Experimental Study On Evaluation Of Anti-angiogenesis Efficacy With MRI Biomarkers In Colon Cancer Subcutaneous Xenograft Tumor In Nude Mice

Objective: To discuss dynamic contrast-enhanced （DCE-MRI） combined withdiffusion-weighted MR imaging （DWI） for noninvasive evaluation of tumor angiogenesisand tumor vessel closure after anti-angiogenesis drugs treatment, and to exploreDCE-MRI and DWI assessment value of early effect of anticancer treatment. Methods:DCE-MRI, DWI scans and conventional MRI were performed for four consecutive daysin10subcutaneous colon cancer xenograft model. The following parameters weredynamic observation, including maximum slope of increase （MSI）, microvascularpermeability transfer constant (K^trans), volume fraction of the plasma space （Vp）,extravascular extracellular volume fraction （Ve）, microvascular permeability refluxconstant (K_ep) and various types of apparent diffusion coefficient (ADC_3b, ADC_10b,ADC_low, ADC_high, ADC_perf).Immunohistochemical examination were observed at third andfourth days, including microvessel density （MVD）, vascular endothelial growth factor（VEGF） and proliferating cell nuclear antigen （PCNA）. Correlation analysis wasperformed between MRI parameters and immunohistochemistry. Subsequently,50subcutaneous colon cancer xenograft model were randomly divided into three groups （10in the control group,20in the anti-angiogenesis drug treatment group,20in the anti-tumorcytotoxic drug treatment group）. DWI and DCE-MRI were acquired at baseline,1h,24hand48h post-treatment. The MRI imaging biomarkers were quantified and correlatedwith immunohistochemical examination in24h and48h post-treatment. Results: In theabsence of any drug intervention case, tumor K^trans, K_ep, MSI and ADC_perfgraduallyincreased, ADC_3band ADC_10bgradually reduce With the extension of the observation time.There was positively correlation between K^transand K_ep, MSI, ADC_perf. However, therewas respectively negative correlation between K^trans, K_epand ADC_3b, ADC_10b. ADC_perfwere positively correlated well with the MVD and VEGF. ADC_10bwere negatively correlated significantly with MVD, VEGF and PCNA. There are positive correlationbetween K^trans, MSI and MVD, VEGF and PCNA. There are linear correlation betweenK_epand MVD and VEGF. Under the drug intervention, the value of ADCs and K^trans, Vp,K_ep, MSI were significant difference between the three groups. Two drug groups1h aftertreatment, all parameters decreased significantly;24h after treatment, ADC_low, ADC_perfand parameters from DCE-MRI continued to decline in the anti-angiogenesis drug group,however, various parameters mild recovery in the anti-tumor cytotoxic drugs group.ADC_3b, ADC_10band immunohistochemistry were negatively correlated. ADC_perf, K^trans, K_ep,MSI and immunohistochemistry were positively correlated. No correlation between Ve,Vp and immunohistochemistry. Analysis of the factor analysis, K^trans, Vp, K_ep, MSI,ADC_perfand ADC_lowclassified as tumor microcirculation factor, ADC_3b, ADC_10bandADC_highnormalized for cell metabolism factor, and Ve is integrated factor. Conclusion:Obtaining MRI quantitative and semi-quantitative parameters from DCE-MRI and DWIused as imaging biomarkers can be noninvasive evaluation of tumor angiogenesis andassessment of tumor vascular closure after anti-angiogenesis drugs treatment. K^trans, K_ep,MSI, ADC_perfand ADC_loware mainly used for the evaluation of tumor microcirculation,ADC_3b, ADC_10band ADC_highvalue mainly reflects the density of tumor cells and tissueedema, and the application value of the Vp and Ve have not confirmed. Combination ofthe two technologies make the more comprehensively reflect the early changes after drugtherapy from tumor microcirculation and cell metabolism, and conducive to the evaluationof the early effects of the drugs. MRI is expected to become one of the main endpoint ofthe evaluation of drug efficacy in the development process of tumor vascular medicine,and to facilitate drug development and clinical application.