Cancer chemopreventive properties of anthocyanins in patients with colorectal cancer and colorectal liver metastases.

CANCER CHEMOPREVENTIVE PROPERTIES OF ANTHOCYANINS IN PATIENTS WITH COLORECTAL CANCER AND COLORECTAL LIVER METASTASES SARAH C THOMASSET Anthocyanins, polyphenolic phytochemicals which render fruit and vegetables bright red or blue, possess anticarcinogenic properties in preclinical models of carcinogenesis. The aim of this study was to elucidate whether consumption of mirtocyan, a standardised anthocyanin extract, would cause pharmacodynamic changes consistent with chemoprevention and generate measurable levels of anthocyanins in blood, urine and target tissue. Twenty-five patients with either primary colorectal cancer or colorectal liver metastases received 1.4, 2.8 or 5.6 g of mirtocyan (containing 0.5-2.0 g anthocyanins) daily for 7 days prior to colon/liver resection. Anthocyanin levels were measured by high performance liquid chromatography. Proliferation (Ki-67), apoptosis (caspase-3) and inflammation (COX-2) were measured in colorectal tumour tissue. Effects on the insulin-like growth factor (IGF) axis were evaluated in plasma and markers of oxidative DNA damage were assessed in blood and urine. Consumption of up to 5.6 g of mirtocyan daily was well tolerated. Analysis of colorectal tumour tissue revealed that consumption of mirtocyan was associated with a 7% decrease in proliferation (p=0.003) and a 1.7% increase in apoptosis (0.044). A trend towards a reduction in circulating IGF-1 levels was observed (p=0.168). Mirtocyan anthocyanins and methyl and glucuronide metabolites were identified in plasma, urine and colorectal tissue, but not in liver. Anthocyanin concentrations in biomatrices were approximately dose-dependent. Following consumption of 5.6 g of mirtocyan daily anthocyanin levels in plasma, urine and colorectal tumour tissue were 117 ng/ml, 3 μg/ml and 179 ng/g, respectively. Mirtocyan did not affect levels of COX-2 or markers of oxidative DNA damage. Administration of mirtocyan furnished levels of anthocyanins in colorectal tumour tissue comparable to those capable of mediating chemopreventive effects in vivo. Consumption of only 1.4 g of mirtocyan daily may exert pharmacodynamic effects commensurate with colorectal cancer chemoprevention. These data support further clinical development of anthocyanins as potential colorectal cancer chemopreventive agents. ACKNOWLEDGEMENTS I am extremely grateful to Mr Berry, Professor Gescher and Professor Steward for their continued advice and help during the last 2.5 years. Their unfaltering support has contributed towards a very enjoyable period spent in research. I wish to thank Mr Dennison, Mr Miller, Mr Hemingway, Mr Thomas, Mr Kelly, Mr Jameson and Mr Scott for allowing me to recruit patients in their care. All have dedicated time to obtaining samples which were used in this research. I also wish to thank Dr West for his advice regarding immunohistochemistry. I am also indebted to everyone who has helped with me with laboratory work, Dr Hong Cai, Dr Tim Marczylo, Dr Darren Cooke, Dr Debbie Marsden, Dr Lynne Howells, Dr Stewart Sale, Richard Edwards, Angie Gillies, Frieda Teichert, Ankur Karmokar and Manijeh Maleki-Dizaji. Finally, I thank family and friends for their understanding during the course of this research, and most importantly, I thank the patients who consented to participate in this study.