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Biomedical subjects

C W Boone

Publications and source records attributed to C W Boone.

At least 19 recordsLinked to original sources
PubMed1994

Progress in cancer chemoprevention: perspectives on agent selection and short-term clinical intervention trials.

The basic cancer-related chemical and biological sciences, pathology, and epidemiology have contributed to the understanding that antimutagenesis and antiproliferation are the important general mechanisms of chemoprevention and to the development of antimutagenic and anti-proliferative agents as potential chemopreventive drugs. These disciplines have also provided the biochemical and histopathological bases for identifying intermediate biomarkers that can be used as surrogate end points for cancer incidence in clinical chemoprevention trials and for selecting cohorts for these trials. Particularly important as histological biomarkers of cancer are the cytonuclear morphological and densitometric changes that define intraepithelial neoplasia (IEN). IEN changes are on the causal pathway to cancer. They may serve as target lesions in Phase II chemoprevention trials and as standards against which other earlier cellular and molecular biomarkers can be evaluated. Strategies for the clinical evaluation of chemopreventive agents have been defined for seven targets--colorectal, prostate, lung, breast, bladder, oral, and cervical cancers. Cohorts have been identified for short-term Phase II trials that investigate the effects of chemopreventive agents on IEN and on earlier biomarkers. Patients with adenomas serve as a cohort for trials in colon. One cohort for Phase II trials in prostate is patients with early stage cancers scheduled for prostatectomy; another is patients with prostatic intraepithelial neoplasia (without prostatic carcinoma). Patients treated for lung cancer are at high risk for bronchial dysplasia and second cancers; such patients are a cohort for Phase II trials in lung cancer. Presurgical breast cancer patients and patients with ductal or lobular carcinoma in situ are cohorts for studies in breast. Patients with superficial bladder cancers (Ta/T1 with or without carcinoma in situ) are cohorts for studies of chemoprevention in bladder, and patients with dysplastic oral leukoplakia are evaluated for chemoprevention of oral cancers. Cervical intraepithelial neoplasia is a prototype IEN, and patients with cervical intraepithelial neoplasia are a cohort for studies of cervical cancer.

Adenoma↗
PubMed1994

Mechanistic considerations in chemopreventive drug development.

This overview of the potential mechanisms of chemopreventive activity will provide the conceptual groundwork for chemopreventive drug discovery, leading to structure-activity and mechanistic studies that identify and evaluate new agents. Possible mechanisms of chemopreventive activity with examples of promising agents include carcinogen blocking activities such as inhibition of carcinogen uptake (calcium), inhibition of formation or activation of carcinogen (arylalkyl isothiocyanates, DHEA, NSAIDs, polyphenols), deactivation or detoxification of carcinogen (oltipraz, other GSH-enhancing agents), preventing carcinogen binding to DNA (oltipraz, polyphenols), and enhancing the level or fidelity of DNA repair (NAC, protease inhibitors). Chemopreventive antioxidant activities include scavenging reactive electrophiles (GSH-enhancing agents), scavenging oxygen radicals (polyphenols, vitamin E), and inhibiting arachidonic acid metabolism (glycyrrhetinic acid, NAC, NSAIDs, polyphenols, tamoxifen). Antiproliferation/antiprogression activities include modulation of signal transduction (glycyrrhetinic acid, NSAIDs, polyphenols, retinoids, tamoxifen), modulation of hormonal and growth factor activity (NSAIDs, retinoids, tamoxifen), inhibition of aberrant oncogene activity (genistein, NSAIDs, monoterpenes), inhibition of polyamine metabolism (DFMO, retinoids, tamoxifen), induction of terminal differentiation (calcium, retinoids, vitamin D3), restoration of immune response (NSAIDs, selenium, vitamin E), enhancing intercellular communication (carotenoids, retinoids), restoration of tumor suppressor function, induction of programmed cell death (apoptosis) (butyric acid, genistein, retinoids, tamoxifen), correction of DNA methylation imbalances (folic acid), inhibition of angiogenesis (genistein, retinoids, tamoxifen), inhibition of basement membrane degradation (protease inhibitors), and activation of antimetastasis genes. A systematic drug development program for chemopreventive agents is only possible with continuing research into mechanisms of action and thoughtful application of the mechanisms to new drug design and discovery. One approach is to construct pharmacological activity profiles for promising agents. These profiles are compared among the promising agents and with untested compounds to identify similarities. Classical structure-activity studies are used to find optimal agents (high efficacy with low toxicity) based on good lead agents. Studies evaluating tissue-specific and pharmacokinetic parameters are very important. A final approach is design of mechanism-based assays and identification of mechanism-based intermediate biomarkers for evaluation of chemopreventive efficacy.

Animals↗
PubMed1994

Strategy and planning for chemopreventive drug development: clinical development plans. Chemoprevention Branch and Agent Development Committee. National Cancer Institute.

At the National Cancer Institute, Division of Cancer Prevention and Control, the Chemoprevention Branch and Agent Development Committee develop strategies for efficiently identifying, procuring, and advancing the most promising drugs into clinical trials. Scientific expertise is applied at each phase of development to critically review the testing methods and results, and to establish and apply criteria for evaluating the agents for further development. The Clinical Development Plan, prepared by the Chemoprevention Branch and the Agent Development Committee, is a summary of the status of the agent regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. It also contains the strategy for further development of the drug that addresses pharmacodynamics, drug effect measurements, intermediate biomarkers for monitoring efficacy, toxicity, supply and formulation, regulatory approval, and proposed clinical trials. Sixteen Clinical Development Plans are presented here: N-acetyl-l-cysteine (NAC), aspirin, calcium, beta-carotene, 2-difluoromethylornithine (DFMO), DHEA analog 8354, 18 beta-glycyrrhetinic acid, N-(4-hydroxyphenyl)retinamide (4-HPR), ibuprofen, oltipraz, piroxicam, Proscar, sulindac, tamoxifen, vitamin D3 and analogs, and vitamin E. The objective of publishing these plans is to stimulate interest and thinking among the scientific community on the prospects for developing chemopreventive drugs.

Clinical Trials as Topic↗
PubMed1994

Chronic toxicity studies of the potential cancer preventive 2-(difluoromethyl)-dl-ornithine.

The synthetic compound 2-(difluoromethyl)-dl-ornithine irreversibly inhibits ornithine decarboxylase and reduces the intracellular levels of the polyamine cell cycle factors putrescine and spermidine. The drug has shown chemopreventive efficacy in numerous laboratory epithelial cancer models and is a prototype for antiproliferative agents. Chronic toxicity studies in rats and dogs were performed to characterize the toxicities of the compound at high dosages and to support its further development in clinical trials as a potential chemopreventive agent. Chronic administration (52 weeks) by gavage to Charles River CD rats at dosages of 400, 800, and 1600 mg/kg produced weight loss, increased platelets, alopecia and skin abrasions, dermatitis, liver necrosis, and gastric inflammation. The no-effect dose in this study was considered 400 mg/kg. Chronic administration by capsule to dogs at dosages of 50, 100, and 200 mg/kg produced conjunctivitis, hyperkeratosis and alopecia, and cystic intestinal crypts. A no-effect dose was not determined in this study. The toxicities demonstrated in these studies may be minimized at lower dosages and support the further development of this compound in chemopreventive clinical investigations.

Animals↗