Decensi A, Formelli F, Torrisi R, Depalo G, Costa A
NATL TUMOR INST,DIV CLIN ONCOL,I-20133 MILAN,ITALY. NATL TUMOR INST,DIV EXPTL ONCOL B,I-20133 MILAN,ITALY. EUROPEAN INST ONCOL,DIV SENOL,I-20141 MILAN,ITALY.
Oncol Rep. 1994 Jul;1(4):817-24. doi: 10.3892/or.1.4.817.
Fenretinide (4-HPR), a synthetic amide derivative of retinoic acid, has proven effective in preventing chemically induced mammary carcinoma in rodents. During the past years, 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 retinol and insulinlike growth factor-I (IGF-I) levels. Accrual of the phase III study was closed on July 31, 1993 including 2,972 Stage I breast cancer patients. The aim is 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%) have interrupted drug intake due to toxicity. The only remarkable adverse effect of 4-HPR administration 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. However, about 50% of the patients with altered dark-adaptometry are asymptomatic and the alterations of dark adaptation are promptly reversible upon drug discontinuation. Plasma level of N-(4-methoxyphenyl) retinamide (4-MPR), the principal metabolite of 4-HPR, which tends to be higher in women over 55 years with a high percentage of adipose tissue, is the major determinant of both retinol and IGF-I decrease. Since the combination of 4-HPR with the antioestrogen tamoxifen has shown a synergistic activity in preclinical models, it is currently an important avenue of clinical investigation in an attempt to prevent breast cancer. Moreover, a dose reduction of one or both agents in an effort to minimise toxicity while maintaining activity, would represent a major improvement in cancer chemoprevention.
芬维A胺（4-HPR）是一种视黄酸的合成酰胺衍生物，已被证明在预防啮齿动物化学诱导的乳腺癌方面有效。在过去几年中，我们小组在旨在评估其在乳腺癌预防中的药理学、毒性和疗效的临床研究中，对该分子进行了特别的研究。我们已经证明，4-HPR的血药浓度在长达5年的给药期间保持恒定，该药物在人乳腺中蓄积，并且它会导致血浆视黄醇和胰岛素样生长因子-I（IGF-I）水平显著下降。III期研究的入组于1993年7月31日结束，共纳入2972例I期乳腺癌患者。目的是评估5年服用4-HPR预防对侧新发原发性乳腺癌的疗效。对方案和治疗的依从性很高，药物耐受性良好；在1397名女性中，只有51名（3.6%）因毒性而中断药物摄入。服用4-HPR唯一显著的不良反应是暗适应能力下降，约四分之一的患者会出现这种情况，这取决于血浆视黄醇降至100 ng/ml的阈值水平以下。然而，约50%暗适应测量改变的患者没有症状，并且停药后暗适应的改变可迅速逆转。4-HPR的主要代谢产物N-（4-甲氧基苯基）视黄酰胺（4-MPR）的血浆水平是视黄醇和IGF-I降低的主要决定因素，在55岁以上且脂肪组织比例高的女性中往往更高。由于4-HPR与抗雌激素他莫昔芬的联合在临床前模型中显示出协同活性，目前它是预防乳腺癌临床研究的一个重要途径。此外，减少一种或两种药物的剂量以在保持活性的同时尽量减少毒性，将是癌症化学预防的一项重大进展。
