Differential Effects of Vitamin K1 on AFP and DCP Levels in Patients with Unresectable HCC and in HCC Cell Lines
Differential Effects of Vitamin K1 on AFP and DCP Levels in Patients with Unresectable HCC and in HCC Cell Lines
复制标题
DOI：
10.1007/s10620-010-1521-x
复制
发表时间：
2011-06-01
影响因子：
3.1
通讯作者：
Wei, Gang
中科院分区：
文献类型：
--
作者：
Carr, Brian I.;Wang, Ziqiu;Wei, Gang
DCP是一种有用的HCC肿瘤标志物，它反映了维生素K代谢的缺陷。我们检验了维生素K治疗肝癌患者可能抑制该标记物和可能抑制AFP的假设，包括AFP和DCP均升高的肝癌患者。一个I期队列接受递增的维生素K1静脉注射每周剂量治疗，一个27例患者的II期队列接受固定的口服每日剂量治疗，最大耐受剂量未达到正常维生素K1剂量的100倍。在高达1，000 mg/输注剂量下未发现毒性。在II期队列中，93%的患者通过DCP水平降低而产生肿瘤标志物应答，但只有22%的患者通过AFP水平降低而产生应答。CT扫描显示11%的患者有PR，59%的患者肿瘤稳定，29.6%的患者肿瘤进展。机制研究表明，维生素K1可诱导JNK和c-Jun磷酸化和caspase介导的细胞凋亡，高剂量时维生素K1无毒，可强烈抑制血浆DCP水平，但对AFP水平的抑制作用较弱。结果提供的证据表明，这两种肿瘤标志物没有直接联系，DCP水平可能不能反映HCC细胞的生长，因为DCP水平在没有AFP变化的患者中降低，并且在体外抑制AFP所需的维生素K1浓度的1%时受到抑制。
DCP is a useful HCC tumor marker, which reflects a defect in vitamin K metabolism. We tested the hypothesis that vitamin K treatment of HCC patients might suppress this marker and possibly AFP also.HCC patients who had both elevated AFP and DCP were included. A phase I cohort was treated with escalating vitamin K1 intravenous weekly doses and a 27-patient phase II cohort was then treated with a fixed oral daily dose.A maximum tolerated dose was not reached up to 100-fold the normal vitamin K1 dose. No toxicities were found up to 1,000 mg/infusion. In the phase II cohort, 93% of patients had tumor marker responses by decreased DCP levels, but only 22% had responses by decreased AFP levels. CT scans showed 11% of patients had PRs, 59% had stable tumors and 29.6% had tumor progression. Mechanism studies showed that vitamin K1 induced phosphorylation of JNK and c-Jun and caspase-mediated apoptosis.Vitamin K1 was non-toxic at high doses, strongly inhibited plasma DCP levels, but weakly suppressed AFP levels. The results provide evidence that the two tumor markers are not directly linked and that DCP levels may not reflect HCC cell growth, as DCP levels were decreased in patients without AFP change, and were suppressed in vitro at 1% of the vitamin K1 concentration needed to inhibit AFP.