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(12) Patent Application Publication (10) Pub. No.: US 2017/0224667 A1 AZUMA Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0224667 A1 AZUMA Et Al US 20170224667A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0224667 A1 AZUMA et al. (43) Pub. Date: Aug. 10, 2017 (54) CANCER CHEMOPREVENTIVE AGENT (30) Foreign Application Priority Data (71) Applicants: Arata AZUMA, Mitaka-shi, Tokyo Oct. 15, 2014 (JP) ................................. 2014-210690 (JP); KDL, Inc., Chiyoda-ku, Tokyo Publication Classification (JP) (51) Int. Cl. (72) Inventors: Arata AZUMA, Tokyo (JP); Yukiko A6II 3/448 (2006.01) MIURA, Tokyo (JP) A6II 45/06 (2006.01) (52) U.S. Cl. CPC .......... A61K 31/4418 (2013.01); A61K 45/06 (21) Appl. No.: 15/519,360 (2013.01) (22) PCT Filed: Apr. 21, 2015 (57) ABSTRACT (86) PCT No.: PCT/UP2015/062117 Provided is a medicine for cancer chemoprevention, the medicine being characterized by containing, as an active S 371 (c)(1), ingredient, pirfenidone or a pharmaceutically acceptable salt (2) Date: Apr. 14, 2017 thereof. Patent Application Publication Aug. 10, 2017 US 2017/0224667 A1 FG. 3 : E 838 C. ii-ECE 8A: i: 833 A883 :8. AER 8 ; ::::A; CARY 88C3S REAE i ! 3: R.EC8: 33 -x 8.8 : 88 38 3: & 2. US 2017/0224667 A1 Aug. 10, 2017 CANCER CHEMOPREVENTIVE AGENT lead to an increase in lung cancer risk (non-patent document 2-3). Although a certain number of new compounds have TECHNICAL FIELD been reported to show chemopreventive activities, none of 0001. This invention is in the field of cancer chemopre them has shown effects in human. (patent document 1-6). vention. More precisely, this invention is to provide the 0008 Pirfenidone, 5-methyl-1-phenyl-2-(1H)-pyridone, method of cancer chemoprevention using the drug contain is widely known as an effective drug for the prevention and ing pirfenidone as a pharmacological active ingredient. treatment for diseases relevant to fibrosis (patent document 7), and especially useful for the treatment such as fibrosis There are also provided the use of pirfenidone for the lesions, transmissibility warts, contact-related dermatitis, a production of a medicament containing pirfenidone for keloid, pulmonary fibrosis, the fibrosis enlargement of the cancer prevention, and methods for cancer chemoprevention prostate, restoration and prevention of nephrosclerosis and comprising administering an effective amount of pirfeni So forth, or post-Surgery burn injury, and Alzheimer's dis done for cancer prevention to mammals including human. ease. Pirfenidone was first approved as pirespaR) 200 mg tablet for the treatment of idiopathic pulmonary fibrosis in BACKGROUND ART Japan in 2008 by the present inventors. In addition, it was 0002 Cancer is the number one cause of death in our approved for the treatment of idiopathic pulmonary fibrosis country and a disease which occupies a high rank as cause in Europe in 2010, and NDA was filed in the United States of death in the developed world. in 2014. 0003 For the treatment of cancer, there are surgery, 0009 Pirfenidone is expected to inhibit cancer growth, radiotherapy, chemotherapy and immune therapy, and these because pirfenidone inhibits beta type variation growth are appropriately combined and then applied. Rapid prog factor (transforming growth factor-B) and epithelium mes ress has been made in cancer treatments, especially in drug enchyma transition (EMT). Burghadtt et al. reported that therapy. Molecular target drugs are currently available in pirfenidone inhibited proliferation of the malignant glioma addition to chemotherapeutic drugs and they have dramati cells (non-patent document 4). Kozono reported the inhibi cally improved the outcome in some cancers. Drug therapy tory effects on fibrosis caused by pancreatic cancer (non is the sole treatment method for patients who developed patent document 5). systemic metastasis, but there is a limitation in their effec 0010 Idiopathic pulmonary fibrosis is often associated tiveness. Therefore, new drug is needed. with lung cancer and Such patients can be considered to be 0004 Recently cytostatic anticancer agents such as anti at high risk of developing lung cancer. Surgery of lung agiogenesis, which inhibit cancer growth indirectly by cancer of the patients with idiopathic pulmonary fibrosis is inhibiting angiogenesis as well as cytotoxic agents which known to cause a development of a serious acute exacerba inhibit cancer cell growth directly. Supporting drugs such as tion. There is a report that this acute exacerbation was antiemetic drugs and G-CSF, which reduce side effects inhibited by pre-treatment with pirfenidone (non-patent caused by chemotherapeutic agents have been available. document 6). 0005. Furthermore, cancer painkillers improve the qual ity of life (QOL) of the patient and, as a result, help CITATION LIST improvement of the cancer treatment. 0006. On the other hand, trials to prevent cancer have Patent Literatures been widely investigated. The 12 cancer prevention method 0011 Patent literature 1 JP2014-55196A including Smoking cessation, the intake of lots of vegetables, 0012 Patent literature 2JP2014-50390A moderate drinking, and lifestyle improvements including a 0013 Patent literature 3.JP2010-138192A limit of salt intake has been issued by the Japanese Cancer 0014 Patent literature 4 JP2012-510965A Association and the activity of cancer prevention is enlight 0.015 Patent literature 5 JP2006-510658A ened. In addition, aggressive intervention with drugs for preventing cancer, so-called "cancer chemoprevention' are 0016 Patent literature 6.JP2002-510667A sought and investigated. This is accomplished not only with 0017 Patent literature 7 JPH02-215719A animal experiments but also in clinical studies. Inspection of Non-Patent Literatures toxicity and effectiveness in cancer prevention and decisions of optimum doses are necessary for cancer prevention 0018 Non-patent literature 1 Advani P. Moreno-Aspitia studies. It is very difficult to develop a chemopreventive A. Current strategies for the prevention of breast cancer. agent because of the evaluation difficulty including decrease Breast Cancer (Dove Med Press). 2014; 6: 59-71. in incidence rate in humans as well as in animal models and (0019 Non-patent literature 2 IARC. IARC Handbook the optimal dose finding with less toxicity. of Cancer Prevention Volume 2 "Cartenoids, IARC Press, 0007. Several clinical trials of the compounds, mainly Lyon (1989). natural compounds, which were found to have their chemo 0020 Non-patent literature 3 Greenberg A. K., Tsay J. preventive effects in animal models, were conducted for C., Tchou-Wong K. M., Jorgensen A. Rom W. N. Chemo Subjects who have high risk factor of carcinogenesis such as prevention of lung cancer: prospects and disappointments in Smoking, colon polyp and so forth based on systemic human clinical trials. Cancers (Basel). 2013; 5: 131-48. epidemiological studies in humans. The only compounds 0021 Non-patent literature 4 Burghardt I, Tritschler F. with confirmed chemopreventive effects are tamoxifen and Opitz CA, Frank B, Weller M, Wick W. Pirfenidone inhibits raloxifen in prevention in breast cancer (non-patent refer TGF-beta expression in malignant glioma cells. Biochem ence 1). A chemopreventive effect of B-carotene on lung Biophys Res Commun. 2007: 354: 542-7. cancer was reported in animal studies, but no effects on lung 0022. Non-patent literature 5 Kozono S. Ohuchida K. cancer were found in Smokers and no-Smokers, and it rather Eguchi D, Ikenaga N. Fujiwara K. Cui L, Mizumoto K. US 2017/0224667 A1 Aug. 10, 2017 Tanaka M. Pirfenidone inhibits pancreatic cancer desmopla 0034 (8) The medicament of cancer chemoprevention sia by regulating stellate cells. Cancer Res. 2013; 73: according to any one of (1) to (7) further comprising any 2345-56. other pharmaceutical active drug as a concomitant drug. 0023 Non-patent literature 6 Successful Resection of 0035 (9) The medicament of cancer chemoprevention Lung cancer with idiopathic pulmonary fibrosis treated by according to (8) wherein said any other pharmaceutical pirfenidone during perioperative period. Jap J. Thorac Surg. active drug is a drug which prevents carcinogenesis, inhibits 2013; 66, 890-893. indirectly growth of cancer and/or directly inhibits growth of CaCC. SUMMARY OF INVENTION 0036 (10) The medicament of cancer chemoprevention method of cancer chemoprevention according to (8) wherein Technical Problem said any other pharmaceutical active drug is used as adju 0024. The aim this invention is to provide a medicament vant chemotherapeutic drug. of cancer chemoprevention. 0037 (11) An oral or parenteral pharmaceutical compo sition comprising an effective amount of pirfenidone Solution to Problem together with one or more pharmaceutically acceptable additive(s). 0025. The present inventors had hypothesized that pir 0038 (12) A method of cancer chemoprevention which fenidone might have a cancer chemoprevention activity comprises a step of administering an effective amount of based on the results that show that pirfenidone can normal pirfenidone for cancer prevention to mammals including ize damaged tissue such as inhibitory effects on Scars, in human. addition to its antifibrotic action. Thus, the present inventors 0039 (13) A method of cancer chemoprevention which evaluated the cancer chemoprevention effect of pirfenidone comprises a step of administering an effective amount of in idiopathic pulmonary fibrosis patients who are said to pirfenidone for cancer prevention to a Subject who has a high have a high risk factor of carcinogenesis. The patients were randomly assigned to a pirfenidone group and a non-pir risk factor of carcinogenesis. fenidone
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