Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies.
Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies.
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DOI：
10.1016/j.ejca.2009.10.026
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发表时间：
2010-01
影响因子：
8.4
通讯作者：
Murgo, Anthony J.
中科院分区：
文献类型：
--
作者：
Kummar, Shivaani;Gutierrez, Martin E.;Gardner, Erin R.;Chen, Xiaohong;Figg, William D.;Zajac-Kaye, Maria;Chen, Min;Steinberg, Seth M.;Muir, Christine A.;Yancey, Mary Ann;Horneffer, Yvonne R.;Juwara, Lamin;Melillo, Giovanni;Ivy, S. Percy;Merino, Maria;Neckers, Len;Steeg, Patricia S.;Conley, Barbara A.;Giaccone, Giuseppe;Doroshow, James H.;Murgo, Anthony J.
I期剂量递增研究，以确定热休克蛋白90(Hsp90)抑制剂17-17-dimethylaminoethylamino-17-demethoxygeldanamycin的毒性和最大耐受量，该药每周两次用于晚期癌症患者。17-DMAG静脉滴注1~2小时，每周两次，共4周。按照加速滴定设计，直到观察到毒性，在这一点上进行标准剂量递增。MTD被定义为6名患者中不超过1人经历剂量限制性毒性(DLT)的剂量。对药物动力学进行了评估，并测定了外周血单核细胞(PBMC)中的Hsp70mRNA，其基因产物是一种伴侣蛋白，在抑制Hsp90后上调。共有31名患者接受了92个疗程的治疗。MTD为21 mg/m~2/d；20例患者按此剂量水平入选。9名患者病情稳定，中位数为4个月(范围2-22个月)。Cmax和AUC均随剂量增加而成比例增加。最常见的毒性是1级或2级乏力、食欲减退、恶心、视力模糊和肌肉骨骼疼痛。DLTS为周围神经病变和肾功能不全。外周血单核细胞中Hsp70mRNA的表达具有很高的变异性。每周两次静脉注射。17-DMAG的输注耐受性良好，联合I期研究是有必要的。
Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer. 17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose escalation proceeded. MTD was defined as the dose at which no more than one of six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs). A total of 31 patients received 92 courses of treatment. The MTD was 21 mg/m2/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2-22) months. Both Cmax and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision, and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable. Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.
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DOI：
10.1007/s00259-009-1158-1
发表时间：
2009-09
影响因子：
9.1
作者：
Niu, Gang;Li, Zibo;Cao, Qizhen;Chen, Xiaoyuan
通讯作者：
Chen, Xiaoyuan
影响因子：
11.5
作者：
Ramanathan, RK;Trump, DL;Egorin, MJ
通讯作者：
Egorin, MJ
影响因子：
11.5
作者：
Eiseman, Julie L.;Guo, Jianxia;Egorin, Merrill J.
通讯作者：
Egorin, Merrill J.
影响因子：
3
作者：
Eiseman, JL;Lan, J;Egorin, MJ
通讯作者：
Egorin, MJ
影响因子：
45.3
作者：
Banerji, U;O'Donnell, A;Judson, I
通讯作者：
Judson, I