Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression
Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression
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DOI：
10.1080/1042819031000077124
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发表时间：
2003-01-01
影响因子：
2.6
通讯作者：
Moore, MAS
中科院分区：
文献类型：
--
作者：
Wang, ES;O'Connor, O;Moore, MAS
PDX（10-炔丙基-10-去氮杂氨基蝶呤）是一种新型抗叶酸剂，在肿瘤细胞中具有改善的膜转运和多聚谷氨酰化。在先前的研究中，PDX在肺癌和乳腺癌异种移植物中表现出比甲氨蝶呤（MTX）更强的疗效。由于MTX在治疗侵袭性非霍奇金淋巴瘤（NHL）中具有活性，我们比较了PDX和MTX对5种淋巴瘤细胞系的疗效：RL（转化滤泡性淋巴瘤）、HT、SKI-DLBCL-1（弥漫性大B细胞）、Raji（伯基特氏）和Hs445（霍奇金病）。在体外连续暴露5天后，PDX在所有细胞系中表现出比MTX高> 10倍的细胞毒性（IC50 PDX = 3 - 5 nM IC50 MTX = 30 - 50 nM）。然后，我们比较了抗叶酸剂对NOD/SCID小鼠中三种已建立的人NHL异种移植物的体内作用。通过腹膜内途径每周两次用盐水（对照）或最大耐受剂量的MTX（40 mg/kg）或PDX（60 mg/kg）治疗荷瘤动物2周。近90%接受PDX治疗的HT淋巴瘤完全消退，而接受MTX治疗的HT淋巴瘤仅出现适度的生长延迟。在另外两种异种移植物中，荷瘤小鼠在PDX治疗后具有56%（RL）和30%（SKI-DLBCL-1）的完全消退率。MTX治疗后未见消退，仅轻微生长抑制。对叶酸代谢相关基因表达的RT-PCR分析表明，对PDX敏感性的增加与RFC-1基因表达的增加相关，而FPGS或FPGH水平无差异，这表明肿瘤RFC-1基因表达水平的测量可能是对PDX反应的预测因子。这些结果表明，PDX对人NHL的潜在活性明显高于MTX，需要进一步的临床前和临床评价。
PDX (10-propargyl-10-deazaaminopterin) is a novel anti-folate with improved membrane transport and polyglutamylation in tumor cells. In prior studies, PDX exhibited enhanced efficacy over methotrexate (MTX) in lung and breast carcinoma xenografts. Because MTX is active in the treatment of aggressive non-Hodgkin's lymphoma (NHL), we compared the efficacy of PDX and MTX against five lymphoma cell lines: RL (transformed follicular lymphoma), HT, SKI-DLBCL-1 (diffuse large B cell), Raji (Burkitt's), and Hs445 (Hodgkin's disease). After 5-day continuous in vitro exposure, PDX demonstrated > 10-fold greater cytotoxicity than MTX in all cell lines (IC50PDX = 3-5 nM IC50 MTX = 30-50 nM). We then compared the in vivo effects of anti-folates against three established human NHL xenografts in NOD/SCID mice. Tumor bearing animals were treated with saline (control) or the maximum tolerated doses of MTX (40 mg/kg) or PDX (60 mg/kg) via an intraperitoneal route twice weekly for 2 weeks. Almost 90% of HT lymphomas treated with PDX completely regressed, whereas, those treated with MTX treatment had only modest growth delays. In two other xenografts, tumor bearing mice had complete regression rates of 56% (RL) and 30% (SKI-DLBCL-1) after PDX therapy. No regressions and only minor growth inhibition was noted after MTX therapy. RT-PCR analysis for the expression of genes involved in folate metabolism demonstrated that increased sensitivity to PDX correlated with higher RFC-1 gene expression with no difference in FPGS or FPGH levels, suggesting that measurement of tumor RFC-1 gene expression level may be a predictor of response to PDX. These results demonstrate that the PDX has markedly greater potential activity against human NHL than MTX and warrants further preclinical and clinical evaluation.