New agents for cancer chemoprevention

Abstract

Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned.The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids [e.g., retinol, retinyl palmitate, all-trum-retinoic acid, and 13-cis-retinoic acid], calcium, pcarotene, vitamin E, tamoxifen, and finaskride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase Ill chemoprevention trials. Prominent in this group are all-truns-N-(4-hydroxy phenylfretmamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylomithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA). A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-I-cysteine, curcumin. DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3carbino1, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., acarotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs. Other agents of high interest are aromatase inhibitors (eg.. (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean hypsin inhibitor). Combinations are also being considered, such as vitamin E with I-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are rus isoprenylation and epidermal growth factor receptor inhibitors. 1997 Wiley-Liss, Inc.* Key words: cancer chemo reventive agents, drug development, retinoids, DFMO, NSAlDs, oltipraz, Phase I clinical trials, b hase II clinical trials evaluation in animal models and human clinical trials: A review.

Selenium redox biochemistry of zinc–sulfur coordination sites in proteins and enzymes

“…The considerable potential of such compounds as antiviral and anticancer drugs is apparent, and the activity of some selenodrugs based on an interaction with zinc-sulfur centers can be anticipated but has not been systematized (29)(30)(31).…”

Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice

“…The importance of metabolism in carcinogenesis is highlighted by the fact that target organ specificity and even species susceptibilities can be determined by the presence or absence of metabolic pathways (2,3). A variety of chemicals protect rodents against neoplastic, mutagenic, and other toxic effects of many types of carcinogens (4,5). Some of these protective substances alter the metabolic fate of carcinogens by modulating the activities of either or both phase 1 and phase 2 drug-metabolizing enzymes.…”

The Role of Lecithin: Retinol Acyltransferase (LRAT) Mediated Esterification of Vitamin A in Regulating Human Breast Cancer Cell Proliferation and Differentiation

“…Retinoids have proven to be effective in suppressing breast cancer development in experimental models of carcinogenesis (Lotan 1980). In addition to breast cancer, retinoids have been shown to be effective in suppressing tumor development and/or treatment of cancers of the skin, oral cavity, lung, prostate, bladder, liver, and pancreas (Kelloff et al 1996;Lotan 1996). The biological effects of retinoids are thought to be mainly mediated through interactions with retinoic acid receptors (RARs) or retinoic X receptors (RXRs), which function as dimeric transcription factors modulating gene expression by binding to RA-response elements (RAREs or RXREs) in the promoter regions of target genes (Chambon 1996).…”