Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126

被引:134
作者
Evelhoch, JL
LoRusso, PM [1 ]
He, ZQ
DelProposto, Z
Polin, L
Corbett, TH
Langmuir, P
Wheeler, C
Stone, A
Leadbetter, J
Ryan, AJ
Blakey, DC
Waterton, JC
机构
[1] Wayne State Univ, Harper Hosp, MR Ctr, Karmanos Canc Inst, Detroit, MI 48201 USA
[2] AstraZeneca, Wilmington, DE USA
[3] AstraZeneca, Waltham, MA USA
[4] Alderley Pk, Macclesfield, Cheshire, England
关键词
D O I
10.1158/1078-0432.CCR-03-0417
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: ZD6126 is a novel vascular targeting agent currently undergoing clinical evaluation. It acts by destabilizing the microtubulin of fragile and proliferating neoendothelial cells in tumors. The drug leads to blood vessel congestion, the selective destruction of the vasculature, and extensive necrosis in experimental tumors. The aim of the study reported here was to assess the ability of dynamic contrast enhanced magnetic resonance imaging (MRI) to measure the antivascular effects of ZD6126 in tumors. Experimental Design: The work was carried out in mice bearing C38 colon adenocarcinoma and in patients with advanced cancers. MRI was performed before and 6 h (human tumors) or 24 h (C38 tumors) after i.v. drug administration. Contrast agent (gadolinium diethylenetriaminepentaacetate) enhancement was characterized by the initial area under the gadolinium diethylenetriaminepentaacetate uptake versus time curve (IAUC). IAUC reflects blood flow, vascular permeability, and the fraction of interstitial space. Results: The median IAUC was reduced in all C38 tumors after ZD6126 administration [by 6-48% at 50 mg/kg (n = 3)], 58-91% at 100 mg/kg (n = 4), and 11-93% at 200 mg/kg (n = 6). In contrast, the administration of vehicle only led to no consistent change in median IAUC (n = 4). The ZD6126-induced changes in median IAUC appeared to be dose dependent (P = 0.045). No ZD6126-induced changes were apparent in murine muscle. Similar effects were seen in preliminary data from human tumors (11 tumors studied, 9 patients). At doses of 80 mg/m(2) and higher, the median IAUC post-ZD6126 treatment was reduced in all of the tumors studied (8 tumors, 6 patients) to 36-72% from the baseline value. There was a significant trend of increasing reductions with increasing exposure (P < 0.01). No drug-induced changes in human muscle or spleen IAUC were apparent. The reproducibility of the median IAUC parameter was investigated in patients. In 19 human tumors (measured in 19 patients) inter- and intratumor coefficients of variation were 64 and 18%. Conclusions: The contrast enhanced-MRI measured median IAUC is a useful end point for quantifying ZD6126 antivascular effects in human tumors.
引用
收藏
页码:3650 / 3657
页数:8
相关论文
共 33 条
[1]   Measuring changes in human tumour vasculature in response to therapy using functional imaging techniques [J].
Anderson, H ;
Price, P ;
Blomley, M ;
Leach, MO ;
Workman, P .
BRITISH JOURNAL OF CANCER, 2001, 85 (08) :1085-1093
[2]   Magnetic resonance imaging and spectroscopy of combretastatin A4 prodrug-induced disruption of tumour perfusion and energetic status [J].
Beauregard, DA ;
Thelwall, PE ;
Chaplin, DJ ;
Hill, SA ;
Adams, GE ;
Brindle, KM .
BRITISH JOURNAL OF CANCER, 1998, 77 (11) :1761-1767
[3]   Differential sensitivity of two adenocarcinoma xenografts to the anti-vascular drugs combretastatin A4 phosphate and 5,6-dimethylxanthenone-4-acetic acid, assessed using MRI and MRS [J].
Beauregard, DA ;
Pedley, RB ;
Hill, SA ;
Brindle, KM .
NMR IN BIOMEDICINE, 2002, 15 (02) :99-105
[4]  
Beauregard DA, 2001, CANCER RES, V61, P6811
[5]  
Blakey DC, 2002, CLIN CANCER RES, V8, P1974
[6]   ZD6126: A novel small molecule vascular targeting agent [J].
Blakey, DC ;
Ashton, SE ;
Westwood, FR ;
Walker, M ;
Ryan, AJ .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2002, 54 (05) :1497-1502
[7]  
BLAKEY DC, 2000, CLIN EXP METASTAS, V17, P776
[8]  
Brookes JA, 1999, JMRI-J MAGN RESON IM, V9, P163, DOI 10.1002/(SICI)1522-2586(199902)9:2<163::AID-JMRI3>3.0.CO
[9]  
2-L
[10]  
Chaplin DJ, 1999, ANTICANCER RES, V19, P189