Hanauske Axel-Rainer, Eismann Ulrike, Oberschmidt Olaf, Pospisil Heike, Hoffmann Steve, Hanauske-Abel Hartmut, Ma Doreen, Chen Victor, Paoletti Paolo, Niyikiza Clet
Asklepios Klinik, St. Georg, Lohmühlenstr. 5, 20099 Hamburg, Germany.
Invest New Drugs. 2007 Oct;25(5):417-23. doi: 10.1007/s10637-007-9060-9. Epub 2007 May 30.
mRNA expression of genes involved in the mechanism of action of pemetrexed was correlated with in vitro chemosensitivity of freshly explanted human tumor specimens.
Chemosensitivity to pemetrexed was studied in soft-agar. Multiplex rtPCR experiments for reduced folate carrier (RFC), folate receptor-alpha (FR-alpha), folylpolyglutamate synthetase (FPGS), thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyl transferase (GARFT), mrp4, and mrp5 were performed in parallel. Correlations, threshold optimization, sensitivity, specificity, and efficiency were analyzed using the appropriate statistical methodologies.
In 61 samples, low levels of TS, GARFT, DHFR, and mrp4 gene expression significantly correlated with chemosensitivity to pemetrexed. Optimization analyses demonstrated threshold values of 144 copies for TS and six copies for mrp4 relative to 10(4) copies of beta-actin.
These results form a rational basis for the design of clinical trials to evaluate the expression of these enzymes as predictors for treatment outcome.
培美曲塞作用机制相关基因的mRNA表达与新鲜分离的人肿瘤标本的体外化学敏感性相关。
在软琼脂中研究对培美曲塞的化学敏感性。同时进行针对还原型叶酸载体（RFC）、叶酸受体-α（FR-α）、叶酰聚谷氨酸合成酶（FPGS）、胸苷酸合成酶（TS）、二氢叶酸还原酶（DHFR）、甘氨酰胺核糖核苷酸甲酰基转移酶（GARFT）、多药耐药相关蛋白4（mrp4）和多药耐药相关蛋白5（mrp5）的多重逆转录聚合酶链反应（rtPCR）实验。使用适当的统计方法分析相关性、阈值优化、敏感性、特异性和效率。
在61个样本中，TS、GARFT、DHFR和mrp4基因的低水平表达与对培美曲塞的化学敏感性显著相关。优化分析表明，相对于β-肌动蛋白的10⁴个拷贝，TS的阈值为144个拷贝，mrp4的阈值为6个拷贝。
这些结果为设计临床试验以评估这些酶的表达作为治疗结果预测指标提供了合理依据。
