毒蕈碱型胆碱受体拮抗剂噻托溴铵抑制小细胞肺癌生长的体内外研究

The role of non-neuron cholinergic signaling in neoplasia has recently received relatively more attention, eapecially the muscarinic cholinergic receptors 3(M3R) playing the most important role. Our previous studies found that 4-DAMP, the M3R antagonist, could inhibit SCLC cell proliferation, migration and adhesion in vitro. Tiotropium, the long-acting M3R antagonist, has been used clinically to treat COPD for a long time owing to the reduction in smooth muscle contraction and mucus secretion. Administered via inhalation in a dosage of 18μg once daily, Tiotropium is well tolerated. The founction of tiotropium in SCLC growth is not clear. Therefor, we designed the following studies for these remained unknown questions: whether tiotropium has effect on SCLC cell apoptosis, whether tiotropium can inhibit tumor growth in mouse orthotopic xenograft model, the relationship of M3R expression and SCLC clinical stage and whether tiotropium can inhibit tumor growth in SCLC patients with COPD at the same time. We can offer experimental and clinical evidences for the role of M3R antagonist in the adjuvant treatment of SCLC.

近年来，非神经元性胆碱能信号通路与肿瘤的关系受到广泛关注。其中毒蕈碱型胆碱受体3（muscarinic cholinergic receptors,M3R）的作用尤为重要。我们之前的体外研究发现M3R拮抗剂4-DAMP抑制小细胞肺癌（small cell lung cancer, SCLC）增殖、粘附和迁移。长效MRs拮抗剂噻托溴铵（主要作用于M3R）粉吸入剂由于其扩张气道、抑制气道分泌等作用在临床上广泛用于慢性阻塞性肺疾病（COPD）。噻托溴铵是否能抑制SCLC的生长尚不清楚。本研究拟观察噻托溴铵对SCLC细胞株凋亡的影响并探讨其机制；通过裸鼠成瘤试验观察噻托溴铵局部注射或雾化吸入能否抑制肿瘤生长；观察SCLC患者M3R的表达以及和临床分期的关系；观察噻托溴铵对于SCLC合并COPD的患者是否有抑制肿瘤生长的作用。为M3R成为SCLC患者联合治疗新靶点提供实验及临床研究的证据。