Lubet Ronald A, Kumar Amit, Fox Jennifer T, You Ming, Mohammed Altaf, Juliana M Margaret, Grubbs Clinton J
Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
Bladder Cancer. 2021 Aug 31;7(3):335-345. doi: 10.3233/BLC-200423. eCollection 2021.
There are few effective treatments specifically aimed at basal bladder cancer.
Female F344 rats administered N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) develop large invasive bladder cancers. We determined the efficacy of daily vs weekly dosing of EGFR inhibitors, determined the efficacy of naproxen combined with an EGFR inhibitor, and performed RNA analysis of bladder tumors treated for 5 days with EGFR inhibitors or NO-naproxen to identify pharmacodynamic biomarkers.
Erlotinib (6 mg/Kg BW daily or 21 or 42 mg/Kg BW weekly), lapatinib (25 or 75 mg/Kg BW daily or 263 or 525 mg/Kg BW weekly) and/or naproxen (30 mg/Kg BW daily) were administered to OH-BBN-treated rats beginning 2-12 weeks post OH-BBN. Rats were sacrificed 28 weeks after the final OH-BBN treatment to determine the effects of the EGFR inhibitors + naproxen on bladder weights and tumor development. In a separate study, rats were treated with OH-BBN. When palpable tumors developed, rats were treated with erlotinib, lapatinib, gefitinib, or the NSAID NO-naproxen for 5 days. RNA analysis was performed on the tumors.
Daily or weekly dosing of erlotinib or lapatinib and daily dosing of naproxen reduced large tumor formation up to 70%, while combining daily lapatinib and naproxen reduced tumors 100%. RNA Analysis: All EGFR inhibitors strongly reduced cell proliferation and chromosome replication pathways, while NO-naproxen altered the G protein receptor, oxygen homeostasis and immune function pathways.
While daily and weekly dosing with EGFR inhibitors and naproxen were effective, combining lapatinib and naproxen yielded no tumors. This might encourage its clinical use in an adjuvant setting with superficial basal tumors, and perhaps even in a more advanced setting. Furthermore, RNA analysis identified specific pathways that might be potential pharmacodynamic biomarkers in clinical trials.
专门针对基底膀胱癌的有效治疗方法很少。
给予雌性F344大鼠N-丁基-N-(4-羟基丁基)-亚硝胺（OH-BBN）可诱发大型浸润性膀胱癌。我们确定了表皮生长因子受体（EGFR）抑制剂每日给药与每周给药的疗效，确定了萘普生联合EGFR抑制剂的疗效，并对用EGFR抑制剂或NO-萘普生治疗5天的膀胱肿瘤进行RNA分析，以鉴定药效学生物标志物。
从给予OH-BBN后2至12周开始，对经OH-BBN处理的大鼠给予厄洛替尼（每日6mg/Kg体重或每周21或42mg/Kg体重）、拉帕替尼（每日25或75mg/Kg体重或每周263或525mg/Kg体重）和/或萘普生（每日30mg/Kg体重）。在最后一次OH-BBN治疗后28周处死大鼠，以确定EGFR抑制剂+萘普生对膀胱重量和肿瘤发生的影响。在另一项研究中，大鼠接受OH-BBN处理。当出现可触及的肿瘤时，大鼠用厄洛替尼、拉帕替尼、吉非替尼或非甾体抗炎药NO-萘普生治疗5天。对肿瘤进行RNA分析。
厄洛替尼或拉帕替尼每日或每周给药以及萘普生每日给药可使大型肿瘤形成减少多达70%，而每日联合使用拉帕替尼和萘普生可使肿瘤减少100%。RNA分析：所有EGFR抑制剂均强烈降低细胞增殖和染色体复制途径，而NO-萘普生改变G蛋白受体、氧稳态和免疫功能途径。
虽然EGFR抑制剂和萘普生每日和每周给药均有效，但联合使用拉帕替尼和萘普生未产生肿瘤。这可能会促使其在浅表基底肿瘤的辅助治疗中，甚至在更晚期的情况下用于临床。此外，RNA分析确定了特定途径，这些途径可能是临床试验中潜在的药效学生物标志物。
