zd-6126 and Rhabdomyosarcoma

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).. 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.. 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 ZD6126 and 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 ADC(all) 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.. The separate calculation of ADC is more useful than conventional averaged ADC in evaluating the efficacy of combination therapy with ZD6126 and thalidomide for solid tumors.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Diffusion Magnetic Resonance Imaging; Liver; Liver Neoplasms, Experimental; Necrosis; Organophosphorus Compounds; Predictive Value of Tests; Rats; Rhabdomyosarcoma; Thalidomide; Time Factors; Tumor Burden

We sought to compare the therapeutic efficacy between two vascular-disrupting agents, combretastatin A4 phosphate (CA4P) and ZD6126, at a clinically relevant dose on tumor models with magnetic resonance imaging (MRI). Thirty rats with liver rhabdomyosarcoma were randomized into CA4P (10 mg/kg), ZD6126 (10 mg/kg), and control group (n=10 for each group). Multiparametric MRI biomarkers including tumor volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC), and K (volume transfer constant) derived from T2-weighted, T1-weighted, contrast-enhanced T1-weighted, and diffusion-weighted imaging, and dynamic contrast-enhanced MRI were compared at pretreatment, 1 h, 6 h, 24 h, 48 h, and 120 h posttreatment; they were validated using ex-vivo techniques. Relative to rapidly growing tumors without necrosis in control rats, tumors grew slower in the CA4P group compared with the ZD6126 group with a higher necrosis ratio at 120 h (P<0.05), as proven by histopathology. In the CA4P group, K decreased from 1 h until 6 h, and partially recovered at 120 h. In the ZD6126 group, the reduced K at 1 h began to rebound from 6 h and exceeded the baseline value at 120 h (P<0.05), parallel to evolving enhancement ratios (P<0.05). ADC revealed more necrotic tumors with CA4P versus ZD6126 at 120 h (P<0.05). The different tumor responses were confirmed by ex-vivo microangiography and histopathology. CA4P was more effective than ZD6126 in impairing blood supply, inducing necrosis, and delaying growth in rat liver tumors at a clinically relevant dose. A single dose of vascular-disrupting agent was insufficient to destroy the tumor. The multiparametric MRI biomarkers enabled in-vivo noninvasive comparison of therapeutic efficacy between CA4P and ZD6126.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biomarkers, Tumor; Contrast Media; Drug Screening Assays, Antitumor; Injections, Intravenous; Liver Neoplasms, Experimental; Magnetic Resonance Imaging; Male; Microvessels; Necrosis; Organophosphorus Compounds; Rats; Rats, Inbred Strains; Rhabdomyosarcoma; Stilbenes; Tumor Burden