从心脏病到阳痿，再到抗肿瘤，“伟哥”有望再度发威！
According to the 2020 global cancer burden data released by the World Health Organization’s International Agency for Research on Cancer (IARC) , esophageal cancer is the 8th most common malignant tumor in the world and the 6th leading cause of annual deaths.根据世界卫生组织国际癌症研究机构（IARC）发布的2020年全球癌症负担数据，食管癌是世界上第八大最常见的恶性肿瘤，也是第六大年度死亡原因。Esophageal cancer is mainly divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) .食管癌主要分为食管鳞状细胞癌（ESCC）和食管腺癌（EAC）。Esophageal adenocarcinoma has a poor prognosis, with a 5-year survival rate of less than 20%. This is largely because of chemotherapy resistance, with 80% of patients not responding to chemotherapy.食管腺癌预后不良，5年生存率低于20%。这主要是因为化疗抵抗，80%的患者对化疗没有反应。On June 21, 2022, researchers from Southampton University Hospital, UK published a research paper entitled: Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts.6月21日，英国南安普敦大学医院的研究人员发表了一篇研究论文，题为：磷酸二酯酶5型抑制剂通过靶向癌相关成纤维细胞，增强食管腺癌临床前模型的化疗效果。
The study found that PDE5 inhibitors can inhibit esophageal adenocarcinoma better than chemotherapy alone by targeting cancer-associated fibroblasts (CAFs) around the tumor, and reverse the chemoresistance of esophageal adenocarcinoma. , and chemotherapy resistance is one of the major challenges in the treatment of esophageal adenocarcinoma.研究发现，PDE5抑制剂通过靶向肿瘤周围的癌相关成纤维细胞（CAFs），比单纯化疗更好地抑制食管腺癌，并逆转食管腺癌的化疗耐药性，化疗耐药是食管腺癌治疗的主要挑战之一。The PDE5 inhibitor used in this study was vardenafil , developed by Bayer and GSK for the treatment of erectile dysfunction (ED) in men .本研究中使用的PDE5抑制剂是伐地那非，由拜耳和葛兰素史克开发，用于治疗男性勃起功能障碍（ED）。Chemotherapy resistance in esophageal cancer is influenced by the tumor microenvironment , such as cancer-associated fibroblasts (CAFs) , which are important for tumor growth, provide nutrients to the tumor, and can play a protective role in preventing chemotherapeutic drugs from being effective.食管癌的化疗耐药性受到肿瘤微环境的影响，例如肿瘤相关成纤维细胞（CAF），它们对肿瘤生长至关重要，为肿瘤提供营养，并在阻止化疗药物有效性方面发挥保护作用。
In this study, the research team found that 5-phosphodiesterase ( PDE5 ) was significantly overexpressed in esophageal adenocarcinoma cells compared with healthy esophageal tissue , whereas cancer-associated fibroblasts (CAFs ) in the tumor microenvironment ) also highly expressed PDE5.在这项研究中，研究团队发现，与健康食管组织相比，5-磷酸二酯酶（PDE5）在食管腺癌细胞中显著过度表达，而肿瘤微环境中的癌相关成纤维细胞（CAF）也高表达PDE5。Meanwhile, high expression of PDE5 was associated with poor overall survival, suggesting that PDE5 may be an effective therapeutic target for esophageal adenocarcinoma.同时，PDE5的高表达与总体生存率低相关，表明PDE5可能是食管腺癌的有效治疗靶点。The research team then tested a PDE5 inhibitor (PDE5i) in CAFs of esophageal cancer tumors .研究小组随后在食管癌肿瘤的CAF中测试了PDE5抑制剂（PDE5i）。The results showed that PDE5i was able to inhibit CAF activity, making them look more like normal fibroblasts.结果表明，PDE5i能够抑制CAF活性，使其看起来更像正常的成纤维细胞。Next, the research team extracted tumor cell samples from 15 tissue biopsy samples from 8 patients with esophageal adenocarcinoma, cultured them, and then tested the combination therapy of PDE5i and standard chemotherapy on these cultured tumors.接下来，研究团队从8例食管腺癌患者的15个组织活检样本中提取肿瘤细胞，进行培养，然后测试PDE5i联合标准化疗和标准化疗对这些肿瘤的细胞的作用。In 9 of 12 samples with poor response to chemotherapy in the clinic, cancer cells were resensitized to chemotherapy when CAF was targeted by PDE5i.在临床上对化疗反应较差的12个癌细胞样本中，有9个样本在PDE5i作用下对化疗重新敏感。The research team further tested the combination therapy using a human-derived tumor xenograft model, and the results showed that the combination therapy had no adverse side effects and was able to suppress and shrink tumors better than chemotherapy alone .研究团队使用人类来源的肿瘤异种移植模型进一步测试了联合治疗，结果表明，联合治疗没有副作用，并且能够比单独化疗更好地抑制和缩小肿瘤。
Including sildenafil (commonly known as Viagra) , vardenafil , avanafil , tadalafil , etc., are all PDE5 inhibitors, exerting therapeutic effects by inhibiting PDE5.西地那非（俗称伟哥）、伐地那非、阿瓦那非、他达拉非等，均为PDE5抑制剂，通过抑制PDE5发挥治疗作用。The earliest PDE5 inhibitor (PDE5i) was sildenafil (commonly known as Viagra) developed by Pfizer , which was originally developed for the treatment of cardiovascular disease, but clinical trials did not achieve the expected effect of dilating blood vessels and relieving cardiovascular disease. Purpose.最早的PDE5抑制剂（PDE5i）是辉瑞公司开发的西地那非（俗称伟哥），最初用于治疗心血管疾病，但临床试验没有达到扩张血管和缓解心血管疾病的预期效果。意图In April 1991, the clinical study of sildenafil officially failed. But the researchers found that the volunteers who participated in the study were reluctant to return the remaining drugs.1991年4月，西地那非的临床研究正式失败。但研究人员发现，参与研究的志愿者不愿意归还剩余的药物。
When pressed, the volunteers said that the drug improved their sex life.当被追问时，志愿者们说这种药物改善了他们的性生活。The researchers at Pfizer then changed direction and investigated the effect of sildenafil on the smooth muscle of the corpus cavernosum.辉瑞的研究人员随后改变了方向，研究了西地那非对海绵体平滑肌的影响。Sildenafil was approved by the FDA in 1998 for the treatment of male erectile dysfunction (ED) . Since then, other PDE5 inhibitors , vardenafil , avanafil , and tadalafil , have been launched one after another.西地那非于1998年被FDA批准用于治疗男性勃起功能障碍（ED）。从那时起，其他PDE5抑制剂，伐地那非，阿伐那非和他达拉非，已陆续推出。With the safety of these drugs confirmed, and the positive results of this preclinical study, the research team said the next step would be to conduct a Phase I/II clinical trial to test PDE5 inhibitors in combination with chemotherapy in patients with advanced esophageal cancer .随着这些药物的安全性得到证实，以及这项临床前研究的积极结果，研究团队表示，下一步将进行一项I/II期临床试验，以测试PDE5抑制剂与化疗联合治疗晚期食管癌患者。If the clinical trial is successful, many patients with esophageal cancer will be saved, and the study may also pave the way for the application of PDE5 inhibitors in other cancer types.如果临床试验成功，许多食管癌患者将获救，该研究也可能为PDE5抑制剂在其他癌症类型中的应用铺平道路。Reference:https://doi.org/10.1016/j.xcrm.2022.100541
