Study of multidrug-resistance mechanism and its overcoming in cutaneous mesenchymal malignant tumor

上皮样肉瘤在软组织恶性肿瘤中的发病率虽低，但其复发和转移率高。迄今为止，晚期上皮样肉瘤的有效化疗尚未建立，此外，上皮样肉瘤已知表现出多药耐药（MDR）。本研究检测了两种上皮样肉瘤细胞系对抗癌药物的化学敏感性。结果表明，ES-OMC-MN和SFT-8606细胞株对新碱（IC_<50>= 1190 nM和872 nM）和阿霉素（IC_<50>=921 nM和650 nM）均有抗性，对放线菌素D （IC_<50><10 nM）敏感。p-糖蛋白（p-Gp）和多药耐药基因1 （MDRI）在这些细胞系中未表达，但肺耐药蛋白（LRP）在这些细胞系中有高表达。两种细胞系建立的原始肿瘤组织也发现lrp阳性，但不表达p- Gp。经2.5 μg/ml抗lrp抗体（LRP-56）预处理的ES-OMC-MN和SFT- 8606细胞株对阿霉素的化学敏感性无显著变化，但长春新碱的IC_<50> （IC_<50>=128 nM和27 nM）明显小于未预处理的细胞株。因此，这两种细胞系的长春新碱耐药是由lrp介导的。已知环孢素A是p-Gp的修饰剂，在ES-OMC- MN和SFT-8606细胞株（IC_<50>=6.2 nM和17 nM）中也能诱导长春新碱耐药逆转，提示环孢素A可能是LRP的修饰剂。

The incidence of epithelioid sarcoma among cases with malignant soft tissue tumors is small, however, the rates of recurrence and metastasis of this type of sarcoma are high. To date, effective chemotherapy for advanced epithelioid sarcoma has not been established, furthermore, epithelioid sarcoma is known to exhibit multidrug resistance (MDR). The chemosensitivities of two cell lines established from epithelioid sarcoma to anticancer agents are examined in this study. The results showed that the ES-OMC-MN and SFT-8606 cell lines were resistant to vincristine (IC_<50>=1,190 nM and 872 nM, respectively) and adriamycin (IC_<50>=921 nM and 650 nM, respectively), but sensitive to actinomycin D (IC_<50><10 nM). The p-glycoprotein (p-Gp) and multidrug resistance gene 1 (MDRI) were not expressed in these cell lines, however, a high expression level of the lung resistance protein (LRP) was observed. The original tumor tissues from which the two cell lines were established were also found to be LRP-positive but not to express p- Gp. Their chemosensitivities to adriamycin of the cell lines, ES-OMC-MN and SFT- 8606, pretreated with 2.5 μg/ml anti-LRP antibody (LRP-56) were not significantly altered, however, the IC_<50> of vincristine became much smaller (IC_<50>=128 nM and 27 nM, respectively) than that in a non-pretreated cell line. It is thus suggested that the vincristine resistance in the two cell lines is LRP-mediated. Since cyclosporin A, known to be a modifier of p-Gp, also induced reversal of vincristine resistance in the ES-OMC- MN and SFT-8606 cell lines (IC_<50>=6.2 nM and 17 nM, respectively), it is suggested that cyclosporin A acts as a modifier against LRP.