Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker.
Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker.
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Vorinostat和阿霉素在实体瘤中的I期试验：组蛋白脱乙酰基酶2表达作为预测标记。
DOI：
10.1038/sj.bjc.6605293
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发表时间：
2009-10-06
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
组蛋白去乙酰化酶抑制剂（HDACi）可以通过增加拓扑异构酶抑制剂的进入和与DNA的结合，使癌细胞对拓扑异构酶抑制剂敏感。该I期试验旨在确定hdac vorinostat的毒性、耐受性和推荐的II期剂量，并每周使用阿霉素。共治疗32例患者；在第1 - 3天给药伏立诺他400mg、600mg、800mg或1000mg，然后在第3天给药阿霉素（20mg m - 2），连续4周中的3周。最大耐受剂量为800 mg /天。剂量限制性毒性为3级恶心/呕吐（2 / 6）和疲劳（1 / 6），1000mg day - 1。非剂量限制性3/4级毒性包括血液学毒性和静脉血栓栓塞。24例可评估患者的抗肿瘤活性包括两种部分反应（乳腺癌和前列腺癌）。两名黑色素瘤患者在大于或等于8个月的时间内病情稳定。外周血单核细胞和肿瘤细胞组蛋白超乙酰化变化具有可比性。组蛋白超乙酰化似乎与预处理前HDAC2表达相关。这些研究结果表明，伏立诺他可与阿霉素每周联合用药，剂量为800 mg day - 1。HDAC2的表达可能是预测HDAC抑制的标志物。这种疗法对乳腺癌、前列腺癌和黑色素瘤的抗肿瘤活性似乎很有趣。
Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA. This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin. In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day−1 on days 1–3, followed by doxorubicin (20 mg m−2) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day−1 of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day−1. Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for ⩾8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression. These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day−1. The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.
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影响因子：
45.3
作者：
Muenster, Pamela;Marchion, Douglas;Daud, Adil
通讯作者：
Daud, Adil
影响因子：
45.3
作者：
O'Connor, OA;Heaney, ML;Kelly, WK
通讯作者：
Kelly, WK
影响因子：
9.2
作者：
Durrieu, F;Samejima, K;Earnshaw, WC
通讯作者：
Earnshaw, WC
DOI：
10.1046/j.1359-4117.2002.01039.x
发表时间：
2002-11-01
影响因子：
--
作者：
Marshall, John L;Rizvi, Naiyer;Hawkins, Michael J
通讯作者：
Hawkins, Michael J
影响因子：
5.7
作者：
Marchion, DC;Bicaku, E;Munster, PN
通讯作者：
Munster, PN