ISSN:
0730-2312
Schlagwort(e):
β-carotene
;
breast cancer
;
chemoprevention
;
clinical trials
;
ductal carcinoma in situ
;
4-HPR
;
intermediate biomarkers
;
lobular carcinoma in situ
;
surrogate endpoints
;
tamoxifen
;
vitamin E
;
Life and Medical Sciences
;
Cell & Developmental Biology
Quelle:
Wiley InterScience Backfile Collection 1832-2000
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
Notizen:
Breast cancer is the second highest cause of cancer mortality (19%) estimated for U.S. women in 1993 and accounts for the highest proportion of new cancer cases (32%) in this population. The rate of documented cases increased during the early 1970s and again in 1980-87, probably due to early mammographic detection. Increased knowledge of personal risk may also have been a consideration; however, 60% of women diagnosed with breast cancer have no known risk factor(s), such as family history, early age at menarche, late age at menopause, nulliparity, late age at first live birth, socioeconomic status, contraceptive use, postmenopausal estrogen replacement, or high fat intake. To prevent cancer, one strategy undertaken by the NCI is cancer chemoprevention, or intervention with chemical agents at the precancer stage to halt or slow the carcinogenic process.An objective of the NCI, DCPC is to develop promising cancer chemopreventive chemical agents as drugs for human use. Briefly, the process begins with identification of potential agents (e.g., pharmaceuticals, natural products, minor dietary constituents) from surveillance and analysis of the literature and from in vitro prescreen assays. Data on both efficacy (i.e., biological activities that either directly or indirectly indicate inhibition of carcinogenesis) and toxicity are gathered these sources. Various criteria are used to select and prioritize agents for entry into the NCI, DCPC preclinical testing program. The program begins with battery of in vitro efficacy screens using both animal and human cells to select agents for further testing; agents positive in these assays are considered for further testing. In the assay used for breat cancer chemoprevention, 7,12-dimethylbenz(a)anthracene (DMBA)-induced mouse mammary organ culture, 64 chemicals have inhibited formation of hyperplastic alveolar-like nodules. A panel of organ-specific animal screening assays are then used to assess efficacy in vivo. Two assays relevant for breast cancer chemoprevention are inhibition of N-methyl-N-nitrosourea- and DMBA-induced rat mammary gland carcinogenesis. Of 89 agents tested, 29 have inhibited cancer incidence, multiplicity, or both in at least one of the mammary assays; 21 agents are currently on test. Highly promising agents are then placed in traditional preclinical toxicity tests performed in two species. Finally, the most promising and least toxic agents enter clinical trials. Phase I clinical trials are designed to investigate human dose-related safety and pharmacokinetics of the drug. Phase II trials are small scale, placebo-controlled studies designed to determine chemopreventive efficacy and optimal dosing regimens. Three Phase II trials are in progress or in the planning stage investigating tamoxifen citrate or N-(4-hydroxyphenyl)retinamide (4-HPR) as single agents; also, both Phase I and Phase II trials evaluating the combination of 4-HPR and tamoxifen are in the planning stage. Phase III trials involve a large target population, with cancer incidence reduction as the endpoint. Tamoxifen citrate is being tested as a breast cancer chemopreventive in high-risk women in a Phase III trial funded by NCI and under the direction of the National Surgical Adjuvant Breast and Bowel Project. Prevention by 4-HPR of a second primary in the contralateral breat of women surgically treated for Stage I/II breat cancer is being evaluated in a Phase III trial in Italy. Finally, the efficacy of β-carotene or vitamin E in decreasing the incidence of breast, lung, and colon cancer is being determined in a Phase III trial involving nurses 45 years of age or older.Essential to the completion of Phase II clinical trials is the use of populations with defined, measurable biological alterations in tissue occurring prior to malignancy (i.e., intermediate biomarkers) which can serve as surrogate trial endpoints, instead of the more time-consuming and costly endpoint of cancer incidence. Intermediate biomarkers may be of several types, including histological/premalignant lesions, or those based on genetic, biochemical, proliferative, or differentiation-related properties. The only well-established premalignant lesions in the human breast are ductal and lobular carcinoma in situ (CIS). In 1993, an estimated 25,000 new cases of CIS will be diagnosed. These lesions are at high risk of progression to invasive cancer and may be amenable to modulation by a chemopreventive agent. In addition, other types of biomarkers could be identified within the lesions. The goal of this workshop is to identify and discuss the best chemopreventive agents and intermediate biomarkers for use as surrogate endpoints in short-term Phase II breast cancer chemoprevention trials, as well as to design protocols for such trials.
Zusätzliches Material:
2 Tab.
Materialart:
Digitale Medien
URL:
http://dx.doi.org/10.1002/jcb.240531103
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