Reduction in cancer risk by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors.

We conducted a series of epidemiologic studies to evaluate the chemopreventive effects of aspirin, ibuprofen, and selective cyxlooxygenase-2 (COX-2) inhibitors (coxibs) against cancers of the breast, colon, prostate, and lung. Composite results across all four cancer sites revealed that regular intake of 325 mg aspirin, 200 mg ibuprofen, or standard dosages of coxibs (200 mg celecoxib or 25 mg rofecoxib) produced risk reductions of 49%, 59%, and 64%, respectively. Use of coxibs for at least 2 years was associated with risk reductions of 71%, 70%, 55%, and 60% for breast cancer, colon cancer, prostate cancer and lung cancer, respectively. Effects of ibuprofen were similar to selective coxibs, and slightly stronger than aspirin. These observed effects are consistent with the relative COX-2 selectivity of ibuprofen, coxibs, and aspirin. Acetaminophen, an analgesic without COX-2 activity, had no effect. Overexpression of COX-2 and increased prostaglandin biosynthesis correlates with carcinogenesis and metastasis at most anatomic sites. These results indicate that regular intake of nonselective or selective COX-2 inhibiting agents protects against the development of major forms of cancer.

Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors.

BACKGROUND: Epidemiologic and laboratory investigations suggest that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against colon cancer perhaps due at least in part to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade. METHODS: We conducted a case control study of colon cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 326 incident colon cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003-2004 and compared with 652 controls with no history of cancer and matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and colon cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR) and 95% confidence intervals. RESULTS: Results showed significant risk reductions for selective COX-2 inhibitors (OR = 0.31, 95% CI = 0.16-0.57), regular aspirin (OR = 0.33, 95% CI = 0.20-0.56), and ibuprofen or naproxen (0.28, 95% CI = 0.15-0.54). Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg) produced no significant change in the risk of colon cancer. CONCLUSION: These results suggest that both non-selective and selective COX-2 inhibitors produce significant reductions in the risk of colon cancer, underscoring their strong potential for colon cancer chemoprevention.

Cancer chemoprevention by cyclooxygenase 2 (COX-2) blockade: results of case control studies.

Significant use of selective cyclooxygenase-2 (COX-2) blocking agents prescribed for the treatment of arthritis during 1999 to 2005 facilitates epidemiologic investigations to illuminate their chemopreventive effects against human cancer. We therefore conducted a set of case control studies of selective COX-2 blocking agents to determine their chemopreventive potential for the four major cancers: breast, prostate, colon, and lung. Newly diagnosed cases (323 breast cancer patients, 229 prostate cancer patients, 326 colon cancer patients, and 486 lung cancer patients) were ascertained during 2002 to September 30, 2004, at The James Cancer Hospital and Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio. All cases of invasive cancer were confirmed by examination of the pathology report. Healthy controls without cancer were ascertained from hospital screening clinics during the same time period. Controls were frequency matched at a rate of 2:1 to the cases by age, gender, and county of residence. We collected information on type, frequency, and duration of use of selective COX-2 inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Other potentially important risk factors (smoking, drinking, body mass, medical history, blood pressure and cholesterol medications, family history of cancer, occupational history, and reproductive history for women) were also recorded for each subject. Estimates of odds ratios were obtained with adjustment for age and other potential confounders using logistic regression analysis. Use of selective COX-2 inhibitors resulted in a significant risk reduction for each type of cancer (71% for breast cancer, 55% for prostate cancer, 70% for colon cancer, and 79% for lung cancer) and an overall 68% risk reduction for all four cancers. This investigation demonstrates that COX-2 blocking agents have strong potential for the chemoprevention of cancers of the breast, prostate, colon and lung.

Reduced risk of human lung cancer by selective cyclooxygenase 2 (COX-2) blockade: results of a case control study.

We conducted a case control study of selective cyclooxygenase-2 (COX-2) blocking agents and lung cancer. A total of 492 newly diagnosed lung cancer cases were ascertained during January 1, 2002 to September 30, 2004, at The Ohio State University Medical Center, Columbus, Ohio. All cases were confirmed by examination of the pathology report. Healthy population controls without cancer were ascertained during the same time period. Controls were frequency matched at a rate of 2:1 to the cases by age, gender, and county of residence. We collected information on type, frequency, and duration of use of selective COX-2 inhibitors (primarily celecoxib or rofecoxib) and nonselective NSAIDs such as ibuprofen and aspirin. Estimates of odds ratios (OR) were obtained with adjustment for cigarette smoking, age and other potential confounders using logistic regression analysis. Odds Ratios for selective COX-2 inhibitors were adjusted for past use of other NSAIDs. Use of any selective COX-2 inhibitor for more than one year produced a significant (60%) reduction in the risk of lung cancer (OR=0.40, 95% CI=0.19-0.81). Observed risk reductions were consistent for men (OR=0.26, 95% CI=0.10-0.62) and women (OR=0.52, 95% CI=0.24-1.13) and for individual COX-2 inhibitors (OR=0.28, 95% CI=-0.12-0.67, for celecoxib and OR=0.55, 95% CI=0.19-1.56, for rofecoxib). Intake of ibuprofen or aspirin also produced significant risk reductions (OR=0.40, 95% CI=0.23-0.73 and OR=0.53, 95% CI=0.34-0.82, respectively), whereas acetaminophen, an analgesic with negligible COX-2 activity, had no effect on the risk (OR=1.36, 95% CI=0.53-3.37). This investigation demonstrates for the first time that selective COX-2 blocking agents have strong potential for the chemoprevention of human lung cancer.

Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors.

BACKGROUND: Epidemiologic and laboratory investigations suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against breast cancer due to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade. METHODS: We conducted a case control study of breast cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 323 incident breast cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003-2004 and compared with 649 cancer free controls matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and breast cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR) and 95% confidence intervals. RESULTS: Results showed significant risk reductions for selective COX-2 inhibitors as a group (OR = 0.29, 95% CI = 0.14-0.59), regular aspirin (OR = 0.49, 95% CI = 0.26-0.94), and ibuprofen or naproxen (0.36, 95% CI = 0.18-0.72). Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg) produced no significant change in the risk of breast cancer. CONCLUSION: Selective COX-2 inhibitors (celecoxib and rofecoxib) were only recently approved for use in 1999, and rofecoxib (Vioxx) was withdrawn from the marketplace in 2004. Nevertheless, even in the short window of exposure to these compounds, the selective COX-2 inhibitors produced a significant (71%) reduction in the risk of breast cancer, underscoring their strong potential for breast cancer chemoprevention.

Synthesis and preliminary chemotherapeutic evaluation of the fully C-linked glucuronide of N-(4-hydroxyphenyl)retinamide.

All-trans retinoic acid analogues such as N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive and chemotherapeutic agents but their utility has been hampered by dose-limiting side effects. The glucuronide derivatives of 4-HPR, the oxygen-linked 4-HPROG and the carbon-linked 4-HPRCG, have been found to be more effective agents. The synthetic route to the fully C-linked analogue of 4-HPROG (4-HBRCG), which employs Suzuki coupling and Umpolung chemistries as key methodologies, is shown. The results of this study show 4-HBRCG to be an effective chemotherapeutic agent in a rat mammary tumor model while being devoid of classical retinoid toxicities.

Inhibition of mammary tumor growth by a novel nontoxic retinoid: chemotherapeutic evaluation of a C-linked analog of 4-HPR-glucuronide.

Previous studies from our laboratory suggest that 4-HPROG, the O-glucuronide derivative of 4-HPR, has improved mammary cancer chemopreventive/ antitumor activities as well as reduced toxicity, as compared to 4-HPR. This O-linked glucuronide derivative is a substrate to the P-glucuronidase enzyme and may also undergo hydrolysis in vivo to the vitamin A metabolite, retinoic acid, that is toxic at high concentrations. In an effort to improve analog potency relative to its toxicity, the 4-HPROG's phenolic oxygen was replaced with a methylene group, thus preventing biological cleavage of the glucuronide moiety. The resulting C-linked analog, 4-HPR-C-glucuronide (4-HPRCG), cannot be hydrolyzed to 4-HPR. The results of this study show that 4-HPRCG is an effective chemotherapeutic agent that caused 49% regression of DMBA-induced mammary tumors in rats, while showing almost no side-effects that are often observed with other natural or synthetic retinoids, such as a reduction in blood retinol level, elevation in blood triglyceride (TG) level, and decrease in bone mineral content (BMC). These results suggest that 4-HPRCG should be considered as a better candidate for breast cancer treatment.

Celecoxib: a novel treatment for lung cancer.

Lung cancer is by far the leading cause of cancer-related deaths. Overall survival is poor and has not improved substantially over the last 50 years. Therefore, it is clear that novel and more effective treatments are needed to improve the outcome of therapy. Recent attention has been drawn to the role of cyclooxygenase (COX)-2 in the pathogenesis of cancer, and it has been considered as an attractive target for therapeutic and chemopreventive strategies in lung cancer patients. Celecoxib (Celebrex), Pfizer), a selective COX-2 inhibitor and potent anti-inflammatory agent, has been approved for the treatment of osteoarthritis and rheumatoid arthritis. This orally administered agent is generally well tolerated and has almost no gastrointestinal or renal toxicity. Phase II clinical trials suggest that COX-2 inhibition by celecoxib would enhance response to cytotoxic chemotherapy or radiation therapy through interference with cellular proliferation and tumor angiogenic processes, promotion of apoptosis and immune surveillance, or other possible mechanisms. Celecoxib has shown promising antitumor efficacy in lung cancer and a large variety of solid tumors that rely on COX-2-related mechanisms for growth and survival. This article reviews the profile of celecoxib and evidence supporting its role in the therapy of lung cancer.

An improved synthesis of the C-linked glucuronide of N-(4-hydroxyphenyl)retinamide.

Retinoic acid analogues such as N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventatives and chemotherapeutics for numerous types of cancer. The C-linked analogue of the O-glucuronide of 4-HPR (4-HPRCG) has been shown to be a more effective agent. The synthetic route to this molecule has been significantly improved by access to a key C-benzyl-glucuronide intermediate through employment of a Suzuki coupling reaction between an exoanomeric methylene sugar and an aryl bromide. Preliminary evidence shows 4-HPRCG has chemotherapeutic activity.