Colorectal cancer is a significant cause of morbidity and mortality for men and women in the United States. Overall, almost 6% of Americans will develop this disease during their lifetime. Estimates for 2001 called for 138,900 incident cases and 57,100 deaths from colorectal cancer, making it the second most common visceral malignancy and the third most common cancer killer in both genders. Twenty percent of patients present with metastatic disease, and approximately 30% of patients ostensibly cured by surgical resection will develop unresectable locally recurrent or distant disease. The 5-year survival rate for patients with metastatic disease is only 6%, suggesting a need for more effective chemotherapy for advanced tumors.
Routine chemotherapy for metastatic colorectal cancer has been unsatisfactory, although fluorouracil(Drug information on fluorouracil) (5-FU)-based chemotherapy has been used for 5 decades. The current standard therapy for patients with untreated colorectal cancer is the 5-FU plus leucovorin combination given with irinotecan(Drug information on irinotecan) (CPT-11, Camptosar), a topoisomerase I inhibitor. "Standard" North American dosing (each drug given weekly × 4 every 6 weeks) achieves response rates of 39% and a median overall survival of 14.8 months, with grade 3/4 diarrhea occurring in 23% and severe to life-threatening neutropenia occurring in 54% of patients. Administering at least some portions of the 5-FU by continuous infusion decreases toxicity and may be associated with longer median survival. Overall, most patients with metastatic colorectal cancer die within 2 years; there is clearly significant room for improvement in outcome.
Chemopreventive agents play a role in impeding the development of colorectal cancer, and some of these drugs might be useful in treating established disease as well. The arachidonic acid cascade contains enzymes linked to colorectal cancer development, and existing chemopreventive agents impair those reactions. Arachidonic acid, which is derived from the diet, resides in cell membranes in ester form with phospholipids. High saturated fat diets promote colorectal cancers initiated by chemical carcinogens, and while the mechanism is not entirely understood, tumor promotion also may be related to a change in the composition of the colorectal cancer cell membranes.
Nicholson et al analyzed the fatty acid content of normal colonic mucosa and tumor mucosa from Wistar rats. Weanling rats were fed a low- or high saturated fat diet, and a subsample of rats in each group received the carcinogen azoxymethane intraperitoneally. After humane killing, colon and rectum were excised, and fatty acid methyl esters in the cell membranes were analyzed. There was a significantly higher proportion of arachidonic acid in tumor cell membranes as compared with normal colorectal tissues, regardless of dietary composition. The higher saturated fat diet was associated with greater tumor promotion than was the low-fat diet.
Eicosanoids are 20-carbon arachidonic acid metabolites that take the form of prostaglandins, thromboxanes, and leukotrienes. Series-2 prostaglandins are specific substances hypothesized to have a role in colorectal carcinogenesis, since they modulate the growth of several cell types. Indirect evidence to support this exists: arachidonic acid mobilization is linked to a wide variety of biologic signal transduction pathways, and this process is fairly tightly regulated in the gastrointestinal (GI) tract. Prostanoid synthesis is enhanced by a variety of growth factors, and PGH2 synthase (another name for cyclooxygenase [COX]) is homologous to the product of a proliferation-associated gene. Human colonic mucosa is known to have the ability to synthesize multiple eicosanoids, and tumor cells produce larger quantities of certain prostaglandins than does surrounding mucosa.
Other non-growth-regulated mechanisms for prostaglandin-induced tumor initiation and promotion exist. For example, tumor growth is enhanced in the setting of immunosuppression. Colony-stimulating factors released by tumors can cause mononuclear cells to secrete PGE2, which influences activity of T cells and natural killer cells, the cells that may be involved in immune surveillance. Prostaglandins regulate platelet function, and tumor-platelet aggregates are proposed to activate cancer cells for vascular attachment, promoting metastases. PGI2, a platelet inhibitor, inhibits metastases of colon carcinoma. Also, E-series prostaglandins are angiogenic, and tumor-induced angiogenesis is strongly tied to growth and metastasis.
Cyclooxygenase-2 (COX-2) Expression and Inhibition