Gefitinib Affects Functions of Platelets and Blood Vesselsvia Changes in Prostanoids Balance

Abstract

Prostaglandins (PGs) and thromboxane (TX) produced by cyclooxygenase (COX) have a great influence on vascular systems and platelet functions. The serum levels of epidermal growth factor (EGF) and PGs were measured in patients with lung cancer treated with gefitinib, and the influence of EGF on platelet aggregation was investigated. Twenty patients were investigated. The serum level of TXB2 increased significantly in all patients who received gefitinib for 2 weeks (before vs. after = 94.1 ± 47.3 vs. 190.9 ± 54.3, p<0.01). TXB2 also increased significantly in responders without concurrent chemotherapy (before vs. after = 79.3 ± 35.5 vs. 194.5 ± 58.1, p<0.05), but not in non-responders (before vs. after = 106. 5 ± 65.8 vs. 162. 2 ± 52.8, N.S.). PG 6-keto F1α and PGE2 did not exhibit significant changes. Furthermore, EGF showed no significant change (after vs. before = 234 ± 35 vs. 276 ± 72, N.S.). Although there was no correlation between the levels of EGF and TXB2 (N.S.), the PG 6-keto F2α/TXB2 ratio decreased significantly (before vs. after = 0.054 ± 0.018 vs 0.033 ± 0.015, p<0.05). The secondary platelet aggregation observed after high-dose adenosine diphosphate stimulation was inhibited after a 1-minute preincubation with EGF. Platelet aggregation in patients after gefitinib administration tended to accelerate and secondary aggregation was observed after low-dose adenosine diphosphate stimulation. We conclude that careful observation is needed for patients with chronic obstructive pulmonary disease, pulmonary fibrosis, and thromboembolic diseases receiving gefitinib. Furthermore, measurement of prostanoids may be a good predictor of the beneficial and adverse effects. Moreover, the combination of gefitinib with a COX inhibitor that regulates TXA2/PGI2 balance should be evaluated.