Strategies for chemoselective treatment of lung cancer targeting methylthioadenosine phosphorylase (MTAP) deficiency-from chemosensitivity test to translational research

针对甲硫腺苷磷酸化酶（MTAP）缺陷的肺癌化疗选择性治疗策略——从化疗敏感性试验到转化研究

• 批准号: 13470270
• 负责人: TAKAO Motoshi
• 金额: $ 3.39万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470270/
• 关键词: Lung cancer; Chemotherapy; Chemosensitivity test; MTAP; MTX; L-alanosine; MTA; プリン新生合成酵素阻害剤; CD-DST法; 感受性試験; 遺伝子変遺; プリン代謝; Translational research

Following are our conclusion of MTAP study on resected non-small cell lung cancer without preoperative treatment.1. Diagnosis of MTAP deficiency in lung cancerNegative expression of MTAP on IHC using MTAP-MoAb and MTAP gene deletion on RT-PCR were found in 36 (44.4%) of 81 cases and in 24 (32.9%) of 73 cases. The rate concordance between two methods was 63/70 (90%) with significant correlation (p<.001). Hypermethylation in the MTAP promoter lesion was observed in all seven samples showing positive PCR and negative IHC results. IHC was specific enough to diagnose MTAP deficiency in solid tumor as lung cancer.2. Correlation of IHC between on MTAP and on P16 of P53Concordance of expression pattern on IHC was found in 71% between MTAP and p16 (MTAP(+)/p16(+) in 35 of 65 cases and MTAP(-)/p16(-) in 11 of 65) showing significant correlation (p<.001), but in only 45% between MTAP and p53 without any correlation.3. In vitro test for Selective chemotherapy by purine de novo synthesis targeting MTAP deficiency in lung cancerMTAP status did not affect the chemosensitivity of MTX nor L-ALA in the culture condition without MTA (ie. Ineffective status for salvage pathway of purine synthesis). Although ddition of MTA in culture medium had no effect on chemosensitivity of MTX nor L-ALA in MTAP (-) cancer cells, it decreased inhibition rate from 60.5% to 42.3% (p<.05) and from 55.7% to 29.9% (P<.001) in MTAP (+) cancer cells when it was tested with MTX and L-ALA, respectively.

以下是我们对未经术前治疗的非小细胞肺癌切除术后MTAP研究的结论. MTAP单克隆抗体免疫组化检测MTAP阴性36例（44.4%），RT-PCR检测MTAP基因缺失24例（32.9%）。两种方法之间的一致率为63/70（90%），具有显著相关性（p <0.001）。在所有7个显示阳性PCR和阴性IHC结果的样品中观察到MTAP启动子损伤的超甲基化。结论：1.免疫组化对实体瘤MTAP缺陷诊断肺癌有足够的特异性. MTAP与P53的P16表达的相关性MTAP与P16表达的一致性为71%（MTAP（+）/p16（+）35/65，MTAP（-）/p16（-）11/65），具有显著相关性（p <0.001），而MTAP与P53之间的一致性仅为45%，无相关性.在体外试验中，通过嘌呤从头合成靶向MTAP缺陷的肺癌选择性化疗在没有MTA的培养条件下，MTAP状态不影响MTX或L-ALA的化疗敏感性（即，嘌呤合成补救途径的无效状态）。在MTAP（-）癌细胞中加入MTA对MTX和L-ALA的化疗敏感性无影响，但在MTAP（+）癌细胞中加入MTA后，MTX和L-ALA的抑制率分别从60.5%下降到42.3%（P <0.05）和55.7%下降到29.9%（P <0.001）。