Berries and Cancer (PDF)
Dr. Gary Stoner is Professor of Medicine at the Medical College of Wisconsin (MCW) Division of Hematology and Oncology, specializing in the fields of chemical carcinogenesis and cancer chemoprevention. He serves as Director of the Molecular Carcinogenesis and Chemoprevention Program in the newly developing Cancer Center. Dr. Stoner received his PhD in microbiology from the University of Michigan in 1970 and became involved in cancer research as a post-doctoral fellow and research scientist at the University of California-San Diego (UCSD). While at UCSD, his research was focused on the development of a mouse model of lung cancer for the identification of environmental carcinogens and for mechanistic studies of lung carcinogenesis. He then joined the Laboratory of Human Carcinogenesis at the National Cancer Institute where he conducted research on the metabolism of tobacco carcinogens in human lung tissues and developed human lung cell culture systems for investigations of carcinogen/oncogene-induced cell transformation. He became involved in chemoprevention research in the early 1980’s while at the Medical College of Ohio, initially investigating the chemopreventive potential of naturally-occurring ellagitannins and isothiocyanates in the rodent lung and esophagus. As an extension of research with ellagic acid, Dr. Stoner’s laboratory developed a “food-based” approach to the prevention of esophagus and colon cancers in rodents and in humans using freeze-dried black raspberries. His research is documented in more than 350 peer-reviewed publications and book chapters, and he has edited several books.
Dr. Stoner joined MCW after nearly 20 years at the Ohio State University College of Medicine where he held the positions of Lucius Wing Endowed Chair in Cancer Research and Therapy, Associate Director for Basic Research and Director of the Chemoprevention Program in the Cancer Center, and Chair of the Division of Environmental Health Sciences and Associate Dean for Research in the College of Public Health. In addition, he served as Director of the Laboratory of Cancer Etiology and Chemoprevention in the Arthur James Cancer Hospital and Richard Solove Research Institute.
Dr. Stoner has served on several grant and contract review committees including the NIH Chemical Pathology Study Section, the NCI Cancer Biology and Immunology Contract Review Committee, and as Chair of the NIH Chemo/Dietary Prevention Study Section and the American Cancer Society Advisory Committee on Carcinogenesis, Environment and Nutrition. He has also served as President of the Carcinogenesis and Molecular Biology Specialty Sections of the American Society of Toxicology and of the Ohio Valley Society of Toxicology. He has received numerous awards including the NIH MERIT award, and the Distinguished Alumni Award and Honorary Doctorate from Montana State University. He is also a Fellow in the American Association for the Advancement of Science.
Prevention of Aerodigestive Tract Cancers in Humans with Berries
1Gary D. Stoner, 1Li-Shu Wang, 2Susan Mallery and 3Carol Burke. 1Department of Internal Medicine, College of Medicine, 2Department of Oral Biology, College of Dentistry, The Ohio State University, Columbus, OH, and 3Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH
Our laboratories have been evaluating the ability of lyophilized black raspberries (BRBs) to prevent cancer in the human oral cavity and colon. In rodent studies, BRB powder, at concentrations of 5 and 10% in a synthetic diet, inhibited chemically-induced oral cancer in hamsters and colon cancer in Fischer 344 rats. The berries were found to inhibit the number of oral tumors by about 50% and colon tumors (adenomas + adenocarcinomas) by 42-71%. Based upon these observations, we conducted studies of the ability of BRBs to regress dysplastic lesions in the human oral cavity, influence the expression of biomarkers in human colon tumors/polyps, and regress rectal polyps in patients with familial adenomatous polyposis (FAP).
In the oral cavity, a 10% bioadhesive BRB gel was applied topically to normal oral mucosa and to oral dysplastic lesions four times per day for 6 weeks. This treatment did not lead to adverse effects in any of the patients, and the anthocyanins in BRBs were readily absorbed into oral mucosa. In addition, BRB treatment led to histologic regression of dysplastic lesions in a subset of patients as well as a significant reduction in loss of heterozygosity (LOH) at three tumor suppressor gene loci [3p14 (FHIT), 9p21 (INK4a/ARF), 17p13 (p53)]. Gene expression studies revealed that the BRB gel reduced the expression of COX-2 and iNOS in dysplastic lesions and uniformally suppressed genes associated with RNA processing, growth factor recycling and inhibition of apoptosis. In a patient subset, berry gel application also reduced vascular densities in the superficial connective tissues and induced genes associated with keratinocyte terminal differentiation.
We also conducted studies to determine if BRBs might exhibit chemopreventive effects in the human colon. In an initial Phase I clinical trial, BRBs, administered orally for 7 days at a dose of 45 grams per day, were found to be well tolerated. Ellagic acid and the anthocyanins; cyanidin 3-glucoside, cyanidin 3-sambubioside, cyanidin 3-xylosylrutinoside and cyanidin 3 rutinoside, were all absorbed into the blood with peak plasma levels occurring within 2-4 hours of berry consumption. The absorption of these compounds into blood was minimal, representing less than 1% of the administered dose. In a pre-surgical model involving patients with diagnosed colon cancer, the short-term (average = 3 wks) oral administration of BRBs (20g/3x/day) led to reduced cell proliferation and down-regulation of multiple biomarkers of the Wnt pathway. In patients with familial adenomatous polyposis (FAP), the administration of BRBs in the form of rectal suppositories, with or without oral administration of BRBs, resulted in a 53% regression rate of rectal polyps in nine months. The mechanism(s) by which BRBs regress rectal polyps in FAP patients is under investigation. Supported by NCI grants CA 096130 and CA103180 and USDA grants 38903-03560 and 38903-19245.
Casto, B.C., Kresty, L.A., Kraly, C.L., Pearl, D.K., Knobloch, T.J., Schut, H.A., Stoner, G.D., Mallery, S.R. and Weghorst, C.M. (2002) Chemoprevention of oral cancer by black raspberries. Anticancer Research 22:4005-4016.
Harris, G.K., Gupta, A., Nines, R.G., Kresty, L.A., Habib, S.G., Frankel, W.L., LaPerle, K., Gallaher, D.D., Schwartz, S.J., and Stoner, G.D. (2002) Effects of lyophilized black raspberries on azoxymethane-induced colon cancer and 8-hydroxy-2-deoxyguanosine levels in Fischer 344 rats. Nutrition and Cancer 40(2):125-133.
Stoner, G.D., Sardo, C., Apseloff, G., Mullet, D., Wargo, W., Pound, V., Singh, A., Sanders, J., Aziz, R., Casto, B., and Sun, X.L. (2005) Pharmacokinetics of anthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 days. J Clin Pharmacol 45:1153-1164.
Mallery, S.R., Stoner, G.D., Larsen, P.E., Fields, H.W., Rodrigo, K.A., Schwartz, S., Tian, Q., Dai, J., and Mumper, R.J. (2007) Formulation and in-vitro and in-vivo evaluation of a mucoadhesive gel containing freeze dried black raspberries: Implications for oral cancer chemoprevention. Pharmaceutical Research 24:728-737.
Stoner, G.D., Zikri, N., Wang, Li-Shu, Chen, T., Hecht, S.S., Huang, C., Sardo, C. and Lechner, J.F. (2007) Cancer prevention with freeze-dried berries and berry components. In: Seminars in Cancer Biol. 17:403-410. (review article)
Shumway, B.S., Kresty, L.A., Larson, P.E., Zwick, J.C., Lu, B., Fields, H.W., Mumper, R.J., Stoner, G.D., and Mallery, S.R. (2008) Effects of a topically applied bioadhesive berry gel on loss of heterozygosity indices in premalignant oral lesions. Clin. Cancer Res.14:2412-2430.
Mallery, S.R., Zwick, J.C., Pei, P., Tong, M., Larsen, P.E., Shumway, B.S., Lu, B., Fields, H.W., Mumper, R.J. and Stoner, G.D. (2008) Application of a bioadhesive black raspberry gel modulates gene expression and reduces cyclooxygenase 2 protein in human premalignant oral lesions. Cancer Res. 68:4945-4957.