Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis;a process known as tumor angiogenesis.Angiogenesis is largely involved in tumor survival,progression and spread,which are known to be significantly attributed to treatment failures.Over the past decades,efforts have been made to understand the difference between nor-mal and tumor vessels.It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes,which provides opportunities for developing novel anticancer strategies.Targeting tumor vasculature is not only a unique therapeutic interven-tion to starve neoplastic cells,but also enhances the efficacy of conventional cancer treatments.Vascular dis-rupting agents(VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors,cause catastrophic vascular shutdown within short time,and induce secondary tumor necrosis.VDAs are cytostatic;they can only inhibit tumor growth,but not eradicate the tumor.This novel drug mechanism has urged us to develop multiparametric imaging biomark-ers to monitor early hemodynamic alterations,cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected.In this article,we review the characteristics of tumor vessels,tubulin-destabilizing mechanisms of VDAs,and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials.We also compare the differ-ent tumor models adopted in the preclinical studies on VDAs.Multiparametric imaging biomarkers,mainly diffu-sion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging,are evalu-ated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.

Separate calculation of DW-MRI in assessing therapeutic effect in liver tumors in rats

AIM:To explore whether the antitumor effect of a vascular disrupting agent(VDA)would be enhanced by combining with an antiangiogenic agent,and whether such synergistic effects can be effectively evaluated with separate calculation of diffusion weighted magnetic resonance imaging(DW-MRI).METHODS:Thirty-seven rats with implanted liver tumors were randomized into the following three groups:(1)ZD6126,a kind of VDA;(2)ZDTHA,ZD6126 in combination with an antiangiogenic,thalidomide;and(3)control.Morphological DW-MRI were performed and quantified before,4 h and 2 d after treatment.The apparent diffusion coefficient(ADC)values were calculated separately for low b values(ADC low),high b values(ADC high)and all b values(ADC all).The tissue perfusion contribution,ADC perf,was calculated as ADC low-ADC high.Imaging findings were finally verified by histopathology.RESULTS:The combination therapy with ZDTHA significantly delayed tumor growth due to synergistic effects by inducing cumulative tumor necrosis.In addition to delaying tumor growth,ZDTHA caused tumor necrosis in an additive manner,which was verified by HE staining.Although both ADC high and ADC all in the ZD6126and ZDTHA groups were significantly higher compared to those in the control group on day 2,the entire tumor ADC high of ZDTHA was even higher than that of ZD6126,but the significant difference was not observed for ADCall between ZDTHA and ZD6126.This indicated that the perfusion insensitive ADC high values calculated from high b value images performed significantly better than ADC all for the monitoring of tumor necrosis on day 2.The perfusion sensitive ADC perf derived from ADC low by excluding high b value effects could better reflect the reduction of blood flow due to the vessel shutdown induced by ZD6126,compared to the ADC low at 4 h.The ADC perf could provide valuable perfusion information from DW-MRI data.CONCLUSION:The separate calculation of ADC is more useful than conventional averaged ADC in evaluating the efficacy of combination therapy with ZD6126and thalidomide for solid tumors.