Zerbe Laura K, Dwyer-Nield Lori D, Fritz Jason M, Redente Elizabeth F, Shroyer Robert J, Conklin Elizabeth, Kane Shawn, Tucker Chris, Eckhardt S Gail, Gustafson Daniel L, Iwata Kenneth K, Malkinson Alvin M
Department of Pharmaceutical Sciences, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, Box C238, Denver, CO, 80262, USA.
Cancer Chemother Pharmacol. 2008 Sep;62(4):605-20. doi: 10.1007/s00280-007-0644-z. Epub 2007 Nov 21.
Erlotinib, a small molecule inhibitor of the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR), increases survival of advanced non-small cell lung cancer patients who failed standard chemotherapy (Phase III study). We evaluated whether erlotinib is also effective at an early stage of primary lung tumorigenesis in a carcinogen-induced lung tumor model in mice.
Sixteen weeks after carcinogen (urethane) injection, when small self-contained adenomas are evident, male and female A/J mice were treated IP with 10 mg/kg erlotinib or Captisol vehicle daily over 3.5 weeks (15 mice per group). The efficacy, metabolism and mechanism of action of erlotinib were evaluated.
Erlotinib reduced tumor burden in males by twofold compared to vehicle (12.7 +/- 1.2 vs 26.2 +/- 2.5 mg, respectively; p < 0.0001), while tumor burden in erlotinib-treated females slightly increased compared to vehicle by 21% (15.1 +/- 1.2 vs 11.9 +/- 0.9 mg, respectively; p < 0.05). Tumor multiplicity, in contrast, was unaffected by erlotinib. The levels of erlotinib that accumulated in plasma, lung tumor tissue and adjacent uninvolved (UI) lung were comparable in males and females. Males, however, accumulated more OSI-420, an active and pharmacologically equipotent metabolite of erlotinib, than females in plasma, lung tumors, and UI lung. In both genders, 80% of tumors contained Kras mutations at codon 61, but no EGFR mutations were detected. The cellular distribution and concentration of EGFR were also similar between genders. In control mice, however, phosphorylated EGFR (pEGFR) levels were nearly 2.5-fold higher in males compared to females in UI lungs and sevenfold higher in lung tumors. Further, erlotinib decreased the contents of pEGFR in UI lungs and lung tumors, particularly in males.
Adenomas from male mice in this early lung cancer model are responsive to erlotinib treatment, possibly because of a greater dependence of male tumor growth on the EGFR pathway compared to females. Importantly, these results indicate that small lung adenomas from male mice that utilize EGFR signaling but also harbor Kras mutations shrink in response to erlotinib, suggesting that erlotinib may be beneficial for some patients very early during lung cancer progression.
厄洛替尼是一种表皮生长因子受体（EGFR）酪氨酸激酶（TK）结构域的小分子抑制剂，可提高标准化疗失败的晚期非小细胞肺癌患者的生存率（III期研究）。我们在致癌物诱导的小鼠肺癌模型中评估了厄洛替尼在原发性肺癌发生早期是否也有效。
在注射致癌物（乌拉坦）16周后，当明显出现独立的小腺瘤时，对雄性和雌性A/J小鼠腹腔注射10mg/kg厄洛替尼或Captisol溶媒，每日一次，持续3.5周（每组15只小鼠）。评估了厄洛替尼的疗效、代谢和作用机制。
与溶媒组相比，厄洛替尼使雄性小鼠的肿瘤负担降低了两倍（分别为12.7±1.2mg和26.2±2.5mg；p<0.0001），而与溶媒组相比，厄洛替尼治疗的雌性小鼠的肿瘤负担略有增加，增加了21%（分别为15.1±1.2mg和11.9±0.9mg；p<0.05）。相比之下，肿瘤数量不受厄洛替尼影响。雄性和雌性小鼠血浆、肺肿瘤组织和相邻未受累（UI）肺中积累的厄洛替尼水平相当。然而，在血浆、肺肿瘤和UI肺中，雄性小鼠积累的OSI-420（厄洛替尼的一种活性且药理学等效的代谢产物）比雌性小鼠更多。在两种性别中，80%的肿瘤在密码子61处含有Kras突变，但未检测到EGFR突变。两性之间EGFR的细胞分布和浓度也相似。然而，在对照小鼠中，UI肺中雄性小鼠的磷酸化EGFR（pEGFR）水平比雌性小鼠高近2.5倍，在肺肿瘤中高7倍。此外，厄洛替尼降低了UI肺和肺肿瘤中pEGFR的含量，尤其是在雄性小鼠中。
在这个早期肺癌模型中，雄性小鼠的腺瘤对厄洛替尼治疗有反应，这可能是因为与雌性相比，雄性肿瘤生长对EGFR通路的依赖性更大。重要的是，这些结果表明，利用EGFR信号传导但也携带Kras突变的雄性小鼠的小肺腺瘤对厄洛替尼有反应而缩小，这表明厄洛替尼可能在肺癌进展的极早期对某些患者有益。
