US 20080045488A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0045488 A1 RODRGUEZ (43) Pub. Date: Feb. 21, 2008 (54) PREVENTION OF OVARIAN CANCER BY Continuation-in-part of application No. 09/528,963, ADMINISTRATION OF PRODUCTS THAT filed on Mar. 21, 2000, now Pat. No. 6,765,002. INDUCE BIOLOGICAL EFFECTS IN THE Continuation-in-part of application No. 09/672,735, OVARIAN EPTHELIUM filed on Sep. 28, 2000, now Pat. No. 6.511,970. Continuation-in-part of application No. 09/532,340, (75) Inventor: Gustavo C. RODRIGUEZ, Durham, filed on Mar. 21, 2000, now abandoned. NC (US) Publication Classification Correspondence Address: JENNER & BLOCK, LLP (51) Int. Cl. ONE IBM PLAZA A6II 3/56 (2006.01) A 6LX 3/57 (2006.01) CHICAGO, IL 60611 (US) A6IP 35/00 (2006.01) (73) Assignee: New Life Pharmaceuticals Inc., Chi (52) U.S. Cl. ............................................ 514/171; 514/178 cago, IL (US) (57) ABSTRACT The present invention relates to compositions and methods (21) Appl. No.: 11/771,473 for preventing the development of epithelial ovarian cancer (22) Filed: Jun. 29, 2007 by administering compounds in an amount capable of regu lating TGF-B expression in the ovarian epithelium and/or Related U.S. Application Data capable of optimally altering expression of other Surrogate biomarkers identified by microarray technology. HRT and (63) Continuation of application No. 09/798,453, filed on OCP regimens comprising such compositions and methods Mar. 2, 2001. are disclosed. US 2008/0045488 A1 Feb. 21, 2008 PREVENTION OF OVARAN CANCER BY have been thought to increase ovarian cancer risk, whereas ADMINISTRATION OF PRODUCTS THAT INDUCE Some factors that Suppress ovulation have been thought to BIOLOGICAL EFFECTS IN THE OVARAN decrease risk. Chapter 21, Ovarian Cancer, Harrison's EPTHELUM Principles of Internal Medicine. These data have led to the 0001. This application is a continuation of Ser. No. “incessant ovulation” hypothesis for the development of 09/798,453 filed Mar. 2, 2001, which is a continuation-in ovarian cancer. Casagrande et al., Incessant Ovulation and part of U.S. Ser. No. 09/528,963 filed Mar. 21, 2000 (now Ovarian Cancer, Lancet at 170-73 (Jul. 28, 1979). This U.S. Pat. No. 6,765,002) and is also a continuation-in-part of hypothesis is that repeated ovulation cycles, each of which application Ser. No. 09/672,735, filed Sep. 28, 2000 (now involves the disruption and repair of the ovarian surface U.S. Pat. No. 6.511,970) which is a continuation-in-part of epithelium, may cause neoplastic transformation of the application Ser. No. 09/532,340 filed Mar. 21, 2000 (now ovarian epithelium in susceptible individuals and that the abandoned). risk of ovarian cancer is positively associated with the number of ovulation cycles in a woman’s lifetime. FIELD OF THE INVENTION 0005 The reduction in risk of ovarian cancer in women 0002 The present invention relates generally to methods who have used estrogen-progestin combination oral contra of preventing or reducing the risk of the development of ceptives for at least three years is approximately 40 percent. ovarian cancer by pharmacological approaches available to Moreover, this protective effect increases with the duration women of all ages. of use and persists for up to two decades after discontinu ation of use. Rosenberg et al., A Case Control Study of Oral BACKGROUND OF THE INVENTION Contraceptive Use and Invasive Epithelial Ovarian Cancer, 0003 Epithelial ovarian cancer is seldom encountered in The WHO Collaborative Study of Neoplasia and Steroid women less than 35 years of age. Its incidence increases Contraceptives, Epithelial Ovarian Cancer and Combined sharply with advancing age and peaks at ages 75 to 80, with Oral Contraceptives, Int'l J. Epidemiology 18: 538-45, the median age being 60 years. The single most important 1989; Lee et al., The Reduction in Risk of Ovarian Cancer risk factor for this cancer is a strong family history of breast Associated with Oral Contraceptive Use, New Engl. J. Med. or ovarian cancer. Oncogenes associated with ovarian can 316: 650-51, 1987: Thomas P. Gross, James J. Schlesselman, cers include the HER-2/neu (c-erbB-2) oncogene, which is overexpressed in a third of ovarian cancers, the fms onco The Estimated Effect of Oral Contraceptive Use on the gene, and abnormalities in the p53 gene, which are seen in Cumulative Risk of Epithelial Ovarian Cancer, Obstetrics about half of ovarian cancers. A number of environmental Gynecology 83: 419-24, 1994; Franceschi et al., Pooled factors have also been associated with a higher risk of Analysis of 3 European Case-Control Studies of Epithelial epithelial ovarian cancer, including a high fat diet and intake Ovarian Cancer. III. Oral Contraceptive Use, Int'l J. Can of lactose in subjects with relatively low tissue levels of cer 49: 61-65, 1991. galactose-1-phosphate uridyl transferase. 0006. It was commonly believed that the protective effect 0004. In epidemiological studies, behaviors associated of oral contraceptives is related to the ability of these drugs with decreased ovulation, Such as pregnancy, breastfeeding to inhibit ovulation. Estrogen-progestin combination oral and use of estrogen-progestin combination oral contracep contraceptives act primarily by Suppressing the pituitary tive medications, decrease the risk of ovarian cancer, use of gland's production of gonadotropins, thereby inhibiting the estrogen-progestin combination oral contraceptives for as hormonal stimulus for ovulation. These combination drugs long as 5 years can reduce the risk of ovarian cancer by 50%. also have direct inhibitory effects on the reproductive tract, Greene et al., The Epidemiology of Ovarian Cancer, Semi including inducing changes in the cervical mucus that nars Oncology, 11: 209-225, 1984: Whitmore et al., Char decrease the ability of sperm to enter the uterus, as well as acteristics Relating To Ovarian Cancer Risk Collaborative changes in the endometrium that reduce the likelihood of Analysis of 12 US Case-Control Studies, American J. Epi implantation, and reducing fallopian tube motility and uter demiology 136: 1212-20, 1992. Conversely, early menarche, ine secretions. late menopause and nulliparity (no pregnancies) have been shown to increase the risk of ovarian cancer. The risk has 0007. The epidemiological studies showing the protec been shown to positively correlate with the number of tive effect of combination oral contraceptives evaluated ovulatory cycles in a woman’s lifetime. Wu et al., Personal older combination preparations which typically contained and Environmental Characteristics Related To Epithelial higher doses of drug than most contraceptive regimens used Ovarian Cancer, American J. Epidemiology, Vol. 108(6) today. Common older regimens contained 50 micrograms or 1216-1227. The long-term use of ovulation-inducing ova more of ethinyl estradiol (an estrogen) or 100 micrograms or rian hyperstimulants such as clomiphene has been shown to more of mestranol (an estrogen) and greater than 1 mg of be associated with an increased risk of ovarian cancer in norethindrone, norethindrone acetate or norethynodrel some women. Rossary et al., Ovarian Tumors in a Cohort Of (progestins). Various combinations of progestin and estro Infertile Women, New Engl. J. Med., 331: 771-6, 1994. Thus, gen that have been used in oral contraceptives are shown in Some factors that favor prolonged and persistent ovulation Table 1. US 2008/0045488 A1 Feb. 21, 2008 TABLE 1. Trends In Combinations of Progestin and Estrogen Norethindrone Dose Equivalent Dose EE Equivalent Progestin (mg) Dose(mg) Estrogen (mg) Dose(mg) PE Ratio Norethynodrel 9.85 9.85 Mestranol O.1SO O.1OS 93.810 S.OO S.OO 0.075 O.OS3 95.238 2.50 2.50 O.036 O.O2S 99.2O6 2.50 2.50 O.100 O.O70 35.714 Norethindrone 10.00 10.00 Mestranol O.O60 O.042 238.095 2.OO 2.00 O.100 O.O70 28.571 1.OO OO O.OSO O.O3S 28.571 1.OO OO O.O8O O.OS6 17.857 Norethindrone 1.OO OO Ethinyl O.OSO O.OSO 2O.OOO OSO O.SO estradiol (EE) 0.035 O.O3S 14.286 O4O O.40 O.O3S O.O3S 11.429 Norethindrone 2.50 2.50 EE O.OSO O.OSO SO.OOO acetate 1.OO OO O.OSO O.OSO 2O.OOO O.6O O.60 O.O3O O.O3O 2O.OOO 1...SO SO O.O3O O.O3O SO.OOO 1.OO OO O.O2O O.O2O SO.OOO Ethynodiol 1.OO OO Mestranol O.100 O.O70 14.286 diacetate Ethynodiol 1.OO OO EE O.OSO O.OSO 2O.OOO diacetate dl-Norgestrel OSO 2.00 EE O.OSO O.OSO 1O.OOO O.30 2O O.O3O O.O3O 1O.OOO Equivalencies 50 mg Mestranol = 35 mg Ethinyl estradiol (EE) 0.5 mg di-Norgestrel = 2 mg Norethindrone Each block describes a specific combination of progestin and estrogen, e.g., norethynodrel and mestranol, and within TABLE 2-continued each block older combinations are listed first, with succes sively newer combinations following. Two trends are evi Composition of Selected Currently Marketed Oral Contraceptives dent. First, over time the dosage of each component has Mg decreased. Second, the downward trend of the progestin 19. component is steeper than the downward trend of the Estrogen content <50 9. estrogen component. On a relative scale, therefore, estrogen Ortho-Novum 135 Ethinyl estradio 35 Norethindrone 1.O has become more important over time. With this downward Norinyl 1 + 35 Ethinyl estradio 35 Norethindrone 1.O trend in dosage, it is apparent that the relative ratio of Modicon Ethinyl estradio 35 Norethindrone O.S progestin to estrogen is trending downward. Brevicon Ethinyl estradio 35 Norethindrone O.S Owcom 35 Ethinyl estradio 35 Norethindrone 0.4 0008 All of the currently used low-dose combination Demulen 1.35 Ethinyl estradio 35 Ethynodiol diacetate 1.O Loestrin 1.5.30 Ethinyl estradio 30 Norethindrone 1.5 oral contraceptives contain lower doses of both progestin acetate and estrogen, as well as a lower ratio of progestin to Loestrin 120 Ethinyl estradio 20 Norethindrone 1.O estrogen.