Mitsiades Constantine S, Mitsiades Nicholas, Richardson Paul G, Treon Steven P, Anderson Kenneth C
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Semin Oncol. 2003 Apr;30(2):309-12. doi: 10.1053/sonc.2003.50065.
Waldenstrom's macroglobulinemia (WM) remains an incurable B-cell malignancy, necessitating urgent development of novel treatment strategies. Building on our experience on bed-to-bedside translational studies for multiple myeloma (mm), we identified a constellation of novel classes of anti-WM agents, including the proteasome inhibitor PS-341; the ansamycin family of inhibitors (eg, geldanamycin and its analogues) of the heat-shock protein 90 (hsp90) molecular chaperone; histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA); and the thiazolidinedione group of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists (eg, ciglitazone or rosiglitazone). Our preclinical data show that these classes of agents induce growth arrest and apoptosis of WM cells, at concentrations relevant to those achieved in previous clinical uses of these drugs, and suggest that novel therapeutic strategies for WM can be designed to include combinations of these agents, to simultaneously target multiple levels of diverse pathways important for tumor cell growth and survival, and thus maximize the pro-apoptotic activities of these agents and/or neutralize protective responses of WM against their effects. These molecular studies provide a framework for rational design of the next generation of combination therapies for WM.
华氏巨球蛋白血症（WM）仍然是一种无法治愈的B细胞恶性肿瘤，因此迫切需要开发新的治疗策略。基于我们在多发性骨髓瘤（MM）从病床到床边转化研究的经验，我们确定了一系列新型抗WM药物，包括蛋白酶体抑制剂PS-341；热休克蛋白90（hsp90）分子伴侣的安莎霉素家族抑制剂（如格尔德霉素及其类似物）；组蛋白去乙酰化酶抑制剂，如辛二酰苯胺异羟肟酸（SAHA）；以及过氧化物酶体增殖物激活受体-γ（PPAR-γ）激动剂的噻唑烷二酮类（如环格列酮或罗格列酮）。我们的临床前数据表明，这些药物类别在与这些药物先前临床使用中所达到的浓度相关的浓度下，可诱导WM细胞生长停滞和凋亡，并表明WM的新治疗策略可设计为包括这些药物的联合使用，以同时针对对肿瘤细胞生长和存活重要的多种不同途径的多个水平，从而最大化这些药物的促凋亡活性和/或中和WM对其作用的保护性反应。这些分子研究为合理设计下一代WM联合疗法提供了框架。
