Development of breast cancer chemopreventive drugs

Abstract

Breast cancer is the second highest cause of cancer mortality (19%) estimated for US. 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(s1, 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 breast cancer chemoprevention, 7,12-dimethylbenz(a)anthracene (DMBAbinduced 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 DMBAinduced 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 1 clinical trials are designed to investigate human dose-related safety and pharmacokinetics of the drug. Phase I1 trials are small scale, placebo-controlled studies designed to determine chemopreventive efficacy and optimal dosing

Anti-Aromatase Activity of Phytochemicals in White Button Mushrooms (Agaricus bisporus)

“…A variety of dietary substances, including plant extracts, fruits and vegetables, vitamins, minerals, and minor dietary constituents, are associated with a lower risk of breast cancer development (16)(17)(18)(19). Published literature on the contribution of fruits and vegetables in relative risk reduction of breast cancer is conflicting and it is difficult to draw absolute conclusions from the data.…”

Breast cancer chemoprevention trials using the fine-needle aspiration model

“…34:7-12, 2000. 2000 Key words: biomarker; breast; breast cancer development; chemoprevention; clinical trials; cytology; ER; EGFR; fine-needle aspiration (FNA); Her-2/neu; high risk; p53; ploidy; risk assessment; study design; surrogate endpoint biomarker For phase II trials of potential agents that might prevent breast cancer, one must identify appropriate cohorts of subjects, select optimum tissue biomarkers for testing, standardize tissue sampling methods, and otherwise develop a reliable model for chemoprevention trials [Dhingra, 1995;Dhingra et al, 1993;Fabian and Kimler, 1997;Fabian et al, 1998;Kelloff et al, 1993; O'Shaughnessy, 1996]. The most appropriate subjects for phase II trials will be those who consider themselves at short-term high risk of developing breast cancer and who possess breast tissue biomarkers that are predictive for breast cancer development and are theoretically reversible.…”

Cancer risk factors for selecting cohorts for large-scale chemoprevention trials

“…Other types of markers may be identified within these lesions. For example, aneuploidy, a genetic biomarker, has been identified in over 50% of DCIS [29]. Proliferation markers such as proliferating cell nuclear antigen (PCNA) and Ki-67 antigen expression may be associated with both PIN and DCIS.…”