In vitro investigations of the potential chemotherapeutic and chemopreventive properties of bismuth(III) complexes of non-steroidal anti-inflammatory drugs

Colorectal cancer (CRC) is the second most common cancer in both men and women in Australia. The upregulation of cyclooxygenase-2 (COX-2), an enzyme involved in the inflammation response, has been linked to a number of cancers, including CRC. This has prompted a number of epidemiological and clinical studies that suggest that prolonged administration of non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the incidence of cancer, in particular, CRC. However, side effects such as gastrointestinal (GI) bleeding limit the prolonged daily use of (NSAIDs) for the chemoprevention of cancer. Bismuth, a group 15 post-transition metal, has been used for centuries to treat an array of GI diseases. The Bi formulations exhibit an acceptable toxicity profile when administered at low doses over extended periods. Thus, it is hypothesised that the combination of Bi and NSAID in a single compound may potentially relieve the adverse GI side effects of NSAIDs if used daily as a chemopreventive agent. The aim of this Thesis was to determine the suitability of Bi complexes of NSAIDs (BiNSAIDs) as potential chemotherapeutic or chemopreventive agents. The starting point was to assess the ability of BiNSAIDs to interact with transformed cells (HCT-8 human ileocecal colon cancer cells) using a selection of BiNSAIDs of the general formula [Bi(L)3]n, (where L = diflunisal (difl), mefenamate (mef) or tolfenamate (tolf)).