A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies.
A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies.
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DOI：
10.1007/s00280-010-1410-1
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发表时间：
2011-06
影响因子：
3
通讯作者：
Piwnica-Worms, Helen
中科院分区：
文献类型：
--
作者：
Fracasso, Paula M.;Williams, Kerry J.;Chen, Ronald C.;Picus, Joel;Ma, Cynthia X.;Ellis, Matthew J.;Tan, Benjamin R.;Pluard, Timothy J.;Adkins, Douglas R.;Naughton, Michael J.;Rader, Janet S.;Arquette, Matthew A.;Fleshman, James W.;Creekmore, Allison N.;Goodner, Sherry A.;Wright, Lisa P.;Guo, Zhanfang;Ryan, Christine E.;Tao, Yu;Soares, Eliane M.;Cai, Shi-rong;Lin, Li;Dancey, Janet;Rudek, Michelle A.;McLeod, Howard L.;Piwnica-Worms, Helen
UCN-01（7-hydroxystaurosporine）是一种多靶点蛋白激酶抑制剂，在临床前研究中与DNA损伤剂表现出协同活性。我们进行了一项I期研究，以确定UCN-01和伊立替康在耐药实体瘤患者中的最大耐受剂量（MTD）、剂量限制性毒性（DLT）、药代动力学和药效学效应。患者每42天接受伊立替康（第1、8、15、22天75-125 mg/m2 IV）和UCN-01（第2天50-90 mg/m2 IV和第23天25-45 mg/m2及后续剂量）。获得用于UCN-01和伊立替康药代动力学的血液，以及用于药效学研究的血液、正常直肠粘膜和肿瘤活检组织。25例患者入组5个剂量水平。第1、8、15、22天的MTD为伊立替康125 mg/m2，第2天为UCN-01 70 mg/m2，第23天为35 mg/m2。DLT包括3级腹泻/脱水和呼吸困难。UCN-01具有延长的半衰期和低清除率。SN-38 Cmax以及氨基戊羧酸（APC）和SN-38葡糖苷酸半衰期显著缩短。在UCN-01后24小时，血液、正常直肠粘膜和肿瘤活检组织中磷酸化核糖体蛋白S6减少。在ER、PgR和HER 2阴性乳腺癌（TBNC）女性中观察到两种部分缓解。两个肿瘤都有p53缺陷。12例患者病情稳定（平均持续时间18周，范围7-30周）。UCN-01和伊立替康表现出可接受的毒性和靶点抑制。观察到了抗肿瘤活性，并且正在TNBC女性中进行这种组合的研究。本文的在线版本（doi：10.1007/s 00280 -010-1410-1）包含补充材料，可供授权用户使用。
UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors. Patients received irinotecan (75–125 mg/m2 IV on days 1, 8, 15, 22) and UCN-01 (50–90 mg/m2 IV on day 2 and 25–45 mg/m2 on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained. Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m2 on days 1, 8, 15, 22 and UCN-01 70 mg/m2 on day 2 and 35 mg/m2 on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 Cmax and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7–30 weeks). UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway. The online version of this article (doi:10.1007/s00280-010-1410-1) contains supplementary material, which is available to authorized users.
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影响因子：
4.8
作者：
Graves, PR;Yu, LJ;Piwnica-Worms, H
通讯作者：
Piwnica-Worms, H
影响因子：
45.3
作者：
Kortmansky, J;Shah, MA;Schwartz, GK
通讯作者：
Schwartz, GK
DOI：
10.1186/bcr1307
发表时间：
2005
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Crowder RJ;Ellis MJ
通讯作者：
Ellis MJ
影响因子：
3.4
作者：
Combes, O;Barré, J;Urien, S
通讯作者：
Urien, S
影响因子：
3.9
作者：
Bredel, M;Pollack, IF;Lazo, JS
通讯作者：
Lazo, JS