Sarah C. Thomasset

Do anthocyanins and anthocyanidins, cancer chemopreventive pigments in the diet, merit development as potential drugs?

Anthocyanins, plant pigments in fruits and berries, have been shown to delay cancer development in rodent models of carcinogenesis, especially those of the colorectal tract. Anthocyanins and anthocyanidins, their aglycons, especially cyanidin and delphinidin, have been subjected to extensive mechanistic studies. In cells in vitro, both glycosides and aglycons engage an array of anti-oncogenic mechanisms including anti-proliferation, induction of apoptosis and inhibition of activities of oncogenic transcription factors and protein tyrosine kinases. Anthocyanins and anthocyanidins exist as four isomers, interconversion between which depends on pH, temperature and access to light. Anthocyanidins are much more prone to avid chemical decomposition than the glycosides, and they only survive for minutes in the biophase. These pharmaceutical issues are very important determinants of the suitability of these flavonoids for potential development as cancer chemopreventive drugs, and they have hitherto not received adequate attention. In the light of their robust cancer chemopreventive efficacy in experimental models and their superior stability as compared to that of the aglycons, the anthocyanins seem much more suitable for further drug development than their anthocyanidin counterparts.

Pilot Study of Oral Anthocyanins for Colorectal Cancer Chemoprevention

Naturally occurring anthocyanins possess colorectal cancer chemopreventive properties in rodent models. We investigated whether mirtocyan, an anthocyanin-rich standardized bilberry extract, causes pharmacodynamic changes consistent with chemopreventive efficacy and generates measurable levels of anthocyanins in blood, urine, and target tissue. Twenty-five colorectal cancer patients scheduled to undergo resection of primary tumor or liver metastases received mirtocyan 1.4, 2.8, or 5.6 grams (containing 0.5-2.0 grams anthocyanins) daily for 7 days before surgery. Bilberry anthocyanins were analyzed by high performance liquid chromatography (HPLC) with visible or mass spectrometric detection. Proliferation was determined by immunohistochemistry of Ki-67 in colorectal tumor. Concentrations of insulin-like growth factor (IGF)-I were measured in plasma. Mirtocyan anthocyanins and methyl and glucuronide metabolites were identified in plasma, colorectal tissue, and urine, but not in liver. Anthocyanin concentrations in plasma and urine were roughly dose-dependent, reaching ∼179 ng/gram in tumor tissue at the highest dose. In tumor tissue from all patients on mirtocyan, proliferation was decreased by 7% compared with preintervention values. The low dose caused a small but nonsignificant reduction in circulating IGF-I concentrations. In conclusion, repeated administration of bilberry anthocyanins exerts pharmacodynamic effects and generates concentrations of anthocyanins in humans resembling those seen in ApcMin mice, a model of FAP adenomas sensitive to the chemopreventive properties of anthocyanins. Studies of doses containing <0.5 gram bilberry anthocyanins are necessary to adjudge whether they may be appropriate for development as colorectal cancer chemopreventive agents.

Determination of anthocyanins in the urine of patients with colorectal liver metastases after administration of bilberry extract.

Anthocyanins possess cancer chemopreventive properties in preclinical models. Their clinical pharmacology is only poorly understood. In this pilot study, anthocyanins and their metabolites were analysed in the urine of two patients with colorectal liver metastases. They received a single dose of 1.88 g standardized bilberry extract (mirtoselect) via either nasogastric or nasojejunal tube intra-operatively during liver resection. HPLC-MS/MS and HPLC-UV analysis showed there were more anthocyanins and metabolites in the urine of the patient who received mirtoselect via the stomach than via the jejunum. This result is consistent with information obtained in rodents which suggests the stomach is the predominant site for anthocyanin absorption.

Cancer chemoprevention: factors influencing attitudes towards chemopreventive agents in high-risk populations.

Information comparing attitudes towards taking cancer chemopreventive agents and assessing drug characteristics that would make chemopreventive agents more acceptable to participants is essential for future trial design and to ultimately promote compliance. We therefore undertook a cross-sectional questionnaire study, the aim of which was to assess current attitudes towards chemopreventive agents and to determine which characteristics make chemopreventive agents more acceptable to potential target populations. Questionnaires were distributed to four groups of participants: university students, cancer patients, partners/spouses of patients with cancer and individuals at a high familial risk for cancer. The survey’s overall response rate was 35.5% (350 participants). The majority of participants (92.9%) considered taking cancer chemopreventive agents. Factors that positively influenced participants towards chemoprevention were a family history of cancer and having children. Diet-derived chemopreventive agents were preferred by 74.6%, who associated these agents with being ‘healthier’ and having a better side-effect profile. Most participants preferred either two medium-sized capsules or four small capsules daily. Overall, participants were keen to consider chemoprevention, particularly in cases in which cancer risk was high, and preferred diet-derived agents, believing them to have minimal side-effects.

Malignant biliary strictures in patients with a normal bilirubin and/or normal liver enzymes.

BACKGROUND To date, no studies have sought to determine the frequency of malignancy in patients presenting with a putative biliary stricture and normal liver function tests (LFTs). The primary aim of this retrospective cohort study was to determine the likelihood of malignancy in patients presenting with a biliary stricture and normal LFTs, a normal bilirubin level either alone or in combination with normal levels of liver enzymes [alkaline phosphatase (ALP) and alanine transaminase (ALT)]. A secondary aim was to determine any clinical/biochemical/sonographic features that may be associated with malignancy. METHODS Patients presenting over a 10-year period were included. Fifteen variables were analysed to determine their association with malignant disease. RESULTS Eight hundred and thirty patients with putative biliary strictures were included. Primary hepatopancreaticobiliary (HPB) cancers presented with a normal bilirubin and normal liver enzymes (ALP and ALT) in 6% of cases. Patients with a putative biliary stricture and a normal bilirubin level whose final diagnoses were pancreatic cancer, ampullary cancer, distal cholangiocarcinoma and hilar cholangiocarcinoma represented 21%, 13%, 7% and 9% of individuals diagnosed with these pathologies, respectively. Hypoalbuminaemia and isolated intrahepatic duct dilatation on ultrasound were significantly associated with malignancy in patients with normal bilirubin and completely normal LFTs. CONCLUSIONS This study has shown that patients with a putative biliary stricture and completely normal LFTs are unlikely to have a primary HPB malignancy. Those presenting with a normal bilirubin level, but deranged liver enzymes (ALP and/or ALT), are more likely to have malignant disease, and this should necessitate a higher degree of clinical suspicion.

Original ArticlesTen-year experience in the management of gallbladder cancer from a single hepatobiliary and pancreatic centre with review of the literature

BACKGROUND There is no consensus regarding the optimum surgical approach to gallbladder cancer. This study reviews the management of gallbladder cancer in a single unit. METHODS Retrospective study of 73 consecutive patients diagnosed with gallbladder cancer. Twenty-three patients underwent surgery with curative intent (surgical group), 28 patients underwent exploratory surgery but had inoperable disease (surgically inoperable group) and 22 patients had inoperable disease radiologically (radiologically inoperable group). Within the surgical group, nine patients (cholecystectomy group) were diagnosed with gallbladder cancer after routine cholecystectomy. RESULTS The inoperable groups had significantly higher bilirubin and alkaline phosphatase (ALP) than the surgical group (p=0.02 and p<0.01, respectively). Age>68, white cell count (WCC)>7.6 x 109/L, platelet>345 x 109/L, bilirubin>16 mol/L, ALP >124 iu/L and sodium < or = 137 mmol/L were markers of inoperability. Age, haemoglobin and neutrophil:lymphocyte ratio (NLR) were predictors for survival following surgery (p=0.04, p=0.01 and p<0.01, respectively). The surgical and cholecystectomy groups had significantly higher median survivals than the surgically and radiologically inoperable groups (18.97 and 26.17 months versus 5.03 and 12.20 months, p=0.04). CONCLUSION Curative surgical resection of gallbladder cancer improved survival. Exploratory laparotomy which revealed inoperable disease reduced survival. Preoperative WCC, platelet, bilirubin and ALP may be used as additional discriminators during the investigation and work up prior to surgery.