Abstract

BACKGROUND:

There are few effective treatments specifically aimed at basal bladder cancer.

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

中文翻译：

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在大鼠模型中 EGFR 抑制剂和 NSAID 对基底膀胱癌的疗效：每日与每周给药、EGFR 抑制剂与萘普生的组合以及对 RNA 表达的影响

摘要

背景：

很少有专门针对基底膀胱癌的有效治疗方法。

客观的：

给予 N-丁基-N-(4-羟基丁基)-亚硝胺 (OH-BBN) 的雌性 F344 大鼠发展为大的浸润性膀胱癌。我们确定了每天和每周给药 EGFR 抑制剂的疗效，确定了萘普生与 EGFR 抑制剂联合的疗效，并对使用 EGFR 抑制剂或 NO-萘普生治疗 5 天的膀胱肿瘤进行了 RNA 分析，以确定药效学生物标志物。

方法：

厄洛替尼（每天 6 毫克/公斤体重或每周 21 或 42 毫克/公斤体重）、拉帕替尼（每天 25 或 75 毫克/公斤体重或每周 263 或 525 毫克/公斤体重）和/或萘普生（每天 30 毫克/公斤体重） ) 在 OH-BBN 后 2-12 周开始给予 OH-BBN 治疗的大鼠。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展的影响。在另一项研究中，大鼠接受了 OH-BBN 治疗。当出现可触及的肿瘤时，大鼠接受厄洛替尼、拉帕替尼、吉非替尼或 NSAID NO-萘普生治疗 5 天。对肿瘤进行RNA分析。

结果：

厄洛替尼或拉帕替尼的每日或每周给药以及萘普生的每日给药减少了高达 70% 的大肿瘤形成，而拉帕替尼和萘普生的每日联合给药减少了 100% 的肿瘤。RNA 分析：所有 EGFR 抑制剂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。

结论：

虽然每天和每周使用 EGFR 抑制剂和萘普生是有效的，但拉帕替尼和萘普生的组合没有产生肿瘤。这可能会鼓励其在浅表基底肿瘤的辅助治疗中的临床应用，甚至可能在更高级的环境中使用。此外，RNA 分析确定了可能成为临床试验中潜在药效学生物标志物的特定途径。