Patients and methods: Capillary density, assessed by sidestream dark field imaging of the mucosal surface of the lip, was measured at baseline, after 6 weeks of bevacizumab treatment and > 3... Show morePatients and methods: Capillary density, assessed by sidestream dark field imaging of the mucosal surface of the lip, was measured at baseline, after 6 weeks of bevacizumab treatment and > 3 months after discontinuation. Additional measurements included blood pressure (BP) measurements, flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD) and aortic pulse wave velocity (PWV). Results: Fourteen patients were included. Seven patients completed measurements at all three predefined time points. Capillary density significantly decreased after 6 weeks of bevacizumab treatment and was reversible after discontinuation of bevacizumab (P = 0.00001 using a general linear model repeated measures test). BP, FMD and NMD remained unchanged. Mean PWV increased after 6 weeks of treatment (P = 0.027) and decreased after bevacizumab discontinuation. Among the six patients with the best response were the three patients showing the clearest decrease in capillary density after 6 weeks of bevacizumab treatment. Conclusions: Bevacizumab-induced decrease in capillary density is reversible. Noninvasive assessment of capillary density during treatment with antiangiogenic drugs may be useful as a marker of treatment efficacy. Show less
Loos, W.; Hamberg, P.; Steeghs, N.; Kroep, J.; Tascilar, M.; Verweij, J.; ... ; Sleijfer, S. 2010
This thesis focuses on targeted anticancer agents. An important class of these agents are the tyrosine kinase inhibitors (TKIs). One of the first steps in TKI treatment development is defining... Show moreThis thesis focuses on targeted anticancer agents. An important class of these agents are the tyrosine kinase inhibitors (TKIs). One of the first steps in TKI treatment development is defining whether a specific type of cancer, for example the sarcomas in chapter 3 of this thesis, express the receptors that are targeted. Once a TKI is developed, phase I studies are conducted to characterize the safety and side effects of the drug when administered to patients. When relevant side effects emerge, studies investigating the underlying mechanisms leading to these side effects are called for. Also pharmacogenetic studies can be performed to investigate whether certain heritable genetic variations influence efficacy or safety of the drug. After the phase I studies have proven the drug to be safe, the drug can be further developed. This includes the investigation of the TKI when combined with other anticancer agents. Items of all the described steps in TKI development are described in this thesis. Show less
Purpose Telatinib is an orally active small-molecule tyrosine kinase inhibitor of kinase insert domain receptor (KDR; VEGFR-2) and fms-related tyrosine kinase 4 (FLT4; VEGFR-3). This study aims at... Show morePurpose Telatinib is an orally active small-molecule tyrosine kinase inhibitor of kinase insert domain receptor (KDR; VEGFR-2) and fms-related tyrosine kinase 4 (FLT4; VEGFR-3). This study aims at the identification of relationships between single nucleotide polymorphisms (SNPs) in genes encoding for transporter proteins and pharmacokinetic parameters in order to clarify the significant interpatient variability in drug exposure. In addition, the potential relationship between target receptor polymorphisms and toxicity of telatinib is explored. Methods Blood samples from 33 patients enrolled in a phase I dose-escalation study of telatinib were analyzed. For correlation with dose normalized AUC((0-12)), ATP-binding cassette (ABC) B1 (ABCB1), ABCC1, and ABCG2 were the genes selected. For correlation with telatinib toxicity, selected genes were the drug target genes KDR and FLT4. Results No association between dose normalized AUC((0-12)) and drug transporter protein polymorphisms was observed. In addition, no association between toxicity and KDR or FLT4 genotype or haplotype was seen. Conclusions Our pharmacogenetic analysis could not reveal a correlation between relevant gene polymorphisms and clinical and pharmacokinetic observations of telatinib. Show less
