EGFR Tyrosine Kinase Inhibition - Induced Cardiomyopathy

描述（由申请人提供）：流行病学研究表明，在癌症高发的老年人中，经常出现低镁血症。抗癌药物；顺铂，卡博铂)可能导致低镁血症和心血管并发症，如心律失常。EGFR抑制抗体（西妥昔单抗）和TKI（厄洛替尼）药物是抗癌药物，而前者众所周知会产生低镁血症。最近，FDA批准的厄洛替尼在小鼠中引起低镁血症，以及更高的胃肠道（GI）副作用的临床发生率。我们的初步研究显示，使用TKI药物tyrphostin治疗的大鼠出现明显的低镁血症和早期收缩功能障碍。我们之前的动物研究表明，饮食诱导的低镁血症可以引发P物质（SP）的大量产生/释放，从而导致肠道（内毒素血症）毒性和心功能障碍（FS %和LVEF降低）。因此，我们认为SP诱导的低镁血症炎症可能是厄洛替尼治疗患者胃肠道副作用和潜在心血管毒性的关键媒介。具体目的是：1)确定大鼠慢性厄洛替尼治疗引起的低镁血症和随后的肠道和心脏炎症/功能障碍的程度；2)评估临床使用的SP受体阻滞剂阿瑞吡坦（Emend）是否可以减轻厄洛替尼诱导的长期肠道和心脏毒性，以及它是否对厄洛替尼治疗的同时存在低镁血症的动物有效（作为年龄或镁消耗药物相关低镁血症的范例）。由于口服Mg替代疗法可能对长期低镁血症无效，特别是对有胃肠道副作用的患者，因此该项目的结果可能对使用EGFR/TKI药物治疗的癌症患者的胃肠道和潜在心脏副作用的治疗具有直接的临床意义，特别是当与顺铂联合使用时。

DESCRIPTION (provided by applicant): Epidemiology studies have documented frequent hypomagnesemia in the elderly who also have a high cancer incidence. Anticancer drugs (eg. cisplatin, caboplatin) may cause hypomagnesemia and cardiovascular complications such as arrhythmias. EGFR inhibiting antibody (cetuximab) and TKI (erlotinib) drugs are anticancer agents, and the former is well known to produce hypomagnesemia. Recently, FDA approved-erlotinib has been reported to cause hypomagnesemia in mice, and a higher clinical incidence of gastrointestinal (GI) side effects. Our pilot study has shown significant hypomagnesemia and early systolic dysfunction in rats treated with the TKI drug, tyrphostin. Our prior animal studies demonstrated that diet-induced hypomagnesemia can trigger a significant production/release of substance P (SP) with resultant intestinal (endotoxemia) toxicity and cardiac dysfunction (decreased % FS & LVEF). Therefore, we propose that SP- induced inflammation due to hypomagnesemia may be a key mediator of the GI side effects and potential cardiovascular toxicity in some patients treated with erlotinib. The specific aims are: 1) Determine the extent of chronic erlotinib treatment-induced hypomagnesemia and subsequent intestinal and cardiac inflammation/dysfunction in rats; and 2) Assess if long-term erlotinib-induced intestinal and cardiac toxicity can be attenuated by the clinically-used SP receptor blocker, aprepitant (Emend), and if it is effective in erlotinib-treated animals with co-existing hypomagnesemia (as a paradigm for age- or Mg-wasting drug-related hypomagnesemia). Since oral Mg replacement therapy may prove ineffective in prolonged hypomagnesemia, particularly in patients with GI side effects, the outcome of this project may have immediate clinical implications for treatment of GI and potential cardiac side effects in cancer patients treated with EGFR/TKI drugs, particularly when combined with cisplatin.