William B. Weglicki, J.H. Kramer, J.J. Chmielinska, C.F. Spurney and I.T. Mak
George Washington University, School of Medicine and Health Sciences, Washington D.C., USA
Prior reports of hypomagnesemia in patients receiving the epidermal growth factor receptor (EGFR)- blocking drug, Cetuximab, suggested that EGFR-tyrosine kinase inhibitors (TKI), like erlotinib (Tarceva), may have a similar side effect. In addition, the possibility of preventing complications of therapy by blockade of neurogenic inflammation was studied. Rats were treated with erlotinib for up to 9 weeks and were investigated for hypomagnesemia, inflammation and cardiac dysfunction. Plasma magnesium decreased progressively (-9 to -26%) between 3-9 weeks, and this was associated with modest increases (+27% at 3 and + 25% at 9 weeks) in circulating levels of the neuropeptide, substance P (SP). In previous work the TKI, tyrphostin AG-1478, caused similar effects. The superoxide-generating activity of circulating neutrophils from erlotinib-treated rats increased 3-fold, and the plasma oxidative marker, 8-isoprostane rose 2.1-fold, together with appearance of cardiac peri-vascular nitrotyrosine. The SP receptor blocker, aprepitant (Emend), attenuated erlotinib-induced hypomagnesemia by 42% and completely prevented the rise in circulating SP; the increases in neutrophil superoxide activity and 8-isoprostane were also suppressed. Echocardiography revealed mild to moderate systolic dysfunction by 7 weeks of erlotinib treatment, with slight decreases in left ventricular ejection fraction (LVEF: -11%) and % fractional shortening (%FS: -17%); the mitral valve E/A ratio was significantly reduced (-17.5%, week 9), suggesting diastolic dysfunction. Also thinning of the left ventricular posterior wall (LVPWd & s in diastole and systole) was detected by 7 - 9 weeks. Most interestingly, the co-administration of aprepitant attenuated all of the erlotinibinduced effects on LV systolic, diastolic and anatomical parameters: At 9 weeks, LVEF improved 87.2%; LV % FS improved 86.4%; and mitral valve E/A ratio improved 84.6%.
In conclusion, prolonged erlotinib treatment in rats induced moderate hypomagnesemia, along with SP-mediated oxidative/inflammation stress, and mild to moderate cardiac dysfunction. These changes were substantially prevented by SP receptor blockade implicating the novel role of neurogenic inflammation due to EGFR-TK inhibition.