fenretinide and Carcinoma-in-Situ

Although tamoxifen appears to markedly reduce breast cancer risk in women with a prior diagnosis of atypical hyperplasia or in situ carcinoma, it is not clear what other groups of women receive substantial benefit. Major breast chemoprevention priorities are to (1) develop new agents that (a) have fewer side effects, (b) are effective in ER--as well as tamoxifen-resistant precancerous tissue, and (c) are compatible with hormone therapy; and (2) develop efficient clinical strategies including prognostic and predictive morphologic and molecular biomarkers. Breast tissue may be repeatedly sampled for evidence of intraepithelial neoplasia by fine needle aspiration, ductal lavage, or needle biopsy to select candidates at highest short-term risk as well as to monitor response in small proof of principle studies prior to a large cancer incidence trial. Molecular marker expression may also be used to select a cohort most likely to respond to a particular agent. A large number of new agents are attractive as potential prevention agents and some are already in clinical prevention testing. Compounds which should be effective in ER + precancerous tissue but may have a better side-effect profile include new selective estrogen receptor modulators which lack uterine estrogen agonist activity, isoflavones, aromatase inactivators/inhibitors for postmenopausal women, and gonadotropin-releasing hormone regimens for premenopausal women. Retinoids, rexinoids, and deltanoids may be efficacious in ER+ tissue resistant to tamoxifen. Agents which should theoretically have activity in ER- or ER+ precancerous tissue include polyamine synthesis inhibitors, tyrosine kinase inhibitors, combined demethylating agents and histone deacetylase inhibitors, as well as metalloprotease and angiogenesis inhibitors. Sample Phase I and Phase II clinical trial designs are reviewed using modulation of molecular markers and breast intraepithelial neoplasia as the major endpoints.

Topics: Aneuploidy; Angiogenesis Inhibitors; Anticarcinogenic Agents; Apoptosis; Aromatase Inhibitors; Breast Neoplasms; Carcinoma in Situ; Clinical Trials, Phase II as Topic; Cyclooxygenase Inhibitors; Disease Progression; Eflornithine; Endpoint Determination; Enzyme Inhibitors; Estrogens; Female; Fenretinide; Gonadotropin-Releasing Hormone; Humans; Hyperplasia; Isoflavones; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Phenotype; Piperidines; Polyamines; Precancerous Conditions; Protein-Tyrosine Kinases; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Thiophenes; Uterine Neoplasms

Topics: Animals; Antineoplastic Agents; beta Carotene; Butylhydroxybutylnitrosamine; Carcinoma in Situ; Carcinoma, Papillary; Carotenoids; Cell Differentiation; Dose-Response Relationship, Drug; Epithelium; Fenretinide; Humans; Isotretinoin; Neoplasms; Neoplasms, Experimental; Tretinoin; Urinary Bladder Neoplasms; Vitamin A

N-(4-hydroxyphenyl)all-trans-retinamide (4-HPR) has shown cancer chemoprevention activity in many experimental and clinical situations. The purpose of this research is to evaluate the in vivo efficacy of 4-HPR in preventing 7,12-dimethylbenz(alpha)antracene (DMBA)-induced oral carcinogenesis and to study histomorphometric changes. 76 Syrian hamsters were separated into four groups: group 1, untreated controls (16 animals); group 2, 4-HPR controls (16 animals); group 3, DMBA-treated animals (28); group 4, animals treated with DMBA and 4-HPR (16). Hamsters were painted with a 0.5% solution of DMBA three times a week in their left buccal pouch. A diet of 2 mmol of 4-HPR/kg was administered. At week 9, 50% of the animals were killed; the remainder were killed at week 12. Pathology and histomorphometric tests were performed on epithelium, dysplasia and carcinomas. At week 9, 5 carcinomas were found in group 3, and 13 in group 4. Cancers in group 4 were more numerous, endophytic and infiltrating than those in group 3 animals. At week 12, 16 carcinomas were detected in group 3 animals, but group 4 developed more carcinomas per animal than group 3. Using these experimental concentrations, 4-HPR cannot express its best chemopreventive effect.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Animals; Anticarcinogenic Agents; Atrophy; Carcinogens; Carcinoma; Carcinoma in Situ; Cell Nucleus; Chemoprevention; Connective Tissue; Cricetinae; Epithelium; Fenretinide; Hyperplasia; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Neoplasm Invasiveness; Time Factors

In most previous chemoprevention studies on inhibition of mammary carcinogenesis, the formation of palpable tumors has been used as an end-point. Little is known about whether chemopreventive agents may similarly or selectively suppress hyperplastic and premalignant stages of the neoplastic process. In this study, we evaluated the effect of 4-(hydroxyphenyl)retinamide (4-HPR) on the development and progression of hyperplastic lesions and carcinoma in situ (CIS) in the N-methyl-N-nitrosourea (MNU) mammary carcinogenesis model in rats. 4-HPR was used as the chemopreventive agent because of its proven inhibitory effect on both the early and late phases of mammary carcinogenesis. Treatment with 4-HPR (2.0 mM/kg diet), beginning 2 days after MNU administration and administered continuously for 10 weeks, suppressed all mammary gland lesions (hyperplasia, CIS and invasive carcinoma) in 35% of animals. In the remaining 65%, 4-HPR allowed the development of hyperplastic lesions, alone or combined with CIS, and/or invasive carcinomas (CA). 4-HPR also increased by 2-fold the ratio between CIS and CA (0.75 per animal in control versus 1.5 in 4-HPR-treated animals), suggesting that it may also suppress the transition of CIS into CA. 4-HPR, when administered beginning 4 weeks after MNU administration [when hyperplastic and premalignant (CIS) lesions are present in the mammary gland], inhibited the frequency of terminal end bud hyperplasia (TEBH) and CA but did not significantly suppress ductal hyperplasia, ductal alveolar hyperplasia, alveolar hyperplasia and CIS. In these animals, 4-HPR induced partial disintegration of mostly peripheral areas of lesions, including carcinomas. Taken together, our data indicate that 4-HPR selectively suppresses the development and progression of hyperplastic lesions and CIS in TEBs. Furthermore, it appears that, in addition to mammary carcinomas, TEBH and CIS could also be used as end-point biomarkers in breast cancer chemoprevention studies.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Carcinoma in Situ; Disease Progression; Drug Screening Assays, Antitumor; Female; Fenretinide; Hyperplasia; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Methylnitrosourea; Precancerous Conditions; Rats; Rats, Sprague-Dawley