Chaklader M, Das P, Pereira J A, Law A, Chattopadhyay S, Chatterjee R, Mondal A, Law S
Stem Cell Research and Application Unit, Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, Kolkata-700073, West Bengal, India.
Exp Oncol. 2012 Jul;34(2):90-6.
Peritoneal or retro-peritoneal sarcomatosis related malignant ascites formation is a rare but serious consequence of the locoregional metastatic event. The present work aimed to study the effect of the Hsp90 inhibitor (17-AAG), an ansamycin analog, on cell cycle and DNA replication specific chaperone-clients interaction in the event of peritoneal sarcoma related malignant ascites formation in mouse model at the late stage of malignant growth.
We administered 17-AAG, an Hsp90 inhibitor, divided doses (330 μg/kg b.w./day for first five days then next ten days with166 μg/kg b.w./day) through intra-peritoneal route of inbred Swiss albino mice bearing full grown peritoneal malignant ascites of sarcoma-180. Our study was evaluated by peripheral blood hemogram analysis, malignant ascitic cytology, cell viability test, survival time and mitotic indexing. Furthermore, flowcytometric HSP90, TERT, CyclinD1, PCNA and GM-CSF expression analysis has been considered for special objective of the study.
Our experimental efforts reduced the aggressive proliferation of malignant ascites by drastic downregulation of TERT and cyclin D1 on the verge of cell cycle entry along with DNA replication processivity factor PCNA by directly modulating their folding machinery - heat shock protein 90. Consequently, we observed that malignant ascitic cells became error prone during the event of karyokinesis and produced micronucleus containing malignant cells with low viability. Peripheral neutrophilia due to over-expression of GM-CSF by the peritoneal malignant ascites were also controlled by the treatment with 17-AAG and overall, the treatment modality improved the median survival time.
Finally we can conclude that 17AAG administration might serve as a prospective pharmacological agent for the management of peritoneal sarcoma related malignant ascites and throws light towards prolonged survival of the patients concerned.
腹膜或腹膜后肉瘤病相关的恶性腹水形成是局部区域转移事件中一种罕见但严重的后果。本研究旨在探讨热休克蛋白90（Hsp90）抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG，一种安莎霉素类似物）对小鼠模型恶性生长晚期腹膜肉瘤相关恶性腹水形成过程中细胞周期及DNA复制特异性伴侣-底物相互作用的影响。
我们通过腹腔注射的方式，对患有肉瘤180完全性腹膜恶性腹水的近交系瑞士白化小鼠给予17-AAG（一种Hsp90抑制剂），分剂量给药（前五天为330μg/kg体重/天，接下来十天为166μg/kg体重/天）。我们通过外周血常规分析、恶性腹水细胞学检查、细胞活力测试、生存时间和有丝分裂指数来评估我们的研究。此外，还通过流式细胞术对Hsp90、端粒酶逆转录酶（TERT）、细胞周期蛋白D1、增殖细胞核抗原（PCNA）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的表达进行分析，以实现本研究的特定目标。
我们的实验通过直接调节TERT和细胞周期蛋白D1在细胞周期进入边缘以及DNA复制持续因子PCNA的折叠机制——热休克蛋白90，显著下调其表达，从而降低了恶性腹水的侵袭性增殖。因此，我们观察到恶性腹水细胞在有丝分裂过程中容易出错，并产生了含有微核的低活力恶性细胞。腹膜恶性腹水过度表达GM-CSF导致的外周嗜中性粒细胞增多也通过17-AAG治疗得到了控制，总体而言，这种治疗方式延长了中位生存时间。
最后我们可以得出结论，给予17AAG可能是治疗腹膜肉瘤相关恶性腹水的一种有前景的药物，并为相关患者的长期生存带来希望。
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