Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-07-16
2001-11-20
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06319911
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods of preventing the development of ovarian cancer by administering progestin products, alone or in association with other agents which promote apoptosis.
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, New York (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 in which cancer cells migrate through the peritoneum to produce multiple metastatic nodules in the visceral and parietal peritoneum and the hemidiaphragms. In addition, metastasis occurs 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.
In epidemiological studies, behavior associated with decreased ovulation, such as pregnancy, breastfeeding and use of estrogen-progestin combination oral contraceptive medications, decrease the risk of ovarian cancer; use of estrogen-progestin combination oral contraceptives for as long as 5 years can reduce the risk of ovarian cancer by 50%. Greene et al.,
The Epidemiology of Ovarian Cancer, Seminars Oncology,
11: 209-225, 1984; Whitmore et al.,
Characteristics Relating To Ovarian Cancer Risk: Collaborative Analysis of
12
U.S. Case-Control Studies, American J. Epidemiology
136: 1212-20, 1992. Conversely, early menarche, late menopause and nulliparity (no pregnancies) have been shown to increase the risk of ovarian cancer. The risk has been shown to positively correlate with the number of ovulatory cycles in a woman's lifetime. Wu et al.,
Personal and Environmental Characteristics Related To Epithelial Ovarian Cancer, American J. Epidemiology,
Vol. 108(6) 1216-1227. The long-term use of ovulation-inducing ovarian hyperstimulants such as clomiphene has been shown to be associated with an increased risk of ovarian cancer in some women. Rossary et al.,
Ovarian Tumors in a Cohort Of Infertile Women, New Eng. J. Med.,
331: 771-6, 1994. Thus, some factors that favor prolonged and persistent ovulation have been thought to increase ovarian cancer risk, whereas some factors that suppress ovulation have been thought to decrease risk. [Chapter 321,
Ovarian Cancer, Harrison's Principles of Internal Medicine,
supra.] These data have led to the “incessant ovulation” hypothesis for the development of ovarian cancer. Casagrande et al., “Incessant Ovulation” and Ovarian Cancer, Lancet at 170-73 (Jul.28, 1979). This hypothesis is that repeated ovulation cycles, each of which involves the disruption and repair of the ovarian surface epithelium, may cause neoplastic transformation of the ovarian epithelium in susceptible individuals and that the risk of ovarian cancer is associated with the number of ovulation cycles in a woman's lifetime.
There is no established pharmaceutical approach to the prevention of ovarian cancer. For all women, especially those at high risk of developing this disease, the only option available at this time is surgical removal of the ovaries, with all of the attendant risks and subsequent adverse health consequences due to resulting estrogen deficiency.
Although epidemiological evidence suggests that the use of combination oral contraceptives, which contain both an estrogen and a progestin, is associated with a subsequent reduced risk of developing epithelial ovarian cancer, the mechanism for this protective effect is unknown, and oral contraceptive preparations are not currently approved for this purpose. The reduction in risk of ovarian cancer in women who have used estrogen-progestin combination oral contraceptives for at least three years is approximately 40 percent. Moreover, this protective effect increases with the duration of use and persists for up to two decades after discontinuation of use. Rosenberg et al.,
A Case Control Study of Oral Contraceptive Use and Invasive Epithelial Ovarian Cancer, The WHO Collaborative Study of Neoplasia and Steroid Contraceptives; Epithelial Ovarian Cancer and Combined Oral Contraceptives, Int'l J. Epidemiology
18: 538-45, 1989; Lee et al.,
The Reduction in Risk of Ovarian Cancer Associated with Oral Contraceptive Use, New Engl. J. Med.
316: 650-51, 1987; Thomas P. Gross, James J. Schlesselman,
The Estimated Effect of Oral Contraceptive Use on the Cumulative Risk of Epithelial Ovarian Cancer, Obstetrics Gynecology
83: 419-24, 1994; Franceschi et al.,
Pooled Analysis of
3
European Case-Control Studies of Epithelial Ovarian Cancer: III. Oral Contraceptive Use, Int'l J. Cancer
49: 61-65, 1991.
It is commonly believed that the protective effect of oral contraceptives is related to the ability of these drugs to inhibit ovulation. Estrogen-progestin combination oral contraceptives act primarily by suppressing the pituitary gland's production of gonadotropins, thereby inhibiting the hormonal stimulus for ovulation. These combination drugs also have direct inhibitory effects on the reproductive tract, including inducing changes in the cervical mucus that decrease the ability of sperm to enter the uterus, as well as changes in the endometrium that reduce the likelihood of implantation, and reducing fallopian tube motility and uterine secretions.
The epidemiological studies sh
Goldberg Jerome D.
New Life Pharmaceuticals Inc.
Nimrod Raymond N.
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