High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinomaReport as inadecuate




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Journal of Translational Medicine

, 9:220

First Online: 21 December 2011Received: 19 September 2011Accepted: 21 December 2011DOI: 10.1186-1479-5876-9-220

Cite this article as: Wang, X., Zhang, L., Goldberg, S.N. et al. J Transl Med 2011 9: 220. doi:10.1186-1479-5876-9-220

Abstract

BackgroundRenal cell carcinoma RCC responds to agents that inhibit vascular endothelial growth factor VEGF pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model.

MethodsMice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1 Conventional dose CD continuous therapy; 2 high dose HD intermittent therapy, 3 CD intermittent therapy and 4 HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled ASL MRI at day 0, 3, 7 and 10.

ResultsTumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion.

ConclusionsA modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.

KeywordsRenal cell carcinoma anti-angiogenic therapy arterial spin labeled magnetic resonance imaging List of abbreviationsRCCrenal cell carcinoma

VEGFvascular endothelial growth factor

TKItyrosine kinase inhibitor

ASL MRIarterial spin labeled magnetic resonance imaging

CDconventional dose

HDhigh dose.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-9-220 contains supplementary material, which is available to authorized users.

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