Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors
Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors
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DOI：
10.1073/pnas.0708101104
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发表时间：
2007-10-23
影响因子：
11.1
通讯作者：
Pastan, Ira
中科院分区：
文献类型：
--
作者：
Zhang, Yujian;Xiang, Laiman;Pastan, Ira
重组免疫毒素是由融合至毒素的肿瘤特异性抗体的Fv部分组成的嵌合蛋白。SS 1 P（CAT-5001）是一种免疫毒素，由抗间皮素Fv与假单胞菌外毒素A的38-kDa部分融合组成。免疫毒素已被证明在淋巴瘤和白血病中有活性，但对实体瘤的活性要低得多。我们最近报道，紫杉醇和其他化疗药物在小鼠中显示出惊人的协同抗肿瘤活性时，免疫毒素SS 1 P，其目标是实体瘤上的间皮素抗原，与紫杉醇。使用一对紫杉醇敏感和紫杉醇耐药KB肿瘤同样敏感的免疫毒素SS 1 P，我们研究了协同作用的机制。我们发现，协同作用只观察到与紫杉醇敏感的肿瘤，排除了紫杉醇对内皮细胞的影响。我们还表明，KB肿瘤在其细胞外空间中具有高水平的脱落间皮素;这些水平随着肿瘤大小而增加，并且在紫杉醇治疗后，在药物敏感性肿瘤中显着下降，但在耐药肿瘤中则没有。由于肿瘤中的间皮素水平超过肿瘤中的SS 1 P水平，并且由于脱落的间皮素以高速率持续释放到循环中，我们提出协同作用是由于紫杉醇诱导的脱落抗原水平下降。
Recombinant immunotoxins are chimeric proteins composed of the Fv portion of a tumor-specific antibody fused to a toxin. SS1P (CAT-5001) is an immunotoxin composed of an antimesothelin Fv fused to a 38-kDa portion of Pseudomonas exotoxin A. Immunotoxins have been shown to be active in lymphomas and leukemias, but are much less active against solid tumors. We recently reported that Taxol and other chemotherapeutic agents show striking synergistic antitumor activity in mice when immunotoxin SS1P, which targets the mesothelin antigen on solid tumors, is given with Taxol. Using a pair of Taxol-sensitive and Taxol-resistant KB tumors equally sensitive to immunotoxin SS1P, we examined the mechanism of synergy. We show that synergy is only observed with Taxol-sensitive tumors, ruling out an effect of Taxol on endothelial cells. We also show that the KB tumors have high levels of shed mesothelin in their extracellular space; these levels increase with tumor size and, after Taxol treatment, dramatically fall in the drug-sensitive but not the drug-resistant tumors. Because the mesothelin levels in the tumor exceed the levels of SS1P in the tumor, and because shed mesothelin is being continuously released into the circulation at a high rate, we propose that synergy is due to the Taxol-induced fall in shed antigen levels.