Wilson W H, Teruya-Feldstein J, Fest T, Harris C, Steinberg S M, Jaffe E S, Raffeld M
Medicine Branch and Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
Blood. 1997 Jan 15;89(2):601-9.
Although the cause(s) of clinical drug resistance in non-Hodgkin's lymphomas (NHL) is unknown, in vitro studies suggest that abnormalities of the p53 gene, bcl-2 overexpression, and low tumor proliferation rates may increase chemotherapy resistance. We analyzed tumor tissue from 75 patients with relapsed/refractory NHL (Working Formulation A through H) for p53 mutation/overexpression (abnormality), bcl-2 expression, and tumor proliferation and correlated them with multiple clinical characteristics, response to therapy, disease-free survival, and overall survival (OS). All tumor biopsy specimens were obtained within 6 weeks of treatment with EPOCH (infusional etoposide, vincristine, and doxorubicin and bolus prednisone and cyclophosphamide) chemotherapy. Overall, 16 (21%) tumors had a p53 abnormality. Of 13 tumors with overexpression, mutations were confirmed by sequence analysis in 11, and, in 44 tumors without overexpression, 3 showed mutations. A multivariate analysis showed that tumors with a p53 abnormality were more likely to be drug resistant than tumors with normal p53 (56% v 17%; P2 = .008) and to have a shorter median progression-free survival (PFS; 2.1 v 8.2 months; P2 = .008) and OS (11.7 v 21.5 months; P2 = .038), respectively. The presence of a p53 abnormality did not correlate with any clinical characteristic, bcl-2 expression, or tumor proliferation. A significant correlation was found between low tumor proliferation and drug resistance in a univariate (P2 < .006) but not multivariate analysis. Patients with tumor proliferation of less than 80% were significantly more likely to have no response to therapy (31% v 6%) or to fail to achieve a complete response (16% v 44%) and tended to have shorter PFS and OS than did patients with higher proliferation. No significant association was found between bcl-2 expression and drug resistance, PFS or OS, although patients with intermediate-grade histologies and high bcl-2 expression tended to be drug resistant as compared with low level expressors (P2 < .065). Of interest was the finding of a significant association between high bcl-2 and low tumor proliferation (P2 = .0045). In studies that have found an association between high bcl-2 expression and short PFS, bcl-2 may have been a surrogate for low tumor proliferation. Further studies are warranted to examine this question. These results suggest that p53 mutation and low tumor proliferation, but not bcl-2, may be important causes of clinical drug resistance in NHL.
尽管非霍奇金淋巴瘤（NHL）临床耐药的原因尚不清楚，但体外研究表明，p53基因异常、bcl-2过表达和低肿瘤增殖率可能会增加化疗耐药性。我们分析了75例复发/难治性NHL患者（工作分类A至H）的肿瘤组织，检测p53突变/过表达（异常）、bcl-2表达和肿瘤增殖情况，并将它们与多种临床特征、治疗反应、无病生存期和总生存期（OS）进行关联分析。所有肿瘤活检标本均在接受EPOCH（静脉输注依托泊苷、长春新碱和多柔比星，推注泼尼松和环磷酰胺）化疗后6周内获取。总体而言，16例（21%）肿瘤存在p53异常。在13例过表达的肿瘤中，11例通过序列分析证实存在突变；在44例无过表达的肿瘤中，3例显示有突变。多因素分析表明，与p53正常的肿瘤相比，p53异常的肿瘤更易产生耐药（56%对17%；P2 = 0.008），且无进展生存期（PFS）中位数更短（2.1个月对8.2个月；P2 = 0.008），总生存期（OS）也更短（11.7个月对21.5个月；P2 = 0.038）。p53异常的存在与任何临床特征、bcl-2表达或肿瘤增殖均无相关性。单因素分析发现低肿瘤增殖与耐药之间存在显著相关性（P2 < 0.006），但多因素分析未发现此相关性。肿瘤增殖低于80%的患者对治疗无反应（31%对6%）或未达到完全缓解（16%对44%）的可能性显著更高，且其PFS和OS往往比增殖较高的患者更短。虽然中级别组织学且bcl-2高表达的患者与低水平表达者相比倾向于产生耐药（P2 < 0.065），但未发现bcl-2表达与耐药、PFS或OS之间存在显著关联。有趣的是，发现bcl-2高表达与低肿瘤增殖之间存在显著关联（P2 = 0.0045）。在那些发现bcl-2高表达与短PFS之间存在关联的研究中，bcl-2可能是低肿瘤增殖的替代指标。有必要进一步研究以探讨这个问题。这些结果表明，p53突变和低肿瘤增殖而非bcl-2可能是NHL临床耐药的重要原因。
