Apoptosis, the morphologically defined form of programmed cell death, is a cellular process that is of tremendous current interest to clinicians who study and treat cancer.¹ Nowhere is this more true than in the area of colorectal cancer and its management. Abnormalities in apoptotic function contribute to both the pathogenesis of colorectal cancer and its resistance to chemotherapeutic drugs and radiotherapy, both of which act, at least in part, by killing cancer cells. In this article, current knowledge of the mechanisms of apoptosis and their place in the pathogenesis of colorectal cancer will be reviewed together with the progress that has been made in the development of therapies designed to target apoptosis.

STRUCTURE OF THE NORMAL COLONIC EPITHELIUM

Before discussing apoptosis itself it is important to understand the hierarchical organisation of intestinal epithelium as this is central to any appreciation of the pathogenesis of colorectal cancer. Colonic epithelial cells are configured in deep invaginations into the wall of the colon called crypts. These cells arise from stem cells that are located at the base of the crypt and migrate to the luminal surface of the crypt where they are shed.² Evidence is accumulating that stem cells do not have unique intrinsic properties but rather are epithelial cells that acquire self renewal together with related properties as a result of being located within a specialised niche.³ To date, no markers for stem cells have been identified although significant advances have been made towards this holy grail.⁴ Stem cells divide asymmetrically, with newly synthesised DNA donated to daughter cells that migrate up the crypt ultimately to be shed while “old” DNA is retained in the stem cell population.⁵ This renders the stem cell particularly vulnerable to developing mutations that might evolve into a malignant clone. To counteract this possibility, cells at the base …