Monitoring antivascular therapy in head and neck cancer xenografts using contrast-enhanced MR and US imaging

Abstract

Background The overall goal of this study was to non-invasively monitor changes in blood flow of squamous cell carcinoma of the head and neck (SCCHN) xenografts using contrast-enhanced magnetic resonance (MR) and ultrasound (US) imaging. Methods Experimental studies were performed on mice bearing FaDu tumors and SCCHN xenografts derived from human surgical tissue. MR examinations were performed using gadofosveset trisodium at 4.7T. Change in T1-relaxation rate of tumors (ΔR1) and tumor enhancement parameters (amplitude, area under the curve - AUC) were measured at baseline and 24 hours after treatment with a tumor-vascular disrupting agent (tumor-VDA), 5,6-dimethylxanthenone-4-acetic acid (DMXAA; ASA404) and correlated with tumor necrosis and treatment outcome. CE-US was performed using microbubbles (Vevo MicroMarker®) to assess the change in relative tumor blood volume following VDA treatment. Results A marked decrease (up to 68% of baseline) in T1-enhancement of FaDu tumors was observed one day after VDA therapy indicative of a reduction in blood flow. Early (24h) vascular response of individual tumors to VDA therapy detected by MRI correlated with tumor necrosis and volume estimates at 10 days post treatment. VDA treatment also resulted in a significant reduction in AUC and amplitude of patient tumor-derived SCCHN xenografts. Consistent with MRI observations, CE-US revealed a significant reduction in tumor blood volume of patient tumor-derived SCCHN xenografts after VDA therapy. Treatment with VDA resulted in a significant tumor growth inhibition of patient tumor derived SCCHN xenografts. Conclusions These findings demonstrate that both CE-MRI and CE-US allow monitoring of early changes in vascular function following VDA therapy. The results also demonstrate, for the first time, potent vascular disruptive and antitumor activity of DMXAA against patient tumor-derived head and neck carcinoma xenografts.

Early quantification of the therapeutic efficacy of the vascular disrupting agent, CKD-516, using dynamic contrast-enhanced ultrasonography in rabbit VX2 liver tumors

“…Although there was no statistical significance (P>0.05), the TTP had increased at the 24-hour follow-up by 46.5%. Our results are in good agreement with previous DCE-US studies evaluating the therapeutic effects of other VDAs, specifically, that AVE8062 induced a marked decrease in the PI and an increase in the TTP as seen at a six-hour followup [18], and 5, 6-dimethylxanthenone-4-acetic acid resulted in a significant decrease in the AUC as seen at a 24-hour follow-up [19]. As VDAs reduce tumor vascularity and the DCE-US contrast agent (SonoVue) is an intravascular tracer, the signal strength generated by microbubbles following VDA treatment should decrease during the entire scanning time, and, therefore, the PI and AUC of the timeintensity curve should decrease [20].…”

Contrast-enhanced ultrasound (CEUS) detects effects of vascular disrupting therapy in an experimental model of gastric cancer

“…So far no vascular-disrupting agents (VDAs) are in clinical use although the VDA ASA404 has been examined in various preclinical models [2,11,27,32]. Clinical phase-II studies with this substance were performed in prostate and lung cancer and two phase-III studies were carried out in lung cancer [4,17,24].…”

“…ASA404 (also known as vadimezan, 5,6-dimethylxanthenone-4acetic acid, DMXAA) is an analog of flavones-8-acetic acid [10]. This compound has shown profound activity as VDA in various preclinical models such as head and neck cancer and melanoma [11,27]. Moreover, comparison of tumor specimens and healthy tissue from these studies revealed hemorrhagic necrosis in experimental tumors due to an irreversible shut down of tumor blood flow whereas normal tissue was not affected [10].…”

Vascular priming enhances chemotherapeutic efficacy against head and neck cancer

“…Studies were carried out using the FaDu head and neck carcinoma cell line (ATCC; Manassas, VA) and HNSCC xenografts derived from surgical tumor tissue. We have previously described the procedures for establishing ectopic (subcutaneous) and orthotopic FaDu tumors and patient tumor-derived HNSCC xenografts (9, 17). Tissue specimens were obtained from patients following written consent and under a research protocol approved by the Institutional Review Board and the research ethics committee.…”

“…Our previous preclinical studies have demonstrated that (i) as single agents, VDAs exhibit moderate antitumor activity against HNSCC evidenced by tumor growth inhibition and delayed tumor regrowth, (ii) functional alterations in tumor vasculature following VDA therapy can be successfully detected using clinically-relevant non-invasive imaging techniques (e.g. magnetic resonance imaging, ultrasound), and, (iii) early vascular response to VDA therapy correlates with treatment outcome (8, 9). Since VDAs compromise blood flow to tumors, it is generally believed that chemotherapy should be administered prior to VDA treatment.…”