Axcan Pharma Inc. disclosed positive results of a proof-of-concept study designed to compare the effectiveness of ursodiol disulfate (SUDCA) to that of regular ursodiol added to an inert vehicle, in the chemoprevention of colorectal tumours. The proof-of-concept study was performed on rats with tumours that were chemically induced by exposure to azoxymethane (AOM), a potent carcinogen.
“We are very happy with the results of this study," commented Dr François Martin, senior vice president, Scientific Affairs at Axcan. "Given the highly superior effect of SUDCA, its lack of absorption and its absence of toxicity, Axcan plans to pursue a programme aimed at evaluating the role of SUDCA in preventing tumour formation in patients at risk of developing colorectal cancer such as patients who form polyp rapidly and have previously undergone polypectomy. We now plan to initiate toxicity studies that will be followed by a Phase I study at the end of fiscal 2004," he concluded.
It has previously been shown that secondary bile acids, such as lithocholic and deoxycholic acids, that are naturally present in the colon, are hydrophobic (water repellent) and promote colonic carcinogenesis. By contrast, ursodiol has been shown to negate such tumour-promoting effects in the AOM rat model. This led to several studies using ursodiol, including a 712-patient study (Larson et al.), on the prevention of the recurrence of adenomatous polyps. One of the major disadvantages of ursodiol is that it is efficiently absorbed in the small intestine and transformed by intestinal bacteria into chenodeoxycholic and lithocholic acids, which not only reduces its delivery to the colon but also produces pro-carcinogenic bile acids.
By contrast, SUDCA is a non-absorbable hydrophilic bile acid. Bacterial transformation to harmful hydrophobic bile acids is prevented by the presence of the sulfate groups found in SUDCA. SUDCA is hence delivered intact to the colon where it exerts its site-specific membrane protective effects.
"Our findings describe, for the first time, the potent chemopreventive effect of SUDCA," commented Dr Kenneth Setchell, Head of a Research Unit at the Children's Hospital Research Foundation (CHRF), an operating division of the Cincinnati Children's Hospital Medical Center. "Studies that were conducted in a classical animal model of human colorectal cancer failed to demonstrate the chemopreventive role of regular ursodiol. In contrast, SUDCA, a new non-absorbable hydrophilic bile acid, demonstrated it could have a clear impact on the development of colonic tumours," he concluded.
The study conducted, by Dr Setchell, was designed to evaluate the effectiveness of SUDCA in the prevention of colonic tumour formation in 240 adult male rats exposed to AOM and to compare the effectiveness of SUDCA to that of regular ursodiol. 60 animals received a regular diet, 60 animals received a regular diet supplemented by 0.4 per cent SUDCA and another group of 60 animals received a regular diet supplemented with ursodiol. After 2 weeks of acclimatization to their respective diet, tumours were induced by sub-cutaneous injection of AOM. Each rat received 15mg/kg body weight of AOM per week for 2 weeks. Additionally, three separate groups of 20 animals were given the same diets but instead were injected with a solvent, DMSO, as a vehicle. After 28 Weeks, the animals' colon was macroscopically and microscopically examined for tumours.
AOM-injected animals fed with SUDCA had a statistically significant 50 per cent reduction in tumour incidence (mean (+/-) 0.62 (+/-) 0.12 tumours per animal, p=0.002) when compared to animals in the control group (1.20 (+/-) 0.16 tumours per animal). By contrast no such decrease in tumour formation was observed in the animals treated with regular ursodiol. No tumour formation was observed in any of the vehicle-injected animals and SUDCA was without toxicity.
The intraluminal bile acid pool of SUDCA-fed rats was largely comprised of unchanged SUDCA; whereas, the bile acid pool of the ursodiol-fed animals was predominantly made up of tumour-promoting hydrophobic chenodeoxycholic and lithocholic bile acids.
On September 20, 2000, Axcan entered into a licensing agreement with the CHRF. According to the terms of this agreement, Axcan has the exclusive worldwide rights to commercially exploit a series of patented SUDCA developed by the CHRF. SUDCA's patent protection in the United States expires in 2015. In a number of other major markets patents are either issued or applications pending.
Axcan is a specialty pharmaceutical company involved in the field of gastroenterology.