Metabolism and Disposition of Vatalanib (PTK787/ZK-222584) in Cancer Patients

Jost, L.; Gschwind, Hans‐Peter; Jalava, Taina; Wang, Yongyu; Guenther, Clemens; Souppart, C.; Rottmann, Antje; Denner, Karsten; Waldmeier, Felix; Groß, Gerhard; Masson, Éric; Laurent, Dirk

doi:10.1124/dmd.106.009944

Cited by 64 publications

(58 citation statements)

References 20 publications

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“…The published literature provides examples of clinically achievable serum concentrations of both VEGF RTKIs used here: ≥40 μmol/L for pazopanib after once-daily administration of ≥800 mg (28) and 15.8 ± 9.5 μmol/L for vatalanib after once-daily administration of 1,000 mg (29). From our observations, comparable concentrations were sufficient to markedly reduce the percentage of living CLL cells, whereas healthy B cells were significantly less affected in this concentration range.…”

Section: Discussionmentioning

confidence: 99%

The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Vatalanib and Pazopanib Potently Induce Apoptosis in Chronic Lymphocytic Leukemia Cells In vitro and In vivo

Paesler

Gehrke

Gandhirajan

et al. 2010

Clinical Cancer Research

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Purpose: There is evidence that vascular endothelial growth factor (VEGF) is a critical microenvironmental factor that exerts angiogenesis-independent effects on the survival of chronic lymphocytic leukemia (CLL) cells. Vatalanib and pazopanib are potent orally available VEGF receptor tyrosine kinase inhibitors. We investigated the efficacy and selectivity of both compounds in CLL cells, simulated potential combination with conventional cytostatics, and tested the effect of both substances on CLL-like tumor xenografts.Experimental Design: Primary CLL and normal peripheral blood cells were tested for viability after incubation with varying concentrations of both inhibitors. Further, phosphorylation status of VEGF receptor on treatment, caspase activation, and poly(ADP-ribose) polymerase cleavage were assessed. Combinations of each inhibitor with fludarabine, vincristine, and doxorubicin were analyzed for possible synergistic effects in vitro. For in vivo testing, mice grafted with the CLL-like cell line JVM-3 were treated orally with each inhibitor.Results: Vatalanib and pazopanib decreased phosphorylation of the VEGF receptor, along with induction of apoptosis in CLL cells in clinically achievable concentrations. Healthy B cells were only mildly affected. Immunoblots showed downregulation of the antiapoptotic proteins XIAP and MCL1, whereas poly(ADP-ribose) polymerase cleavage was increased. Combinations with conventional cytostatic agents resulted in synergistic effects. Treatment of xenografted mice with 100 mg/kg of body weight for 21 days resulted in tumor inhibition rates of 76% (vatalanib) and 77% (pazopanib). In two mice, a total tumor eradication could be observed. No gross systemic toxicity occurred.Conclusion: We conclude that VEGF inhibition is a promising new therapeutic approach in CLL. Vatalanib and pazopanib seem to be effective and safe candidates to be further evaluated for this purpose.

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Section: Discussionmentioning

confidence: 99%

The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Vatalanib and Pazopanib Potently Induce Apoptosis in Chronic Lymphocytic Leukemia Cells In vitro and In vivo

Paesler

Gehrke

Gandhirajan

et al. 2010

Clinical Cancer Research

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“…The background for blood and plasma was determined and subtracted from the measurements of study samples. The limit of quantification (LOQ) of LSC was determined as described previously (Jost et al, 2006) and was defined as the minimal number of sample disintegrations that are statistically significant above background and that show a relative statistical uncertainty equal to or smaller than 20%. Thus, the LOQ was 17 ng-Eq/ml (2.8 dpm) for blood (counting time 60 min), 11.4 ng-Eq/ml (1.8 dpm) for plasma (counting time 180 min), and approximately 0.01% of dose for urine and feces.…”

Section: Methodsmentioning

confidence: 99%

Absorption, Distribution, Metabolism, and Elimination of the Direct Renin Inhibitor Aliskiren in Healthy Volunteers

Waldmeier

Glaenzel²,

Wirz³

et al. 2007

Drug Metab Dispos

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120

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“…The current dogma is that angiogenesis inhibitors should preferably be given continuously. Because of the short half-life of vatalanib (4.7 hours), once-daily dosing may have caused intermittent inhibition [27]. A recent phase I study has provided support for twice-daily dosing [28].…”

Section: Vatalanibmentioning

confidence: 99%

Target Practice: Lessons from Phase III Trials with Bevacizumab and Vatalanib in the Treatment of Advanced Colorectal Cancer

2007

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LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Describe the safety of using bevacizumab in clinical practice.2. Explain the benefit of adding bevacizumab to chemotherapy in colorectal cancer.3. Discuss mechanisms of targeting the VEGF/VEGFR pathway.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME Disclosure of potential conflicts of interest is found at the end of this article. ABSTRACT

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Metabolism and Disposition of Vatalanib (PTK787/ZK-222584) in Cancer Patients

Cited by 64 publications

References 20 publications

The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Vatalanib and Pazopanib Potently Induce Apoptosis in Chronic Lymphocytic Leukemia Cells In vitro and In vivo

The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Vatalanib and Pazopanib Potently Induce Apoptosis in Chronic Lymphocytic Leukemia Cells In vitro and In vivo

Absorption, Distribution, Metabolism, and Elimination of the Direct Renin Inhibitor Aliskiren in Healthy Volunteers

Target Practice: Lessons from Phase III Trials with Bevacizumab and Vatalanib in the Treatment of Advanced Colorectal Cancer

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