Faculty Bibliography

PURPOSE/OBJECTIVE:Vascular endothelial growth factor (VEGF)-A is an important mediator of angiogenesis in almost all solid tumors. The aim of this study was to evaluate the effect of VEGF-A expression on tumor growth, perfusion, and chemotherapeutic efficacy in orthotopic 9L gliosarcomas. EXPERIMENTAL DESIGN/METHODS:Stable 9L cell lines underexpressing and overexpressing VEGF-A were generated. Anatomic, susceptibility contrast, and continuous arterial spin-labeling magnetic resonance imaging were used to quantify the volume, blood volume, and blood flow of tumors orthotopically grown from these and wild-type 9L cells. Histologic, immunohistochemical, and quantitative reverse transcription-PCR analyses were also done on excised tumors. Finally, the effects of carmustine chemotherapy were also evaluated. RESULTS:Orthotopic tumors underexpressing VEGF-A had slower growth rates (increased median survival), greater blood flow, vessel density, and VEGF-D expression, but no statistical difference in blood volume and chemotherapeutic sensitivity, compared with tumors with wild-type levels of VEGF-A. Tumors overexpressing VEGF-A had faster growth rates, greater blood volume, vessel density, and blood flow but no statistical difference in VEGF-D expression and chemotherapeutic sensitivity compared with wild-type VEGF-A-expressing tumors. CONCLUSION/CONCLUSIONS:Blood volume and blood flow are independent and different biomarkers of tumor perfusion. Therefore, both should be measured when characterizing the efficacy of antiangiogenic therapies. Underexpression of VEGF-A does not result in complete inhibition of angiogenesis. Moreover, these tumors have a different perfusion phenotype, suggesting that angiogenesis is mediated by an alternative pathway. The results indicate that VEGF-D is a plausible alternative mediator of this angiogenesis.

This study investigates the comparative changes in the sodium MRI signal and proton diffusion following treatment using a 9L rat glioma model to develop markers of earliest response to cancer therapy. Sodium MRI and proton diffusion mapping were performed on untreated (n = 5) and chemotherapy 1,3-bis(2-chloroethyl)-1-nitrosourea-treated rats (n = 5). Animals were scanned serially at 2- to 3-day intervals for up to 30 days following therapy. The time course of Na concentration in a tumor showed a dramatic increase in the treated brain tumor compared to the untreated tumor, which correlates in time with an increase in tumor water diffusion. The largest posttreatment increase in sodium signal occurred 7-9 days following treatment and correlated to the period of the greatest chemotherapy-induced cellular necrosis based on diffusion and histopathology. Both Na MRI and proton ADC mapping revealed early changes in tumor sodium content and cellularity. This study demonstrates the possibility of Na MRI to function as a biomarker for monitoring early tumor treatment and validates the use of monitoring changes in diffusion MRI values for assessing tumor cellularity.

To investigate diffusion weighted magnetic resonance imaging as a quantitative surrogate marker for evaluating the therapy-induced cellular changes in an orthotopic experimental glioma model, tumors were treated with direct intratumoral administration of DTI-015, a solution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in 100% EtOH. Intracerebral 9L tumors were induced in Fischer 344 rats, and three treatment groups were established: DTI-015, EtOH, and sham. Two groups of rats received intratumoral injection of either 67 mg/mL BCNU in EtOH or EtOH alone at 50% of the tumor volume up to a maximum of 30 mul under stereotactic guidance. Diffusion magnetic resonance images were acquired before treatment and after treatment at 1, 24, 48, and 72 hours and then 3 times per week thereafter. Tumor cell viability was examined using multislice diffusion weighted magnetic resonance imaging with diffusion weighted transverse magnetic resonance images and histogram plots of each tumor quantified over time. Control animals (EtOH- or sham-treated animals) showed mean apparent diffusion coefficients (ADCs) that remained essentially unchanged over the experimental time course. In contrast, rats treated with DTI-015 showed a significant increase in ADC relative to the pretreatment within 24 hours, which further increased over time, followed by a significant therapeutic response as evidenced by subsequent tumor volume shrinkage, development of a cystic region, and enhanced animal survival. Finally, not only were ADC measurements predictive of differences between treatment groups, but they also yielded spatial and temporal data regarding the efficacy of treatment within individual treated animals that could be used to guide subsequent therapy.