聚烯丙胍應用於克服吉非替尼抗藥性肺癌之研究

Abstract

吉非替尼是針對非小型細胞肺癌的標靶藥物，倘若使用之初未完全殺死癌細胞，幾乎接受過吉非替尼治療的病患都會產生藥物失效的問題，這導致病患後續的治療方式受限且預後不好，因此我們亟需克服這項問題，本文使用聚丙烯弧合併吉非替尼進行治療，提供嶄新治療策略。 在體外實驗中，我們觀察到低濃度的聚丙烯弧合併吉非替尼處理抗藥性肺癌細胞，相較只用吉非替尼處理，更能輕易地殺死癌細胞，為了探討這背後的可能機制，我們透過分析細胞膜的通透性及膜上所受影響之蛋白，發現在不殺死細胞的聚丙烯弧濃度下，細胞通透性會增加，且原因是因為其破壞細胞外的連接蛋白，讓藥物更大量的進入細胞內，成功使被磷酸化的表皮生長因子受體減少，因而抑制細胞增生。 此外，在後續的小鼠動物實驗中，我們也觀察到相同的表現，我們使用免疫缺陷的小鼠作為模型，異種移植人類抗藥性肺癌細胞後再進行治療，在四種不同的治療方式中，同時使用聚丙烯弧及吉非替尼於皮下注射的方式有著最好的抑制腫瘤體積增大的效果，而且在病理組織切片的分析中，結合治療的視野下幾乎看不到任何腫瘤細胞，雖然有留下一些疤痕組織，但這樣的療效對克服抗藥性肺癌的問題，著實是一大進展。

Gefitinib is a targeted therapy for non-small cell lung cancer (NSCLC). However, if the cancer cells are not completely eradicated at the beginning of the treatment, almost all patients will develop resistance to the drug, which limits subsequent treatment options and leads to poor prognosis. Therefore, it is crucial to overcome this issue. In this study, we combined polyallylamine with gefitinib to provide a new therapeutic approach. In in vitro experiments, we found that low concentrations of poly (allyl guanidine) (PAG) combined with gefitinib were more effective in inhibiting the activity of resistant lung cancer cells compared to gefitinib alone. To investigate the mechanism behind this phenomenon, we analyzed cell membrane permeability and the affected proteins on the membrane. We discovered that at non-cytotoxic concentrations of PAG, cell permeability increased due to the disruption of extracellular junction proteins, allowing a greater amount of the drug to enter the cells. This led to a reduction in phosphorylated epidermal growth factor receptor (P-EGFR), thereby inhibiting cell growth. Furthermore, in subsequent mouse animal experiments, we observed a similar trend. We used immunodeficient mice as models, xenografting them with human resistant lung cancer cells before treatment. Among the four different treatment methods, the combination of subcutaneous injections of PAG and gefitinib exhibited the best tumor growth inhibition. Pathological tissue analysis showed that in the combination treatment group, almost no tumor cells were observed, although some scar tissue remained. This therapeutic effect represents a significant advancement in overcoming drug-resistant lung cancer.