Hypertension and Rarefaction during Treatment with Telatinib, a Small Molecule Angiogenesis Inhibitor

Steeghs, Neeltje; Gelderblom, Hans; Roodt, Jos Op ‘t; Christensen, Olaf; Rajagopalan, Prabhu; Hovens, Marcel M.C.; Putter, Hein; Rabelink, Ton J.; Koning, Eelco J.P. de

doi:10.1158/1078-0432.ccr-07-5050

Cited by 174 publications

(109 citation statements)

References 41 publications

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“…5 Indeed, prolonged treatment with the RTKIs sunitinib and telatinib has been reported to be associated with capillary rarefaction. 9,25,26 To increase vascular resistance in a particular vascular bed by 5%, it has been estimated that 40% rarefaction of fourth-order vessels is required. 27 It is inconceivable that such an extensive degree of systemic rarefaction can occur within 4 hours after initiation of angiogenesis inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…7 However, clinical studies, using flow-mediated dilatation (FMD) as an index of NO bioavailability, do not unequivocally support the hypothesis that a decrease in NO bioavailability underlies the increase in MABP, because decreases in both endothelium-dependent and endothelium-independent vasodilatation have been reported in patients treated with RTKIs. 8,9 In previous clinical and experimental studies, we and others have shown that activation of the endothelin (ET) system is involved in the sunitinib-induced rise in MABP. 10 -12 Apart from inducing vasoconstriction, ET-1 activates vascular NADPH oxidase, leading to an increase in oxidative stress through enhanced reactive oxygen species (ROS) production.…”

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Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress

et al. 2012

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Abstract-Angiogenesis inhibition with agents targeting tyrosine kinases of vascular endothelial growth factor receptors is an established anticancer treatment, but is, unfortunately, frequently accompanied by systemic hypertension and cardiac toxicity. Whether vascular endothelial growth factor receptor antagonism also has adverse effects on the pulmonary and coronary circulations is presently unknown. In chronically instrumented awake swine, the effects of the vascular endothelial growth factor receptor antagonist sunitinib on the systemic, pulmonary, and coronary circulation were studied. One week after sunitinib (50 mg PO daily), mean aortic blood pressure (MABP) had increased from 83Ϯ5 mm Hg at baseline to 97Ϯ6 mm Hg (PϽ0.05) because of a 57Ϯ20% increase in systemic vascular resistance as cardiac output decreased. In contrast, sunitinib had no discernible effects on pulmonary and coronary hemodynamics or cardiac function. We subsequently investigated the mechanisms underlying the sunitinib-induced systemic hypertension. Intravenous administration of NO synthase inhibitor N G -nitro-L-arginine increased MABP by 24Ϯ1 mm Hg under baseline conditions, whereas it increased MABP even further after sunitinib administration (32Ϯ3 mm Hg; PϽ0.05). Reactive oxygen species scavenging with a mixture of antioxidants lowered MABP by 13Ϯ2 mm Hg before but only by 5Ϯ2 mm Hg (PϽ0.05) after sunitinib administration. However, intravenous administration of the dual endothelin A/endothelin B receptor blocker tezosentan, which did not lower MABP at baseline, completely reversed MABP to presunitinib values. These findings indicate that sunitinib produces vasoconstriction selectively in the systemic vascular bed, without affecting pulmonary or coronary circulations. The sunitinib-mediated systemic hypertension is principally attributed to an increased vasoconstrictor influence of endothelin, with no apparent contributions of a loss of NO bioavailability or increased oxidative stress. (Hypertension. 2012;59:151-157.) Key Words: endothelin 1 Ⅲ hypertension Ⅲ oxidative stress Ⅲ pulmonary hypertension Ⅲ vascular endothelial growth factor A ngiogenesis inhibition, by targeting the tyrosine kinases of the vascular endothelial growth factor (VEGF) receptors (VEGFRs), has become an established treatment of several tumor types. This therapy is associated with adverse effects, including the development of hypertension and cardiac and renal toxicity. 1 Hypertension has been reported in Յ60% of patients treated with sunitinib, an orally active multitarget receptor tyrosine kinase inhibitor (RTKI), targeting, among others, the VEGFR-1 and -2, which is used as first-line treatment of metastatic renal cell carcinoma or imatinib-resistant gastrointestinal stromal tumors. 1 In addition, impaired cardiac function, as reflected by a decrease in left ventricular ejection fraction of 10% to 15%, has been observed in Յ28% of patients treated with sunitinib. 2 Angina pectoris and increased levels of biomarkers reflecting ischemic myocardial damage may als...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress

et al. 2012

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“…However, the off-target and broad-spectrum activity associated with these multitargeted drugs confers them with a unique toxicity profile (61)(62)(63). At present, 6 targeted agents are approved for the treatment of metastatic RCC in Europe and/or the United States.…”

Section: Discussionmentioning

confidence: 99%

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

Aparicio-Gallego

Blanco

Figueroa

et al. 2011

Molecular Cancer Therapeutics

102

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The introduction of targeted therapy represents a major advance in the treatment of tumor progression. Targeted agents are a novel therapeutic approach developed to disrupt different cellular signaling pathways. The tyrosine kinase inhibitor sunitinib specifically blocks multiple tyrosine kinase receptors that are involved in the progression of many tumors. Sunitinib is the current standard of care in first-line treatment of advanced renal cell carcinoma, and it is approved in imatinib-intolerant and imatinib-refractory gastrointestinal stromal tumors. However, it is increasingly evident that sunitinib may display collateral effects on other proteins beyond its main target receptors, eliciting undesirable and unexpected adverse events. A better understanding of the molecular mechanisms underlying these undesirable sunitinib-associated side effects will help physicians to maximize efficacy of sunitinib and minimize adverse events. Here, we focus on new insights into molecular mechanisms that may mediate sunitinib-associated adverse events. Mol Cancer Ther; 10(12); 2215-23. Ó2011 AACR.

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“…Hypertension as a common class toxicity phenomenon was clinically well manageable in most of the patients with a standard antihypertensive treatment. Recently, Steeghs et al (2008) reported that small vessel rarefaction may be one of the underlying haemodynamic mechanisms causing hypertension. The average increase in diastolic blood pressure in our study was comparable to those reported results.…”

Section: Discussionmentioning

confidence: 99%

Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours

Strumberg¹,

Schultheis²,

Adamietz

et al. 2008

Br J Cancer

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Telatinib is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor b tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500 mg BID continuous dosing. Telatinib was rapidly absorbed with median t max of 3 hours or less. Geometric mean C max and AUC 0À12 increased in a less than doseproportional manner and plateaued in the 900 -1500 mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC 0À12 of telatinib. Telatinib is safe and well tolerated up to a dose of 1500 mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900 mg telatinib BID continuously administered was selected as the recommended phase II dose.

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Hypertension and Rarefaction during Treatment with Telatinib, a Small Molecule Angiogenesis Inhibitor

Cited by 174 publications

References 41 publications

Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress

Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours

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