肿瘤坏死因子-α和美法仑热灌注隔离肢体前后人软组织肉瘤中P-糖蛋白、多药耐药相关蛋白1和肺耐药相关蛋白的表达

Expression of P-glycoprotein, multidrug resistance-associated protein 1, and lung resistance-related protein in human soft tissue sarcomas before and after hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan.

作者信息

Komdeur R, Plaat B E, Hoekstra H J, Molenaar W M, Hollema H, van den Berg E, Mastik M F, van der Graaf W T

机构信息

Division of Surgical Oncology, University Hospital Groningen, Groningen, The Netherlands.

出版信息

Cancer. 2001 May 15;91(10):1940-8.

PMID:11346877

Abstract

BACKGROUND

Multidrug resistance (MDR) is associated with expression of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and lung resistance-related protein (LRP). Tumor necrosis factor (TNF-alpha) is able to modify the expression of these three proteins in different cell types. The effect of TNF-alpha in the clinical situation on patients with soft tissue sarcomas (STS) is indeterminate.

METHODS

Thirty-seven patients with a locally advanced extremity STS underwent hyperthermic isolated limb perfusion (HILP) with TNF-alpha and melphalan; 15 patients received additional interferon gamma. Clinical and histologic responses were documented and used to define the overall response. Samples before and after HILP were analyzed immunohistochemically for P-gp, MRP1, and LRP. Samples were scored as negative or positive (< or = 5% or > 5% positive tumor cells).

RESULTS

Six patients had an overall complete response, 25 patients had a partial response, and 4 patients with STS revealed no change; in 2 patients, the response remained unclear. The percentage STS samples that were positive for all three proteins dropped from 92% before HILP to 85% after HILP. P-gp positive samples were encountered more often than MRP1 positive samples (P < 0.05). The percentage of samples that were negative for all three MDR proteins increased after HILP from 6% to 16%. MDR status had no significant correlation with tumor response.

CONCLUSIONS

HILP with TNF-alpha and melphalan results in excellent overall tumor response in patients with locally advanced STS. STS more often are positive for P-gp than for MRP1. MDR status in patients with STS is not predictive for tumor response after HILP. Data from the current study suggest that the combination of TNF-alpha and melphalan does not induce MDR positive STS: a result with clinical importance when consecutive, adjuvant, doxorubicin-containing chemotherapy is considered.

摘要

背景

多药耐药（MDR）与P-糖蛋白（P-gp）、多药耐药相关蛋白1（MRP1）和肺耐药相关蛋白（LRP）的表达有关。肿瘤坏死因子（TNF-α）能够改变这三种蛋白在不同细胞类型中的表达。TNF-α在软组织肉瘤（STS）患者临床情况下的作用尚不确定。

方法

37例局部晚期肢体STS患者接受了TNF-α和美法仑的热灌注隔离肢体灌注（HILP）；15例患者额外接受了干扰素γ。记录临床和组织学反应并用于定义总体反应。对HILP前后的样本进行P-gp、MRP1和LRP的免疫组化分析。样本分为阴性或阳性（肿瘤细胞阳性率<或=5%或>5%）。

结果

6例患者总体完全缓解，25例患者部分缓解，4例STS患者无变化；2例患者的反应仍不明确。三种蛋白均为阳性的STS样本百分比从HILP前的92%降至HILP后的85%。P-gp阳性样本比MRP1阳性样本更常见（P<0.05）。三种MDR蛋白均为阴性的样本百分比在HILP后从6%增加到16%。MDR状态与肿瘤反应无显著相关性。

结论

TNF-α和美法仑的HILP对局部晚期STS患者产生了良好的总体肿瘤反应。STS中P-gp阳性的情况比MRP1更常见。STS患者的MDR状态不能预测HILP后的肿瘤反应。本研究数据表明，TNF-α和美法仑联合使用不会诱导MDR阳性的STS：当考虑连续、辅助、含阿霉素的化疗时，这一结果具有临床重要性。