Celecoxib With Chemotherapy in Colorectal Cancer

Celecoxib With Chemotherapy in Colorectal Cancer

ABSTRACT: Cyclooxygenase-2 (COX-2) is the enzyme that normally synthesizes prostaglandins during an inflammatory response. Many primary and metastatic cancers express COX-2, and its presence is correlated with tumor angiogenesis, more invasive tumor phenotype, resistance to apoptosis, and systemic immunosuppression. The expression of COX-2 is associated with a worse prognosis. Inhibition of prostaglandin synthesis may be beneficial in human malignancy. Regular consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of, and mortality rate resulting from, a number of types of gastrointestinal cancers. Premalignant colonic lesions regress following the administration of nonspecific COX inhibitors, such as sulindac (Clinoril). Advanced solid tumor patients treated with indomethacin (Indocin) survive twice as long as do such patients who receive supportive care alone. The U.S. Food and Drug Administration has approved specific COX-2 inhibitors for the treatment of arthritis, pain, and familial adenomatous polyposis. Preclinical studies show that these drugs block angiogenesis, suppress solid tumor metastases, and slow the growth of implanted gastrointestinal cancer cell lines. The COX-2 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies. Ongoing clinical trials are currently assessing the potential therapeutic role of COX-2 inhibitors in both prevention and treatment of a diverse range of human cancers. [ONCOLOGY 16(Suppl 3):17-21, 2002]

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.[1] Twenty percent of patients present with
metastatic disease,[2] 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%,[2] suggesting a need for more effective chemotherapy for advanced tumors.

Routine chemotherapy for metastatic colorectal cancer has been
unsatisfactory, although 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
(CPT-11, Camptosar), a topoisomerase I inhibitor.[3] "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.[4] Overall, most patients with metastatic colorectal cancer die within
2 years; there is clearly significant room for improvement in outcome.

Arachidonic Acid and
Eicosanoids: Roles in Carcinogenesis and Potential

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,[5] 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

Nicholson et al analyzed the fatty acid content of normal colonic mucosa and
tumor mucosa from Wistar rats.[6] 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,[7] 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.[8] 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.[9] Prostaglandins regulate platelet function, and tumor-platelet
aggregates are proposed to activate cancer cells for vascular attachment,
promoting metastases.[10] 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.[11]

Cyclooxygenase-2 (COX-2) Expression and Inhibition


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