ISSN:
0730-2312
Keywords:
Breast cancer
;
chemoprevention
;
EGF
;
4-HPR
;
growth factors
;
IGF-I
;
retinoid
;
retinol
;
tamoxifen
;
TGF-β
;
Life and Medical Sciences
;
Cell & Developmental Biology
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
Notes:
Fenretinide (4-HPR), a synthetic derivative of retinoic acid, has proven effective at inhibiting in vitro breast cancer cell growth and preventing the progression of chemically induced mammary carcinoma in rodents. Our group has made a particular effort with regard to this molecule in clinical studies aimed at evaluating its pharmacology, toxicity, and efficacy in breast cancer prevention. We have demonstrated that 4-HPR blood levels remain constant during administration for as long as 5 years, that the drug accumulates in the human breast, and that it induces a significant decline of plasma insulin-like growth factor-I (IGF-I) levels. To date, 2,972 Stage I breast cancer patients have been randomized to evaluate the efficacy of a 5-year administration of 4-HPR to prevent new contralateral primary breast cancers. Compliance to protocol and treatment is high and tolerability of the drug is good; only 51 women out of 1,397 (3.6%) had to interrupt drug intake due to toxicity. The only potential limitation to the extensive use of 4-HPR is diminished dark adaptation, which occurs in about one-fourth of the patients and is dependent on the decline of plasma retinol below the threshold level of 100 ng/ml. Plasma levels of (4-methoxyphenyl)retinamide (4-MPR), the principal metabolite of 4-HPR, which are higher in elderly women with a high percentage of adipose tissue, are the major determinants of the retinol decrease. However, about 50% of the patients with altered dark-adaptometry are asymptomatic and the alterations are promptly reversible upon drug discontinuation. Since the combination of 4-HPR with the antiestrogen tamoxifen has shown a synergistic activity in the prevention of breast cancer in preclinical models, it is currently an important avenue of investigation in an attempt to reduce human breast cancer incidence and mortality. Moreover, a dose reduction of one or both agents in an effort to minimize toxicity while maintaining activity, would represent a major improvement in cancer chemoprevention. For these reasons, a randomized study of different dose combinations in Stage I-II breast cancer patients using a number of circulating growth factors as surrogate endpoints has been initiated. The main endpoint is the reduction of plasma IGF-I levels.
Additional Material:
1 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/jcb.240531142
Permalink
