In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5236-5236
Abstract:
Sunitinib is an orally bio-available small-molecule inhibitor that targets multiple pro-angiogenic receptor tyrosine kinases including VEGFR, PDGFR, c-KIT, FLT3, CSF-1R and RET. Sunitinib treatment induces growth arrest or regression in a range of preclinical tumour models via its anti-tumour and anti-angiogenic effects. An intermittent 4 weeks on, 2 weeks off sunitinib dosing schedule is routinely used in the clinic to reduce pharmacologic toxicity of the compound. However, the effects of treatment withdrawal on tumour vasculature are currently poorly defined. The aim of this study was to use dynamic contrast enhanced ultra high frequency sonography (DCE-UHS) to investigate the effects of intermittent therapy on vascular function in a preclinical xenograft tumour model. Nude mice bearing A431 human squamous cell tumours (mean volume 296 +/− 19 mm3) were randomized to receive either vehicle or 80 mg/kg sunitinib p.o. daily following a treatment regimen of 6 days on, 7 days off, 7 days on (n = 4/group). During the 20 day regimen period, mean tumour volumes in the sunitinib treated group regressed by 42% at day 6 but increased by 38% during the off treatment period days 6 - 13. Upon resuming sunitinib therapy, tumour volumes decreased once again by 13% (days 13 - 20). Mean tumour volumes in the vehicle treated group reached 561+/−27 mm3 at day 6 becoming too large for DCE-UHS measurements and were thus removed from the remainder of the experiment. DCE-UHS was performed at baseline and during the treatment regimen at days 4, 6, 11, 13, 17 and 20. Measures of tumour perfusion including relative fractional blood volume (RFBV; percentage of tumour volume with blood flow) and mean refill rate (MRR, mean rate at which blood re-perfuses a defined tumour area) are calculated from the DCE-UHS data. During the treatment periods, mean RFBV in the treated animals decreased by 52% (p = 0.011; days 0-6) and 55% (p = 0.021; days 13-20) and MRR by 77% and 72% (p values not significant). However, during the intervening off treatment period tumor perfusion increased by 66% RFBV and 58% MRR. While these data clearly demonstrate the inhibitory effects of sunitinib treatment on tumour perfusion they also highlight the rapid reversibility of the anti-vascular effects of the drug. Further, the study demonstrates the utility of DCE-UHS to investigate effects of intermittent sunitinib therapy on vascular parameters. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5236.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-5236
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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