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1.  Vascular development in mouse lung metastases 
Dissemination of cancer cells is strongly associated with reduction in quality of life, worsening of prognosis, and remains the primary cause of therapeutic failure and high mortality in cancer. A crucial factor in the progression of metastases is the ability to establish a functioning blood vessel network. Consequently therapeutic strategies which selectively target tumor vasculature may hold promise for the treatment of metastatic disease. A complicating factor in the assessment of the efficacy of vascular targeting therapies is that the metastatic process can result in multiple neoplastic lesions at various stages of growth and vascularity in a single organ. The goal of this project was to utilize a rodent squamous cell carcinoma (SCCVII) model to characterize the development of metastatic lung lesions and their associated vasculature. Mice were injected with tumor cells via the tail vein to introduce a reproducible number of lung metastases. At various times after cell injection, lungs were removed and serial sections were taken throughout the lobes for morphometric analysis. Tumor volumes were calculated for each nodule using 2 hematoxylin and eosin (H&E) stained sections that were a known distance apart. Sections adjacent to those used for size determination were reserved for immunohistochemical staining with CD31 to identify blood vessels associated with each nodule. The results showed that although the median tumor volume increased from 0.006 to 0.51 mm3 between 7 and 18 days post SCCVII cell injection, a range of tumor sizes existed at all-times. Irrespective of the time of assessment, nodules with volumes ≤ 0.5 mm3 had a constant vessel density while those with volumes >0.5 mm3 showed increasing vessel densities with increasing size. These findings indicate that the methodology outlined in this study can identify metastases in various stages of vascular development and could therefore be applied to evaluate and distinguish therapeutic interventions that seek to prevent the initiation of blood vessel networks and those targeting already established expanding tumor vasculature. Examining the efficacy of such approaches, alone or in combination, in the treatment of metastases in a preclinical model could lead to the development of more effective therapeutic strategies for metastatic disease.
PMCID: PMC3433106  PMID: 22957309
Metastasis; vascular development; carcinoma
2.  Monitoring the Treatment Efficacy of the Vascular Disrupting Agent CA4P 
The purpose of this study was to investigate two non-invasive methods for determining the treatment efficacy of the vascular disrupting agent (VDA) CA4P: gadolinium enhanced dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for perfusion analysis and ELISA of blood samples. Candidate proteins were identified by Multi-Analyte Profile analysis of plasma from KHT sarcoma-bearing C3H/HeJ mice after CA4P administration. Candidate proteins were further analyzed by ELISA of plasma from treated C3H/HeJ, BALBc, and C57BL6 mice. Changes in selected proteins, tumour perfusion and tumour necrotic fraction after CA4P treatment were then compared in individual animals. The cytokines KC and MCP-1 were observed to increase after CA4P treatment in all tested models. No correlation was found between KC or MCP-1 levels and tumour necrosis. However, tumour perfusion correlated (r=0.89, p<0.00001) with CA4P treatment efficacy as measured by necrotic fraction, suggesting DCE-MRI may have utility in a clinical setting.
PMCID: PMC2962830  PMID: 17451938
vascular targeting; CA4P KHT sarcoma; DCE-MRI; cytokines

Results 1-2 (2)