Impact of High and Low Folate Diets on Tissue Folate Receptor Levels and Antitumor Responses Toward Folate-Drug Conjugates
Impact of High and Low Folate Diets on Tissue Folate Receptor Levels and Antitumor Responses Toward Folate-Drug Conjugates
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DOI：
10.1124/jpet.108.143206
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Westrick, Elaine
中科院分区：
文献类型：
--
作者：
Leamon, Christopher P.;Reddy, Joseph A.;Westrick, Elaine
在此，我们提出了一个详细的分析喂养实验室小鼠高和低叶酸（叶酸）的饮食相关的血清和红细胞（RBC）叶酸水平的变化，组织衍生的叶酸受体水平，叶酸-药物结合物的能力，结合和实现对叶酸受体（FR）阳性肿瘤异种移植物的活性的影响。我们的数据显示，小鼠转换为低叶酸饮食后，血清和RBC叶酸浓度立即急剧下降;然而，这两个参数在6周后达到稳态，“类似人类”的水平。有趣的是，组织相关的叶酸结合能力也降低在饮食调节期间，而放射性标记的叶酸共轭物的净摄取同时增加2.6和5倍，分别在FR阳性肾脏和肿瘤组织。最后，评价了几种临床和临床前相关的叶酸-药物偶联物在喂食高或低叶酸饮食的小鼠中对抗肿瘤的性能。除了以低于内源性FR饱和所需剂量6倍的剂量水平给药外，未观察到抗肿瘤活性的显著损失。从这些发现中，我们得出结论，降低小鼠叶酸的饮食摄入量对重复给药的叶酸靶向药物的生物活性影响不大，但低叶酸饮食方案将使血清和RBC叶酸水平降低至更接近正常人体范围的水平。
Herein, we present a detailed analysis on the effects of feeding laboratory mice both high and low folic acid (folate)-containing diets as related to associated changes in serum and red blood cell (RBC) folate levels, tissue-derived folate receptor levels, and the ability of folate-drug conjugates to bind and effectuate activity against folate receptor (FR)-positive tumor xenografts. Our data show that serum and RBC folate concentrations sharply drop immediately after mice are switched to low folate diets; however, both parameters reach steady-state, "humanlike" levels after 6 weeks. Interestingly, tissue-related folate binding capacities were also lowered during the dietary modulation period, whereas the net uptake of a radiolabeled folate conjugate was simultaneously increased 2.6- and 5-fold in FR-positive kidney and tumor tissue, respectively. Finally, the performances of several clinically and preclinically relevant folate-drug conjugates were evaluated against tumors in mice that were fed high or low folate diets. Except when administered at a dose level 6-fold less than that required to saturate endogenous FRs, no significant loss of antitumor activity was observed. From these findings, we conclude that lowering the dietary intake of folates in mice has little impact on the biological activity of repetitively dosed folate-targeted agents but that low folate diet regimens will reduce serum and RBC folate levels down to levels that more closely approximate the normal human ranges.