Preclinical evaluation of the antitumor activity of bortezomib in combination with vitamin C or with epigallocatechin gallate, a component of green tea.
Preclinical evaluation of the antitumor activity of bortezomib in combination with vitamin C or with epigallocatechin gallate, a component of green tea.
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DOI：
10.1007/s00280-011-1591-2
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发表时间：
2011-11
影响因子：
3
通讯作者：
Berger, Allison
中科院分区：
文献类型：
--
作者：
Bannerman, Bret;Xu, Ling;Jones, Matthew;Tsu, Christopher;Yu, Jie;Hales, Paul;Monbaliu, Johan;Fleming, Paul;Dick, Lawrence;Manfredi, Mark;Claiborne, Christopher;Bolen, Joseph;Kupperman, Erik;Berger, Allison
研究临床相关水平的表没食子儿茶素没食子酸酯（EGCG，绿茶的一种成分）或维生素 C（抗坏血酸）是否可以拮抗 CWR22 人前列腺异种移植肿瘤中硼替佐米的抗肿瘤活性。在免疫功能低下的小鼠中测定了 EGCG 和抗坏血酸的药代动力学 (PK)，并与人类膳食补充剂 PK 研究中测量的浓度进行比较。使用几种给药方案来评估 EGCG 和抗坏血酸的不同目标血浆浓度，从而确定硼替佐米与 EGCG 或抗坏血酸组合的抗肿瘤活性。硼替佐米每周两次以 0.8 mg/kg IV 给药，显示肿瘤生长抑制 (TGI) 为 53.9–58.9%。然而，当与 EGCG 联合使用时，硼替佐米给药时 EGCG 的血浆浓度>200 μM，所有抗肿瘤活性均被消除（TGI = -17.7%）。较低浓度的 EGCG (11–16 μM) 比服用 EGCG 补充剂的人类临床测量值 (0.6–3 μM) 高出几倍，但与硼替佐米 (TGI 63.5%) 没有拮抗作用。蛋白酶体抑制的药效学研究反映了这些发现。抗坏血酸（每日 40 和 500 mg/kg PO）在类似的研究设计下进行了评估，并且不会拮抗硼替佐米的抗肿瘤活性（TGI 57.2 和 72.2%）。在临床前体内实验中未发现硼替佐米的拮抗作用，其中 EGCG 或抗坏血酸血浆浓度与饮食或补充摄入量相当。数据表明，接受硼替佐米治疗的患者不需要避免正常饮食中绿茶、含维生素 C 的食物、或 EGCG 或维生素 C 膳食补充剂。本文的在线版本 (doi:10.1007/s00280-011-1591-2) 包含补充材料，可供授权用户使用。
To investigate whether clinically relevant levels of epigallocatechin gallate (EGCG, a component of green tea) or vitamin C (ascorbic acid) could antagonize bortezomib antitumor activity in CWR22 human prostate xenograft tumors. The pharmacokinetics (PK) of EGCG and ascorbic acid were determined in immunocompromised mice and compared with concentrations measured in human PK studies of dietary supplements. Antitumor activity of bortezomib in combination with EGCG or ascorbic acid was determined using several dosing regimens to evaluate different target plasma concentrations of EGCG and ascorbic acid. Bortezomib dosed twice-weekly at 0.8 mg/kg IV demonstrated tumor growth inhibition (TGI) of 53.9–58.9%. However, when combined with EGCG such that the plasma concentrations of EGCG were >200 μM at the time of bortezomib dosing, all antitumor activity was abrogated (TGI = −17.7%). A lower concentration of EGCG (11–16 μM), which is severalfold higher than measured clinically in humans taking EGCG supplements (0.6–3 μM), was not antagonistic to bortezomib (TGI 63.5%). Pharmacodynamic studies of proteasome inhibition reflected these findings. Ascorbic acid (40 and 500 mg/kg PO daily) was evaluated under a similar study design and did not antagonize bortezomib antitumor activity (TGI 57.2 and 72.2%). No antagonism of bortezomib is seen in preclinical in vivo experiments, where EGCG or ascorbic acid plasma concentrations are commensurate with dietary or supplemental intake. The data suggest that patients receiving bortezomib treatment do not need to avoid normal dietary consumption of green tea, vitamin C-containing foods, or EGCG or vitamin C dietary supplements. The online version of this article (doi:10.1007/s00280-011-1591-2) contains supplementary material, which is available to authorized users.
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影响因子：
11.5
作者：
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通讯作者：
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45.3
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