Urban D, Myers R, Manne U, Weiss H, Mohler J, Perkins D, Markiewicz M, Lieberman R, Kelloff G, Marshall M, Grizzle W
University of Alabama at Birmingham, Ala. 35294, USA.
Eur Urol. 1999;35(5-6):429-38. doi: 10.1159/000019875.
An NCI-sponsored, phase II trial of N-(4-hydroxyphenyl)- retinamide (4-HPR) in patients with organ-confined prostate cancer in the period prior to radical prostatectomy was carried out. Thirty-seven men with the histologic diagnosis of prostate cancer planning to have radical prostatectomy entered the study after informed consent and were given 4-HPR (or matching placebo) as a single daily dose (two 100-mg capsules of 4-HPR or two capsules of placebo daily) for 3 weeks prior to surgery. Four men dropped out for unrelated reasons. Thirty-three men completed the study. At the time of surgery, repeat biopsies of the prostate were performed to study the effects of the drug on potential surrogate endpoint biomarkers (SEBs) of malignancy within the tissue. The panel of potential SEBs of malignancy include p53, cytomorphometric indices, ploidy, PNCA, erbB-2, erbB-3, EGF receptor, TGF-alpha tumor-associated glycoprotein-72, fatty acid synthetase and Lewis Y antigen. Twenty-three patients had matching pre- and posttherapy lesions and were considered informative. Results from the patients indicate significant differential expression of biomarkers in pretreatment specimens of uninvolved prostatic tissue (normal-appearing epithelia) prostatic intraepithelial neoplasia (PIN) and prostate cancer. The mean erbB-2 expression was 0.58 in uninvolved vs. 1.04 in PIN (p = 0.002); while the mean erbB-2 expression was 1.35 in prostate cancer (p = 0.0007, uninvolved vs. prostate cancer). A similar pattern of increased biomarker expression between uninvolved and PIN or prostate cancer tissues can be observed for EGF receptor (mean = 1.21, 1.87 and 1.76 for uninvolved, PIN and prostate cancer, respectively) and erbB-3 (mean = 0.81, 1.59 and 1.30 for uninvolved, PIN and prostate cancer, respectively). There were no statistically significant differences in biomarkers observed in the 4-HPR-treated patients when compared with placebo-treated control patients. There was a posttreatment up-regulation of biomarkers observed in both groups of patients. This observation is most likely explained by an effect due to the diagnostic sextant biopsy equally affecting both groups of patients. Results from this study do not demonstrate a chemoprevention effect of 4-HPR on tissue-based SEBs at the dose given.
美国国立癌症研究所（NCI）资助开展了一项二期试验，研究N-(4-羟苯基)视黄酰胺（4-HPR）在根治性前列腺切除术之前用于器官局限性前列腺癌患者的情况。37名经组织学诊断为前列腺癌且计划进行根治性前列腺切除术的男性在签署知情同意书后进入研究，在手术前3周每天服用一次4-HPR（或匹配的安慰剂）（每天两粒100毫克的4-HPR胶囊或两粒安慰剂胶囊）。4名男性因无关原因退出。33名男性完成了研究。在手术时，对前列腺进行重复活检，以研究该药物对组织内恶性肿瘤潜在替代终点生物标志物（SEB）的影响。潜在的恶性肿瘤SEB包括p53、细胞形态计量指标、倍性、增殖细胞核抗原（PCNA）、erbB-2、erbB-3、表皮生长因子（EGF）受体、转化生长因子-α（TGF-α）、肿瘤相关糖蛋白-72、脂肪酸合成酶和Lewis Y抗原。23名患者有治疗前和治疗后的匹配病变，被视为有参考价值。患者的结果表明，在未受累前列腺组织（外观正常的上皮）、前列腺上皮内瘤变（PIN）和前列腺癌的治疗前标本中，生物标志物有显著差异表达。未受累组织中erbB-2的平均表达为0.58，而PIN中为1.04（p = 0.002）；前列腺癌中erbB-2的平均表达为1.35（未受累与前列腺癌相比，p = 0.0007）。对于EGF受体（未受累、PIN和前列腺癌的平均值分别为1.21、1.87和1.76）和erbB-3（未受累、PIN和前列腺癌的平均值分别为0.81、1.59和1.30），在未受累组织与PIN或前列腺癌组织之间也可观察到生物标志物表达增加的类似模式。与安慰剂治疗的对照患者相比，在接受4-HPR治疗的患者中观察到的生物标志物没有统计学上的显著差异。两组患者在治疗后均观察到生物标志物上调。这一观察结果很可能是由于诊断性六分区活检的影响对两组患者相同所致。该研究结果未证明在给予的剂量下4-HPR对基于组织的SEB有化学预防作用。
