Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis

Lorenzo, Giuseppe Di; Autorino, Riccardo; Bruni, Gianni; Cartenì, Giacomo; Ricevuto, Enrico; Tudini, Marianna; Ficorella, Corrado; Romano, Carmela; Aieta, Michele; Giordano, Antonio; Giuliano, Mario; Gonnella, A.; Nunzio, Cosimo De; Rizzo, Mimma; Montesarchio, Vincenzo; Ewer, Michael S.; Placido, Sabino De

doi:10.1093/annonc/mdp025

Cited by 185 publications

(120 citation statements)

References 21 publications

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“…18 Sunitinib has been associated with many side effects, including severe cutaneous toxicities and cardiotoxicity. 11,[19][20][21][22] To avoid these side effects, targeted delivery of sunitinib to the target cells, ie, the proximal tubular cells of the kidneys, is a comprehensive approach. We have shown that small-molecule inhibitors can be delivered to the kidney by conjugation to lysozyme, [23][24][25] a low molecular weight protein that is rapidly filtered through the glomeruli of the kidneys and subsequently taken up at the apical membrane of proximal tubular cells via megalin receptor-mediated internalization.…”

Section: Introductionmentioning

confidence: 99%

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Dolman¹,

Harmsen²,

Pieters³

et al. 2012

IJN

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Background: Activated proximal tubular cells play an important role in renal fibrosis. We investigated whether sunitinib and a kidney-targeted conjugate of sunitinib were capable of attenuating fibrogenic events in tubulointerstitial fibrosis. Methods: A kidney-targeted conjugate was prepared by linkage of a sunitinib analog (named 17864) via a platinum-based linker to the kidney-specific carrier lysozyme. Pharmacological activity of 17864-lysozyme was evaluated in human kidney proximal tubular cells (HK-2); the capability of the kidney-directed conjugate to accumulate in the kidneys was studied in mice. Potential antifibrotic effects of a single-dose treatment were evaluated in the unilateral ureteral obstruction (UUO) model in mice. Results: The 17864-lysozyme conjugate and its metabolites strongly inhibited tyrosine kinase activity. Upon intravenous injection, 17864-lysozyme rapidly accumulated in the kidneys and provided sustained renal drug levels for up to 3 days after a single dose. Renal drug level area under the curve was increased 28-fold versus an equimolar dose of sunitinib malate. Daily treatment of UUO mice with a high dose of sunitinib malate (50 mg/kg) resulted in antifibrotic responses, but also induced drug-related toxicity. A single dose of 17864-lysozyme (equivalent to 1.8 mg/kg sunitinib) was safe but showed no antifibrotic effects. Conclusion: Multikinase inhibitors like sunitinib can be of benefit in the treatment of fibrotic diseases, provided that their safety can be improved by strategies as presented in this paper, and sustained renal levels can be achieved.

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Section: Introductionmentioning

confidence: 99%

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Dolman¹,

Harmsen²,

Pieters³

et al. 2012

IJN

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show abstract

“…This is a significant issue because such symptoms might be due to sunitinib-induced hypothyroidism and could therefore be reversible with thyroid hormone replacement. Secondly, fatigue can also be related to cardiac failure, which also has recently been reported as an important side effect of sunitinib (Chu et al, 2007;Schmidinger et al, 2008;Telli et al, 2008;DiLorenzo et al, 2009). Unfortunately, detailed information on cardiac toxicity is also lacking, but the authors reported that at least one patient died because of treatment-related congestive heart failure.…”

Section: Sirmentioning

confidence: 99%

Ongoing under-reporting of clinically relevant safety data in phase II studies of tyrosine kinase inhibitors

et al. 2010

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“…In addition, unrecognized hypothyroidism or thyrotoxicosis may affect the metabolism of other medications [151]. Finally, it should be considered that thyroid dysfunction, although rarely, can lead to life-threatening consequences in cancer patients, as warned by case reports of patients who experienced myxedematous coma [152] or impaired cardiac function [153,154] as a complication of TKIinduced hypothyroidism (i.e. sunitinib).…”

Section: Why Is It Important To Assess Thyroid Function In Cancer Patmentioning

confidence: 99%

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents

Torino¹,

Barnabei²,

Baldelli³

et al. 2012

Thyroid Hormone

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Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis

Abstract: Patients undergoing sunitinib, especially those with a previous history of hypertension and coronary heart disease, are at increased risk for cardiovascular events and should be monitored for exacerbations of their hypertension and for evidence of LVEF dysfunction during treatment.

Cited by 185 publications

References 21 publications

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Ongoing under-reporting of clinically relevant safety data in phase II studies of tyrosine kinase inhibitors

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents

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