Dhaini Hassan R, Thomas Dafydd G, Giordano Thomas J, Johnson Timothy D, Biermann J Sybil, Leu Kirsten, Hollenberg Paul F, Baker Laurence H
Department of Environmental Health Sciences, Toxicology Program, University of Michigan, Ann Arbor 48109, USA.
J Clin Oncol. 2003 Jul 1;21(13):2481-5. doi: 10.1200/JCO.2003.06.015.
Osteosarcoma, the most common pediatric primary bone tumor, is an aggressive malignancy with a tendency for early pulmonary metastasis. A reliable biomarker to predict clinical outcome at diagnosis has not yet been identified. To date, pathological review of neoadjuvant chemotherapy-induced necrosis is the most useful determinant of which patients are likely to develop metastatic disease. There is a clinical need to identify patients who will benefit from more aggressive preoperative therapy or perhaps require less aggressive chemotherapy. More than 30 human P450 isoenzymes have been characterized, with at least nine possessing some clinical relevance. One of these, CYP3A4/5 is involved in metabolic activation and detoxification of a wide number of carcinogens and chemotherapeutic agents, including many drugs that are useful in the treatment of osteosarcomas.
Osteosarcoma tissue microarray blocks containing biopsies from 18 primary tumors were used to analyze the expression of P450s 1A1/2, 1B1, 2B6, 2D6, and 3A4/5 by enzyme-linked avidin-biotin complexed immunohistochemistry. The frequencies of expression were 83%, 67%, and 83% for P450s 1A1/2, 1B1, and 3A4/5, respectively. P450s 2B6 and 2D6 were not detectable.
These results were extended by developing a fluorescent-based quantitative immunocytochemistry technique to assess the levels of CYP3A4/5 in 18 paraffin-embedded primary biopsy sections. Expression of CYP3A4/5 was found to be significantly higher in primary biopsies of patients who developed distant metastatic disease compared with biopsies from patients with nonmetastatic disease (P = 0.0004).
High cytochrome P450 CYP3A4/5 expression may predict metastasis and poor prognosis in osteosarcomas. Its use as a biomarker of therapeutic response will have implications for the treatment of these tumors.
骨肉瘤是最常见的儿童原发性骨肿瘤，是一种侵袭性恶性肿瘤，有早期肺转移倾向。目前尚未确定一种可靠的生物标志物来预测诊断时的临床结果。迄今为止，新辅助化疗诱导坏死的病理评估是判断哪些患者可能发生转移性疾病最有用的决定因素。临床上需要识别出哪些患者将从更积极的术前治疗中获益，或者可能需要强度较低的化疗。已鉴定出30多种人细胞色素P450同工酶，其中至少9种具有一定临床相关性。其中之一，CYP3A4/5参与多种致癌物和化疗药物的代谢激活与解毒，包括许多对骨肉瘤治疗有用的药物。
采用含18例原发性肿瘤活检组织的骨肉瘤组织芯片块，通过酶联抗生物素蛋白-生物素复合物免疫组化分析细胞色素P450 1A1/2、1B1、2B6、2D6和3A4/5的表达。细胞色素P450 1A1/2、1B1和3A4/5的表达频率分别为83%、67%和83%。未检测到细胞色素P450 2B6和2D6。
通过开发一种基于荧光的定量免疫细胞化学技术来评估18例石蜡包埋原发性活检切片中CYP3A4/5的水平，扩展了这些结果。发现发生远处转移性疾病患者的原发性活检中CYP3A4/5的表达明显高于非转移性疾病患者的活检（P = 0.0004）。
高细胞色素P450 CYP3A4/5表达可能预示骨肉瘤转移及预后不良。将其用作治疗反应的生物标志物将对这些肿瘤的治疗产生影响。
