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Breast tumor xenografts: diffusion-weighted MR imaging to assess early therapy with novel apoptosis-inducing anti-DR5 antibody.

ABSTRACT: To measure the early therapeutic response to a novel apoptosis-inducing antibody, TRA-8, by using diffusion-weighted magnetic resonance (MR) imaging in a mouse breast cancer model.Animal experiments had institutional animal care and use committee approval. Four groups of nude mice bearing luciferase-positive breast tumors (four to five mice with eight to 10 tumors per group) were injected intravenously with 0 mg (group 1), 0.025 mg (group 2), 0.100 mg (group 3), or 0.200 mg (group 4) of TRA-8 on days 0 and 3. Diffusion-weighted imaging, anatomic MR imaging, and bioluminescence imaging were performed on days 0, 3, and 6 before dosing. Averaged apparent diffusion coefficients (ADCs) for both whole tumor volume and a 1-mm peripheral tumor shell were calculated and were compared with tumor volume and living tumor cell changes. After imaging at day 6, proliferating and apoptotic cell densities were measured with Ki67 and terminal deoxynucleotidyl transferase mediated dUTP nick end labeling, or TUNEL, staining, respectively, and were compared with cleaved caspase-3 density.The ADC increase at day 3 was dependent on TRA-8 dose level, averaging 6% +/- 3 (standard error of mean), 19% +/- 4, 14% +/- 4, and 34% +/- 7 in the whole tumor volume and 1% +/- 2, 9% +/- 5, 13% +/- 5, and 30% +/- 8 in the outer 1-mm tumor shell only for groups 1, 2, 3, and 4, respectively. The ADC increase in group 4 was significantly higher (P = .0008 and P = .0189 for whole tumor volume and peripheral region, respectively) than that in group 1 on day 3, whereas tumor size did not significantly differ. At day 3, the dose-dependent ADC increases were linearly proportional to apoptotic cell and cleaved caspase-3 densities and were inversely proportional to the density of cells showing Ki67 expression.Diffusion-weighted imaging enabled measurement of early breast tumor response to TRA-8 treatment, prior to detectable tumor shrinkage, providing an effective mechanism to noninvasively monitor TRA-8 efficacy.http://radiology.rsnajnls.org/cgi/content/full/248/3/844/DC1.

SUBMITTER: Kim H

PROVIDER: S-EPMC2657851 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

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Breast tumor xenografts: diffusion-weighted MR imaging to assess early therapy with novel apoptosis-inducing anti-DR5 antibody.

Kim Hyunki H Morgan Desiree E DE Zeng Huadong H Grizzle William E WE Warram Jason M JM Stockard Cecil R CR Wang Deli D Zinn Kurt R KR

Radiology 20080901 3

<h4>Purpose</h4>To measure the early therapeutic response to a novel apoptosis-inducing antibody, TRA-8, by using diffusion-weighted magnetic resonance (MR) imaging in a mouse breast cancer model.<h4>Materials and methods</h4>Animal experiments had institutional animal care and use committee approval. Four groups of nude mice bearing luciferase-positive breast tumors (four to five mice with eight to 10 tumors per group) were injected intravenously with 0 mg (group 1), 0.025 mg (group 2), 0.100 m ...[more]

PMID: 18710978

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Project description:ObjectivesTo evaluate the use of diffusion-weighted MRI (DW-MRI) and volume measurements for early monitoring of antiangiogenic therapy in an experimental tumor model.Materials and methods23 athymic nude rats, bearing human colon carcinoma xenografts (HT-29) were examined before and after 6 days of treatment with regorafenib (n = 12) or placebo (n = 11) in a clinical 3-Tesla MRI. For DW-MRI, a single-shot EPI sequence with 9 b-values (10-800 s/mm2) was used. The apparent diffusion coefficient (ADC) was calculated voxelwise and its median value over a region of interest, covering the entire tumor, was defined as the tumor ADC. Tumor volume was determined using T2-weighted images. ADC and volume changes between first and second measurement were evaluated as classifiers by a receiver-operator-characteristic (ROC) analysis individually and combined using Fisher's linear discriminant analysis (FLDA).ResultsAll ADCs and volumes are stated as median±standard deviation. Tumor ADC increased significantly in the therapy group (0.76±0.09×10(-3) mm2/s to 0.90±0.12×10(-3) mm2/s; p<0.001), with significantly higher changes of tumor ADC than in the control group (0.10±0.11×10(-3) mm2/s vs. 0.03±0.09×10(-3) mm2/s; p = 0.027). Tumor volume increased significantly in both groups (therapy: 347.8±449.1 to 405.3±823.6 mm3; p = 0.034; control: 219.7±79.5 to 443.7±141.5 mm3; p<0.001), however, the therapy group showed significantly reduced tumor growth (33.30±47.30% vs. 96.43±31.66%; p<0.001). Area under the curve and accuracy of the ADC-based ROC analysis were 0.773 and 78.3%; and for the volume change 0.886 and 82.6%. The FLDA approach yielded an AUC of 0.985 and an accuracy of 95.7%.ConclusionsRegorafenib therapy significantly increased tumor ADC after 6 days of treatment and also significantly reduced tumor growth. However, ROC analyses using each parameter individually revealed a lack of accuracy in discriminating between therapy and control group. The combination of both parameters using FLDA substantially improved diagnostic accuracy, thus highlighting the potential of multi-parameter MRI as an imaging biomarker for non-invasive early tumor therapy monitoring.

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Breast tumor xenografts: diffusion-weighted MR imaging to assess early therapy with novel apoptosis-inducing anti-DR5 antibody.

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Breast tumor xenografts: diffusion-weighted MR imaging to assess early therapy with novel apoptosis-inducing anti-DR5 antibody.

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