Cancer Chemoprevention Drug Targets

Abstract

Cancer chemoprevention is a new approach in the management of cancer. Traditional cytotoxic chemotherapeutic approaches cannot cure most advanced solid malignancies. Chemoprevention can be defined as the use of non-cytotoxic drugs and natural agents to block the progression to invasive cancer. Chemoprevention can either prevent DNA damage that initiates the neoplastic transformation process or reverses the progression of pre-invasive lesions. Epidemiological observations, experimental evidence from animal carcinogenesis models, knock-out models, cancer cell lines and clinical trials have shown the efficacy of this approach. Recent advances in our understanding of carcinogenesis have led to the synthesis of new drugs that target specific receptors. Non-steroidal anti-inflammatory drugs target the prostaglandin pathway. The identification of the role of cyclooxygenase-2 in epithelial carcinogenesis led to the synthesis of selective cyclooxygenase-2 inhibitors (Celecoxib). Celecoxib was subsequently approved for the prevention of colon polyps in familial adenomatous polyposis after the completion of a randomized clinical trial. The large chemoprevention clinical trial with the selective estrogen receptor modulator, tamoxifen, showed the benefit of tamoxifen in the prevention of breast cancer in high-risk women. Retinoids and rexinoids target the retinoid receptors and have a role in chemoprevention of aerodigestive, hepatic and cervical neoplasia. Selenium, an inhibitor of the glutathione peroxidase system, is being tested in the chemoprevention of prostate cancer and lung cancer. The different isoforms of vitamin E (tocopherols) may be chemopreventive. Recent evidence indicates that gamma-tocopherol may be a more powerful chemopreventive than the alpha-tocopherol. The review details the rationale, experimental and clinical evidence and the drug targets of the chemopreventive agents that are currently in various phases of clinical development.

Carotenoid metabolism in mammals, including man: formation, occurrence, and function of apocarotenoids

“…Chemoprevention can be defi ned as the application of natural or synthetic molecules to prevent, inhibit, or reverse the carcinogenic machinery ( 113 ). Epidemiologic studies demonstrated that individuals eating more fruits and vegetables that are rich in carotenoids and people having higher serum ␤ -carotene levels have a lower risk of cancer, particularly lung cancer ( 114 ).…”

Effect of celecoxib on E-cadherin, VEGF, microvessel density and apoptosis in gastric cancer

“…For example, aspirin, other NSAIDS and calcium have demonstrated considerable reductions of risk in colorectal cancer, and NSAIDs have been shown to effectively protect against the development of oesophageal and gastric cancers from their premalignant conditions. 2,3 The mechanisms of chemopreventive effects of NSAIDs may be largely due to inhibition of cyclooxygenase-2 (COX-2), the crucial enzyme in the conversion of arachidonic acid to prostaglandins, whereas the side effects of NSAIDs are largely attributable to the nonspecific inhibition of cyclooxygenase-1 (COX-1). COX-2 is frequently over-expressed in various gastrointestinal malignancies, such as gastric and colon cancers, 4,6 whereas its expression in normal gastric and colonic mucosa is relatively low.…”

Formulation Design of Self-Microemulsifying Drug Delivery Systems for Improved Oral Bioavailability of Celecoxib

“…It is being used successfully for the treatment of rheumatoid arthritis, osteoarthritis, acute pain, familial adenomatous polyposis and primary dysmenorrhea. 1,2) Celecoxib also demonstrated significant chemopreventive activity in colon carcinogenesis, ultraviolet B radiation (UVB) induced skin cancer and breast cancer. [3][4][5] Celecoxib is weakly acidic (pK a is 11.1) and hydrophobic (Log P is 3.5) and its low aqueous solubility (3-7 mg/ml) contributes to high variability in absorption after oral administration.…”