甲氨蝶呤、氨喋呤、培美曲塞和替莫唑胺在儿童白血病中的临床疗效。

Clinical potency of methotrexate, aminopterin, talotrexin and pemetrexed in childhood leukemias.

机构信息

Division of Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Abramson Research Center, 3615 Civic Center Blvd., Suite 916, Philadelphia, PA 19104, USA.

出版信息

Cancer Chemother Pharmacol. 2010 May;65(6):1125-30. doi: 10.1007/s00280-009-1120-8. Epub 2009 Sep 27.

DOI:10.1007/s00280-009-1120-8

PMID:19784838

Abstract

PURPOSE

Renewed interest in antifols for the treatment of childhood cancers has resulted from identification of novel antifols with broad spectrums of anti-cancer activity and from re-evaluation of the original clinical antifol, aminopterin. In this pre-clinical study we evaluated the in vitro activity of both traditional antifols (methotrexate, aminopterin) and novel antifols (pemetrexed, talotrexin) in childhood acute leukemias and lymphomas.

METHODS

We compared the in vitro cytotoxicity of methotrexate, aminopterin, pemetrexed, and talotrexin in a panel of six pediatric leukemia and lymphoma cell lines using the sulforhodamine B assay. In addition to defining a 50% growth inhibitory concentration (IC50) for a 120-h drug exposure, we contrasted the activity of the drugs in the context of clinically achievable (tolerable) drug exposures using the area under the plasma concentration-time curve (AUC). We defined each agent's clinical potency index (CPI) as the AUC achieved with standard pediatric dosing regimens divided by the in vitro IC50.

RESULTS

Across all cell lines, talotrexin (median IC50 7 nM) and aminopterin (median IC50 17 nM) had lower IC50's than methotrexate (median IC50 78 nM) and pemetrexed (median IC50 155 nM). However, the CPI for methotrexate (median 0.9) was significantly greater than that for aminopterin (median 0.4). In contrast, pemetrexed had a significantly better CPI (median 13) than the traditional antifols.

CONCLUSIONS

Aminopterin does not appear to offer any advantage over methotrexate for the treatment of childhood ALL. Further study of pemetrexed in childhood leukemias is warranted.

摘要

目的

新型抗叶酸药物具有广谱抗癌活性，且重新评估了最初的临床抗叶酸药物氨甲蝶呤，因此人们对其治疗儿童癌症的应用产生了新的兴趣。在这项临床前研究中，我们评估了传统抗叶酸药物（甲氨蝶呤、氨甲蝶呤）和新型抗叶酸药物（培美曲塞、他罗替森）在儿童急性白血病和淋巴瘤中的体外活性。

方法

我们使用磺酰罗丹明 B 测定法比较了六种儿科白血病和淋巴瘤细胞系中氨甲蝶呤、氨甲蝶呤、培美曲塞和他罗替森的体外细胞毒性。除了定义 120 小时药物暴露的 50%生长抑制浓度（IC50）外，我们还使用血浆浓度-时间曲线下面积（AUC）来对比药物在临床可达到（可耐受）药物暴露下的活性。我们将每个药物的临床效力指数（CPI）定义为标准儿科剂量方案下获得的 AUC 除以体外 IC50。

结果

在所有细胞系中，他罗替森（中位 IC50 7 nM）和氨甲蝶呤（中位 IC50 17 nM）的 IC50 均低于甲氨蝶呤（中位 IC50 78 nM）和培美曲塞（中位 IC50 155 nM）。然而，甲氨蝶呤的 CPI（中位数 0.9）显著大于氨甲蝶呤（中位数 0.4）。相比之下，培美曲塞的 CPI（中位数 13）明显优于传统抗叶酸药物。