Walmesley, A.J.; Christmas, S.E.; Watson, A.J.M.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA57
Academic Journal
Background: We have previously demonstrated effective suicide gene therapy of MC26 colorectal cancer cells in viva using the HSVTK/GCV model system in mice. This therapy achieves successful tumour regression, possibly involving the immune response. This may be enhanced by inhibition of the cyclooxygenase-2 (COX-2) enzyme, which produces potentially immunosuppressive prostaglandins in viva (e.g. PGE[sub 2]). COX-2 is also overexpressed in colon tumours, suggesting it has a role in colon carcinogenesis. Hypothesis: Selective COX-2 inhibition will augment the specific host immune response to colon carcinoma cells. Methods: The effect of a COX-2 inhibitor was studied on murine T-cell proliferation in response to mitogen and tumour cells. Splenocytes were isolated from control mice and mice that had undergone turnout induction with MC26 ceils and regression following HSV-TK suicide gene therapy without tumour recurrence. The erythrocytes were lysed and the splenocytes were treated with either Con-A (2µg/ml) or irradiated MC26 cells (1:100 ratio of irradiated MC26: splenocytes), and the COX-2 inhibitor Rofecoxib. Proliferation was measured by 3H-thymidine incorporation after 3 or 7 days. Results: Rofecoxib increased splenocyte proliferation in a mitogenic response over 3 days by 50% at concentrations above 1 µM, which are known to inhibit PGE[sub 2] production by >90% in vivo. Irradiated MC26 cells induced a 60% increase in control splenocyte proliferation over 7 days, enhanced to 100% by 1µM Rofecoxib. Splenocytes from treated mice showed a 300% increase in proliferation in response to irradiated MC26 cells also over 7 days, amplified to 450% by 1 µM Rofecoxib. Conclusions: A specific immune response is generated to tumour cells in mice that have undergone HSV-TK suicide gene therapy. COX-2 inhibition enhances this effect, possibly by inhibition of PGE[sub 2] production.


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