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

以下是我们对未进行术前治疗的切除非小细胞肺癌的MTAP研究的结论。81例肺癌中MTAP基因表达阴性者36例(44.4%)，73例中24例(32.9%)。两种方法的符合率为63/70(90%)，有显著相关性(p&lt；.001)。在所有7个PCR阳性而IHC阴性的样本中，都观察到MTAP启动子损伤的高甲基化。结论：1.免疫组化对实体瘤MTAP缺乏的诊断具有足够的特异性，诊断为肺癌。65例乳腺癌中MTAP与P16表达模式的符合率为71%(35例MTAP(+)/p16(+)，11例MTAP(-)/p16(-))，两者之间有显著相关性(P<0.01)，而MTAP与P53表达模式的符合率仅为45%，两者无相关性。针对肺癌MTAP缺乏症的嘌呤从头合成选择性化疗的体外实验MTAP状态不影响MTX和L-ALA在不含MTA的培养条件下的化疗敏感性(即。嘌呤合成的挽救途径处于无效状态)。甲氨蝶呤和L-丙氨酸对甲氨蝶呤和L-丙氨酸的敏感性无明显影响，但甲氨蝶呤和L-丙氨酸对甲氨蝶呤和L-丙氨酸的抑制率分别从60.5%和55.7%降至42.3%和29.9%。

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.