A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors
A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors
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DOI：
10.1093/annonc/mdm204
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发表时间：
2007-09-01
影响因子：
50.5
通讯作者：
Duenas-Gonzalez, A.
中科院分区：
文献类型：
--
作者：
Candelaria, M.;Gallardo-Rincon, D.;Duenas-Gonzalez, A.
背景资料：表观遗传畸变导致化疗耐药，因此，他们的逆转DNA甲基化和组蛋白脱乙酰酶的抑制剂可能克服it.Patients和方法：11期，单组研究肼苯哒嗪和丙戊酸镁添加到相同的化疗方案，患者的进展。方案包括顺铂、卡铂、紫杉醇、长春瑞滨、吉西他滨、培美曲塞、拓扑替康、多柔比星、环磷酰胺和阿那曲唑。患者在化疗前一周开始接受肼苯哒嗪182 mg（快速乙酰化）或83 mg（缓慢乙酰化）和丙戊酸镁40 mg/kg。反应，毒性，DNA甲基化，组蛋白去乙酰化酶活性，血浆丙戊酸，肼苯哒嗪水平进行了evaluated.Results：17例患者可评价的毒性和15的反应。原发部位包括宫颈癌（3例）、乳腺癌（3例）、肺癌（1例）、睾丸癌（1例）和卵巢癌（7例）。在12例（80%）患者中观察到临床获益：4例PR和8例SD。最显著的毒性是血液学毒性。观察到整体DNA甲基化、组蛋白脱乙酰酶活性和启动子脱甲基化的减少。结论：表观遗传药物肼苯哒嗪和丙戊酸盐在该选定患者人群中的临床获益进展为化疗，并在启动肼苯哒嗪和丙戊酸盐后用相同的化疗方案重新激发，这支持了表观遗传驱动的肿瘤细胞化疗耐药性假说（ClinicalTrials.gov标识符：NCT 00404508）。
Background: Epigenetic aberrations lead to chemotherapy resistance; hence, their reversal by inhibitors of DNA methylation and histone deacetylases may overcome it.Patients and methods: Phase 11, single-arm study of hydralazine and magnesium valproate added to the same schedule of chemotherapy on which patients were progressing. Schedules comprised cisplatin, carboplatin, paclitaxel, vinorelbine, gemcitabine, pemetrexed, topotecan, doxorubicin, cyclophosphamide, and anastrozole. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow, acetylators, and magnesium valproate at 40 mg/kg, beginning a week before chemotherapy. Response, toxicity, DNA methylation, histone deacetylase activity, plasma valproic acid, and hydralazine levels were evaluated.Results: Seventeen patients were evaluable for toxicity and 15 for response. Primary sites included cervix (3), breast (3), lung (1), testis (1), and ovarian (7) carcinomas. A clinical benefit was observed in 12 (80%) patients: four PR, and eight SD. The most significant toxicity was hematologic. Reduction in global DNA methylation, histone deacetylase activity, and promoter demethylation were observed.Conclusions: The clinical benefit noted with the epigenetic agents hydralazine and valproate in this selected patient population progressing to chemotherapy' and re-challenged with the same chemotherapy schedule after initiating hydralazine and valproate' lends support to the epigenetic-driven tumor-cell chemoresistance hypothesis (ClinicalTrials.gov Identifier: NCT00404508).