Nevada Cancer Institute, 1 Breakthrough Way, Las Vegas, NV 89135, USA.
Transl Oncol. 2008 Sep;1(3):141-7. doi: 10.1593/tlo.08136.
Oral valproic acid (VPA), which is a histone deacetylase inhibitor, was used in a phase II trial to treat patients with castration-resistant prostate cancer (CRPC). Ten patients with CRPC were treated with oral VPA. Oral VPA was not well tolerated in this patient population at a dose targeted to a serum level less than 50 microg/L. The main toxicities were grades 1 and 2 neurologic events and grades 1 and 2 fatigue that caused interruption in the administration of oral VPA and dose delays. Two (20%) of 10 patients had prostate-specific antigen (PSA) responses, and one response was durable. Intensive biomarker collections (weekly) revealed that PSA levels were inversely correlated with total VPA levels. Histone acetylation could not be consistently observed in peripheral lymphocytes using oral VPA. Oral VPA can be administered to CRPC patients with resultant PSA responses. However, oral VPA cannot be administered reliably to achieve consistent levels or duration to be useful in the treatment of CRPC patients. It is unlikely that PSA responses from oral VPA are related to histone deacetylase inhibition. Development of oral VPA in prostate cancers is not recommended using an oral formulation. An intensive biomarker strategy is useful to develop clinical hypotheses in patients with CRPCs in small numbers of patients.
口服丙戊酸（VPA）是一种组蛋白去乙酰化酶抑制剂，曾在一项 II 期临床试验中用于治疗去势抵抗性前列腺癌（CRPC）患者。10 名 CRPC 患者接受了口服 VPA 治疗。在该患者人群中，口服 VPA 的耐受情况不佳，目标血清水平低于 50μg/L 时，主要毒性为 1 级和 2 级神经事件以及 1 级和 2 级疲劳，导致口服 VPA 给药中断和剂量延迟。10 名患者中有 2 名（20%）出现前列腺特异性抗原（PSA）应答，其中 1 名应答持久。密集的生物标志物采集（每周）显示 PSA 水平与总 VPA 水平呈反比。使用口服 VPA 未能在周围淋巴细胞中观察到组蛋白乙酰化。口服 VPA 可用于治疗 CRPC 患者，从而导致 PSA 应答。然而，口服 VPA 不能可靠地给药以达到一致的水平或持续时间，因此对 CRPC 患者的治疗没有帮助。口服 VPA 的 PSA 应答不太可能与组蛋白去乙酰化酶抑制有关。不建议使用口服制剂开发前列腺癌中的口服 VPA。在少数患者中，采用密集的生物标志物策略有助于针对 CRPC 患者开发临床假设。
