Chemoprevention of Colorectal Cancer
Colorectal cancer is a significant problem in Australia. It is the second largest cause of cancer death affecting as many as 1:18 Australian men and 1:23 Australian women their lifetime.
There is strong epidemiological and experimental evidence suggesting that the regular use of aspirin-like drugs (NSAIDs) reduces the risk of colorectal cancer by 40-60%. However, the inherent toxicity of these agents, particularly their gastric side-effects, makes them unacceptable for use in broadbased community chemoprevention programmes.
Alternative agents which lack the toxicity of NSAIDs (selective COX-2 agents, and non-cycloxygenase active drugs such as sulindac sulphone, olsalazine and 5-ASA), are now available. However, their ability to inhibit colorectal cancer in vivo has not been fully established.
Using a rodent model we have compared these agents to standard NSAIDs examining:
- Their ability to inhibit colorectal cancer at both the early phase and later phases of the disease
- Their toxic effect on the stomach.
The first phase of the study assessed the effect of a range of these agents and standard NSAIDs on aberrant crypt foci, the earliest morphologically identifiable phase of colorectal cancer. In these studies selective COX-2 inhibitors, non-cyclooxygenase active agents and standard NSAIDs all effectively reduced the number of these precursors. When the relative gastrotoxicity of each test agent was compared we found that standard NSAIDs were significantly more gastrotoxic than selective COX-2 inhibitors.
In the second phase of the study, the ability of standard NSAIDs, selective COX-2 inhibitors and non cyclooxygenase active agents to inhibit colorectal tumours was examined. All tested agents effectively reduced the number and volume of tumour developing in our model.
After establishing that these agents were chemopreventive, underlying mechanisms of this inhibitory effect were explored. We were able to demonstrate that the inhibition of colorectal tumours by these agents is due to induction of tumour cell apoptosis (programmed cell death) (figure 1) and reduction of tumour cell proliferation (figure 2). This effect was not due to an effect on either isoform of cyclooxygenase as the expression of both of these proteins remained constant as detected by immunohistochemistry. Rather, we have demonstrated that NSAIDs have an effect on the intracellular protein b -catenin, suggesting that they are inhibiting the translocation of this intracellular protein (figure 3).
This has lead us to suggest a novel theory on how NSAIDs inhibit colorectal cancer - by inhibiting the translocation of b -catenin the transcription of genes involved with tumour cell apoptosis and proliferation is affected with a resultant increased rate of apoptosis and reduced rate of proliferation. This ultimately leads to a reduced tumour volume and number. Ongoing studies will explore this hypothesis further.
Figure 1 - examples of apoptotic cells
Figure 2 - rodent colorectal tumour stained with Brd-U as an assessment of tumour cell proliferation
Figure 3 - alterations in the intracellular distribution of b -catenin in rodent colorectal tumours after treatment with NSAIDs.
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