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CHEMOPREVENTION OF COLORECTAL CANCER (CRC)

R.N. DuBois, MD, PhD, Vanderbilt University Medical Center, Nashville, Tenn, described recent research showing delayed CRC tumor growth by inhibition of cyclooxygenase-2 (COX-2). The gene for COX-2 is elevated in 85% of CRC patients and in 50% with premalignant adenomas. Preclinical experiments show prostaglandin E2 to reverse COX-2 via the upregulated apoptotic gene, Bcl 2. Long-term, routine use of aspirin (ASA) and nonsteroidal antiinflammatory drugs (NSAIDs), both inhibitors of COX-2, cannot be recommended due to gastrointestinal toxicity.

Introduction to chemoprevention

The aim of chemoprevention is to reverse, suppress, or prevent carcinogenesis using specific chemicals. According to Hong, the procedure seeks to decrease cancer development, reverse the premalignant process, and reregulate cellular growth and differentiation. Clinically, the therapy targets high-risk, healthy persons, individuals with premalignant lesions, and patients in remission. Molecular and cell biology research led to identification of specific targets for preventing carcinogenesis. Some of these are COX-2 (CRC), estrogen receptors (breast cancer), and retinoid receptors (kidney cancer).

Pathogenesis of CRC

Normal colon epithelial cells hyperproliferate to form adenoma and later, adenocarcinoma. Mutated antigen-presenting complex (APC) genes lead to familial adenomatous polyposis (FAP) and mismatched repair genes to hereditary nonpolyposis CRC. According to DuBois, about 75% of CRC is sporadic, 17% hereditary, and the rest due to germ line mutations. In addition, a high fat diet or increased consumption of red meat predispose individuals to CRC.

NSAIDs protect against CRC development

In a review of some 35 clinical studies, DuBois et al ranked the evidence on a scale 0-3+ for the protective effect of NSAIDs:

Organ

Evidence

Lg Bowel

  3+

Stomach

  1+

Esophagus

  1+

Skin

0/1+

Breast

0/1+

Giavannucci et al found a significant (45%) decrease in CRC occurence in the Nurses' Health Study, but only after 20 years' consistent use of ASA (N Engl J Med 1995;333:609). Shorter periods of ASA use led to little or no reduction in CRC development.

Another NSAID, sulindac, taken twice daily for 9 months, reduced the size and number of polyps in FAP patients according to Giardello et al (N Eng J Med 1993;328:1313). Twenty-two patients participated in a double- blind, randomized, placebo-controlled comparison of sulindac tablets and placebo. Overall compliance with scheduled doses averaged 85%. No adverse events could be attributed to sulindac.

Human colon adenoma (HCA) cell lines

DuBois shared recent unpublished data:

  • Cell line HCA-7 has an elevated expression of COX-2.
  • Prostaglandin E2, a product of COX-2 enzyme, decreases after addition of SC 58125, a highly selective COX-2 inhibitor.
  • SC 58125, in nude mice, blocks the growth of injected HCA-7 cells; if treatment is delayed, cytostasis and inhibition of angiogenesis occurs.
  • Addition of prostaglandin E2 reverses the effects of SC 58125.

More information on proposed mechanisms for NSAIDs and prevention of CRC appears in the editorial of Gupta and DuBois (Gastroenterology 1998;114:1095).

For professional correspondence, please contact Dr. DuBois by Fax at: (615) 343-6229 or by E-mail at: duboisrn@ctrvax.vanderbilt.edu

Eugene A. Conrad

Presented at the American Society of Clinical Oncology (ASCO) Meeting, May 16-19, 1998
Copyright © 1998 Conrad Group Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / June 1998
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