converted into an active hormone by hydroxylation reactions occurring in the liver to produce 25-hydroxyvitamin D
3
which is then converted in the kidneys to produce 1,25-dihydroxyvitamin D
3
(1,25-dihydroxycholecalciferol, calcitriol, 1,25(OH)
2
D
3
) which is transported via the blood to its classic target organs, namely, the intestine, kidney, and bones. Vitamin D
3
and 1,25-dihydroxy vitamin D
3
are shown below:
Vitammin D deficiency in childhood produces rickts, which is characterized by inadequate calcification of cartilage and bone. In adults, Vitamin D deficiency lead to softening and weakening of bones, known as osteomalacia. The major therapeutic uses of Vitamin D are divided into four categories: (1) prophylaxis and cure of nutritional rickets, (2) treatment of metabolic rickets and osteomalacia, particularly in the setting of chronic renal failure, (3) treatment of hypoparathyroidism, and (4) prevention and treatment of osteoporosis. Recommended daily dietary allowances of Vitamin D by the Food and Nutrition Board of the United states National Research Council (1989) were 10 mg cholecalciferol (400 IU Vitamin D) daily for females age 11-24 and 5 mg cholecalciferol (200 IU Vitamin D) daily for females age 25 and older. Normal serum levels of 25-hydroxyvitamin D
3
are not closely regulated and it has a biological half-life of several weeks with blood levels typically ranging from 15 to 80 ng/mL. Serum levels of 1,25-dihydroxyvitamin D
3
are more closely regulated and typically range from 15-60 pg/mL. Serum 1,25-dihydroxyvitamin D
3
has a half-life of 6-8 hours. 1,25-dihydroxyvitamin D
3
partitions into cells by virtue of its lipophilicity, binds to intracellular receptors, and translocates to the nucleus where the complex controls the transcription of a number of genes, many of which relate to calcium metabolism. Corder et al.,
Cancer Epidemiology, Biomarkers
&
Prevention
2:467-472 (1993).
Certain compounds are known to upregulate the functional human Vitamin D receptor (“VDR”). For example, Santiso-Mere et al.,
Molecular Endocrinology
Vol. 7, No. 7, pp.833-839 (1993) teach the expression of functional human vitamin D receptor (VDR) in
Saccharomyces cerevisiae
. This reference further teaches up-regulation of the VDR by 1,25-dihydroxyvitamin D
3
. Davoodi et al.,
J. Steroid Biochem. Molec. Biol
. 54: No. 3/4, pp. 147-153 (1995) relates to the effect of 1,25-dihydroxyvitamin D
3
on upregulation of the VDR. Davoodi et al. teach that progestins and trans-retinoic acid may also upregulate the VDR. Davoodi et al., at pp. 149-50.
Vitamin D and its analogues and derivatives are taught to have possible utility in the treatment, rather than prevention, of cancers by retarding tumor growth and in stimulating the differentiation of malignant cells to normal cells. For example, 1,25-dihydroxyvitamin D
3
possesses potent antileukemic activity by virtue of inducing the differentiation of leukemia cells to non-malignant macrophages.
Colston et al.,
Endocrinology
Vol. 108, No. 3,
Rodriguez Gustavo C.
Whitaker Regina Salas
Goldberg Jerome D.
New Life Pharmaceuticals Inc.
Nimrod Raymond N.
LandOfFree
Prevention of ovarian cancer by administration of a vitamin... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Prevention of ovarian cancer by administration of a vitamin..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Prevention of ovarian cancer by administration of a vitamin... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2892501