Shin D M, Xu X C, Lippman S M, Lee J J, Lee J S, Batsakis J G, Ro J Y, Martin J W, Hittelman W N, Lotan R, Hong W K
Departments of Thoracic/Head and Neck Medical Oncology, Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Houston, Texas 770.
Clin Cancer Res. 1997 Jun;3(6):875-80.
Although retinoids have proven to be effective as chemopreventive agents in reversing premalignant oral lesions and preventing second primary tumors, their mechanisms of chemopreventive efficacy in clinical settings have not been established. To better define this mechanism, we studied p53 protein and retinoic acid receptor beta (RAR-beta) expression in 52 baseline biopsy samples taken from premalignant oral lesions. We then studied p53 expression in 39 matched samples and RAR-beta expression in 38 matched samples before and after treating them with isotretinoin. The study results were then compared with clinical responses. To detect p53 protein expression, 4-micrometer sections of formalin-fixed, paraffin-embedded tissue specimens were used for immunohistochemical analysis with a monoclonal anti-p53 antibody, and levels of p53 expression were recorded with a labeling index (LI). Expression of RAR-beta mRNA was determined using nonradioactive in situ hybridization, and the staining intensity of RAR-beta mRNA was semiquantitated using scores from 0 (no expression) to 3+ (highest expression). p53 protein was detected in 85% of all lesions. High p53 protein expression (LI >/= 0.2) was detected in 25% of the lesions at baseline and in 18% of the lesions after isotretinoin therapy. The clinical response was 65% for lesions having low p53 expression (LI < 0.2) and 27% for lesions having high p53 expression (P = 0.027). Expression of RAR-beta mRNA was detected in 40% of the patients at baseline and increased to 90% of the patients after isotretinoin therapy (P < 0. 001). Seventy-two percent of the patients having low p53 expression had no RAR-betamRNA expression at baseline, whereas 22% of the patients having high p53 expression had no RAR-beta expression, which suggests that patients having low p53 expression tended to lose RAR-beta mRNA expression in their tissues. Eighty-three percent of patients having low p53 expression had up-regulation of RAR-beta mRNA after isotretinoin therapy, compared with 22% of patients with high p53 expression (P = 0.003). We correlated baseline p53 protein expression with RAR-beta modulation and clinical responses to isotretinoin therapy. The patients with low p53 protein expression at baseline and up-regulation of RAR-beta after isotretinoin therapy achieved a 70% rate of major response. The patients with low p53 protein expression and either no change or down-regulation of RAR-beta or with high p53 expression and up-regulation of RAR-beta had a response rate of 50%. The patients with high p53 protein expression and either no change or down-regulation of RAR-beta had a response rate of only 14% to isotretinoin therapy. The basic mechanisms underlying the association between clinical responses and these two biomarkers need to be explored.
尽管维甲酸已被证明作为化学预防剂在逆转口腔癌前病变和预防第二原发性肿瘤方面是有效的，但其在临床环境中的化学预防功效机制尚未明确。为了更好地确定这一机制，我们研究了取自口腔癌前病变的52份基线活检样本中的p53蛋白和维甲酸受体β（RAR-β）表达。然后我们研究了39份匹配样本在异维甲酸治疗前后的p53表达以及38份匹配样本在异维甲酸治疗前后的RAR-β表达。随后将研究结果与临床反应进行比较。为检测p53蛋白表达，使用福尔马林固定、石蜡包埋组织标本的4微米切片，用单克隆抗p53抗体进行免疫组织化学分析，并用标记指数（LI）记录p53表达水平。使用非放射性原位杂交法测定RAR-β mRNA的表达，并使用从0（无表达）到3 +（最高表达）的评分对RAR-β mRNA的染色强度进行半定量。在所有病变中，85%检测到p53蛋白。在基线时，25%的病变检测到高p53蛋白表达（LI≥0.2），异维甲酸治疗后，18%的病变检测到高p53蛋白表达。p53表达低（LI < 0.2）的病变临床反应率为65%，p53表达高的病变临床反应率为27%（P = 0.027）。在基线时，40%的患者检测到RAR-β mRNA表达，异维甲酸治疗后增加到90%的患者（P < 0.001）。p53表达低的患者中，72%在基线时无RAR-β mRNA表达，而p53表达高的患者中，22%无RAR-β表达，这表明p53表达低的患者其组织中倾向于失去RAR-β mRNA表达。异维甲酸治疗后，p53表达低的患者中83%有RAR-β mRNA上调，而p53表达高的患者中这一比例为22%（P = 0.
