semaxinib and Thromboembolism

An increased incidence of thromboembolic events was observed during treatment with cisplatin-gemcitabine plus SU5416 (CG+SU5416), a tyrosine kinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor-1 and -2. Nine thromboembolic events occurred in eight of 19 patients. We performed an analysis of parameters of the coagulation cascade and vessel wall activation.. Markers for thrombin generation and endothelial cell activation were measured in three patients treated with CG+SU5416, two of whom developed a thromboembolic event. The results were compared with measurements in six patients treated with CG alone, and in 17 patients treated with SU5416 alone.. During cycles 1 and 2 of treatment with CG+SU5416, a significant cycle-dependent activation of both the coagulation cascade and endothelial cells occurred, whereas platelet counts decreased. Change in platelet number had a significant negative predictive effect on soluble (s)-E-selectin levels. Significant activation of the coagulation cascade only was observed in the patients treated with CG alone, whereas in patients treated with SU5416 alone, significant endothelial cell activation was observed.. We hypothesize that endothelial cells deprived of VEGF after exposure to SU5416 became activated and more susceptible to damage during treatment with CG+SU5416, which was aggravated by a transient decrease in platelets, which are, among other things, carriers of VEGF. These results suggests that VEGF, in addition to being a permeability, proliferation, and migration factor, also is a maintenance and protection factor for endothelial cells, and that platelets may have a role in maintaining vascular integrity.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; Cisplatin; Deoxycytidine; E-Selectin; Endothelial Growth Factors; Endothelium, Vascular; Female; Gemcitabine; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Lymphokines; Male; Middle Aged; Multivariate Analysis; Platelet Count; Pyrroles; Regression Analysis; Thromboembolism; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416.. Patients received cisplatin 80 mg/m(2) on day 1, gemcitabine 1,250 mg/m(2) on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m(2)) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine.. In the first cohort of three patients entered at the 85 mg/m(2) dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m(2)), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m(2) developed a thromboembolic event. The dose was then reduced to 85 mg/m(2) in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle-dependent manner.. The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Drug Administration Schedule; Female; Gemcitabine; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Pyrroles; Thromboembolism; Treatment Outcome

Topics: Angiogenesis Inhibitors; Endothelium, Vascular; Humans; Indoles; Neoplasms; Pyrroles; Thromboembolism; Thrombophilia; Treatment Outcome