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Background: Magnetic resonance elastography (MRE) is an emerging imaging technique that affords non-invasive quantitative assessment and visualization of tissue mechanical properties in vivo. Methods: In this study, MRE was used to quantify (kPa) the absolute value of the complex shear modulus |G*|, elasticity Gd and viscosity Gl of SW620 human colorectal cancer xenografts before and 24 h after treatment with either 200 mg kg−1 of the vascular disrupting agent ZD6126 (N-acetylcolchinol-O-phosphate) or vehicle control, and the data were compared with changes in water diffusivity measured by diffusion-weighted magnetic resonance imaging. Results: A heterogeneous distribution of |G*|, Gd and Gl was observed pre-treatment with an intertumoral coefficient of variation of 13% for |G*|. There were no significant changes in the vehicle-treated cohort. In contrast, ZD6126 induced a significant decrease in the tumour-averaged |G*| (P

The tumor vasculature of solid tumors offers unique characteristics compared to the normal vasculature and, therefore, represents an attractive target in anti-cancer therapy. Besides the classic anti-angiogenic agents, which inhibit tumor neovascularization, a novel promising class of anti-tumor drugs has emerged in the last years, the vascular-disrupting agents (VDAs). In contrast to angiogenesis inhibitors, VDAs act on already established tumor blood vessels of large solid tumors and induce a vascular shutdown by targeting tumor endothelial cells. This results in extensive necrotic tumor cell death. The sources of VDAs are quite divers, however, the plant-derived compounds represent the largest and most prominent class. Plant-derived VDAs have undergone extensive preclinical investigations and are now tested in several advanced clinical trials. In this review we summarize preclinical data, including drug-target relationships as well as functional in vitro and in vivo assays, discuss their molecular way of action, and update the clinical status of the most prominent plant-derived VDAs: FAA/DMXAA, CA-4-P, OXi4503, AVE8062, and ZD6126. All these data emphasize the value of secondary plant metabolites and their (semi-)synthetic derivatives for current drug discovery.

To evaluate effects of a vascular-disrupting agent on rodent tumour models. Twenty rats with liver rhabdomyosarcomas received ZD6126 intravenously at 20 mg/kg, and 10 vehicle-treated rats were used as controls. Multiple sequences, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) with the microvascular permeability constant (K), were acquired at baseline, 1 h, 24 h and 48 h post-treatment by using 1.5-T MRI. [18F]fluorodeoxyglucose micro-positron emission tomography (18F-FDG µPET) was acquired pre- and post-treatment. The imaging biomarkers including tumour volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC) and K from MRI, and maximal standardised uptake value (SUVmax) from FDG µPET were quantified and correlated with postmortem microangiography and histopathology. In the ZD6126-treated group, tumours grew slower with higher necrosis ratio at 48 h (P

Background ZD6126 is a novel vascular-targeting agent that disrupts the endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature and extensive tumor necrosis. This Phase I clinical study was conducted to evaluate the dose and administration schedule of ZD6126. Methods Adult patients with solid tumors refractory to existing treatments received a 10-min, single-dose intravenous infusion of ZD6126 every 14 or 21 days. Subsequent dose escalation was performed, based on the incidence of adverse events (AEs) within the first cycle of drug administration. Blood samples were obtained for pharmacokinetic analysis, and the effects of ZD6126 on tumor vasculature were visualized using DCE-MRI technology. Results Forty-four patients received ZD6126 (5−112 mg/m2 in the 21-day schedule, n = 35; 40−80 mg/m2 in the 14-day schedule, n = 9). Common AEs were similar in both groups and included abdominal pain, nausea and vomiting, which appeared to be dose related. The incidence of abdominal pain at 112 mg/m2 in the 21-day study prevented further dose escalation. Pharmacokinetic studies confirmed that ZD6126 is rapidly hydrolyzed to ZD6126 phenol. There was no difference in the pharmacokinetics of ZD6126 phenol upon repeat administration or between the two dosing regimens. DCE-MRI evaluation has demonstrated the antivascular effects of ZD6126. Conclusions This study identified that ZD6126 administered every 2 or 3 weeks at 80 mg/m2 was well tolerated, with mild but manageable gastrointestinal AEs. In approximately 11% (5 out of 44) of patients, ZD6126 was associated with cardiac events categorized as dose limiting toxicities (one patient with asymptomatic decreased left ventricular ejection fraction (LVEF), two with increased troponin concentrations, one with myocardial ischemia, and one with ECG signs of myocardial ischemia).

The effect of vascular disrupting agent ZD6126 with time on the sensitivity to the hypoxic cytotoxin tirapazamine (TPZ) and gamma-rays was examined in large and small solid tumors.Mice bearing SCC VII tumors 1 or 1.5 cm in diameter received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells, followed by injection with or without ZD6126. In the absence of ZD6126, or 1 or 24 h following ZD6126 injection, the response to TPZ or gamma-ray irradiation in quiescent (Q) cells was assessed in terms of induced micronucleus (MN) frequency using immunofluorescence staining for BrdU. The MN frequency in the total cell population was determined from the tumors not pretreated with BrdU. Another group of tumor-bearing mice received a series of test doses of gamma-rays while alive or after tumor clamping to obtain hypoxic fractions (HFs) in the tumors.One hour after ZD6126 injection, both small and large tumors showed lower and higher sensitivity, and 24 h after, higher and lower sensitivity, to gamma-rays and TPZ, respectively, than the tumors not treated with ZD6126. Further, they showed larger and smaller HFs 1 and 24 h after ZD6126 injection, respectively. Without ZD6126 and 1 h after injection, small tumors were more sensitive to gamma-rays and less sensitive to TPZ than large tumors, probably due to the smaller HFs than large tumors. In contrast, 24 h after the injection, these differences in sensitivity and the HF between small and large tumors were reversed. The changes in sensitivity and the size of the HF were more marked in the total cell population than in Q cells.Following ZD6126 treatment, in terms of tumor control, especially large tumors and total tumor cell population, administering TPZ 1 h later and gamma-ray irradiation 24 h later were effective. Intratumor physiologic factors such as the size of the HF, depending on the time after ZD6126 injection, have to be taken into account when combining another treatment with ZD6126.

Low-molecular-weight vascular-disrupting agents (VDAs) cause a pronounced shutdown in blood flow to solid tumours, resulting in extensive tumour-cell necrosis, while they leave the blood flow in normal tissues relatively intact. The largest group of VDAs is the tubulin-binding combretastatins, several of which are now being tested in clinical trials. DMXAA (5,6-dimethylxanthenone-4-acetic acid) - one of a structurally distinct group of drugs - is also being tested in clinical trials. A full understanding of the action of these and other VDAs will provide insights into mechanisms that control tumour blood flow and will be the basis for the development of new therapeutic drugs for targeting the established tumour vasculature for therapy.

Metastases require a functional blood supply for progressive growth. Thus, therapies that target metastatic vasculature have potential clinical utility. The effects of the vascular-targeting agent (VTA), ZD6126, and the anti-angiogenic agent, ZD6474, on vascular development and function within metastases were compared in an experimental liver metastasis model. Ras-transformed PAP2 fibroblasts were injected into the mesenteric veins of SCID mice to produce a control liver metastasis burden of approximately 40% at 14 days. Mice given a single dose of ZD6126 (200 mg/kg, i.p.) on day 13 were examined 24 h later. Histology revealed a significant reduction in metastatic burden, associated with extensive tumor necrosis, increased tumor cell apoptosis and a reduction in tumor-associated vasculature. In vivo videomicroscopy (IVVM) revealed disrupted, non-functional vascular channels within metastases, with no blood flow. Mice given ZD6474 on days 4 to 10 (50 mg/kg daily, oral gavage) were examined on day 11. Histology revealed a lower metastatic burden, significant reductions in metastasis size and vasculature, and a significant increase in tumor cell apoptosis. IVVM revealed extensive reductions in vascularity and blood flow within metastases. Neither ZD6126 nor ZD6474 treatment affected surrounding normal liver tissue. This study shows that both agents can reduce experimental liver metastasis with no apparent effect on normal vasculature. However, these reductions were attained through distinct effects on the metastatic vasculature. Understanding differences in the modes of action of VTAs and anti-angiogenic agents will be important in optimizing their clinical application and in developing appropriate combination strategies.

The tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA) causes dramatic haemorrhagic necrosis in murine tumours, but activity is seen only at doses close to the toxic limit. This study investigates two approaches for increasing the therapeutic ratio of DMXAA. The first approach combines DMXAA with a second tumour blood flow inhibitor, 5-hydroxytryptamine (5-HT). Co-administration of 5-HT (700 micromol kg(-1)) to C3H mice caused marked enhancement of DMXAA effects against MDAH-MCa-4 tumours, with dose-modifying factors (DMFs) of >3 for blood flow inhibition (at 4 h), 2.3 for necrosis (at 12 h) and 2.0 for growth delay, without compromising the maximum tolerated dose of DMXAA (90 micromol kg(-1)). The data are consistent with ischaemic injury to the tumour being the major mechanism of anti-tumour activity. The second approach combines DMXAA (+/- 5-HT) with hypoxia-selective bioreductive drugs. Anti-tumour activity of all three bioreductive drugs tested (tirapazamine, CI-1010, SN 23816) was strongly potentiated by DMXAA, suggesting that there is a population of reversibly hypoxic tumour cells after DMXAA treatment. Co-administration of 5-HT further potentiated anti-tumour activity, but also increased host toxicity of tirapazamine and CI-1010 so that little therapeutic benefit was achieved. In contrast, the host toxicity of the dinitrobenzamide mustard SN 23816 was only slightly increased by DMXAA/5-HT, whereas the tumour growth delay at the maximum tolerated dose of SN 23816 was increased from 3.5 to 26.5 days. This study demonstrates that 5-HT and/or bioreductive drugs can improve the therapeutic activity of DMXAA in mice, and that with SN 23816 both approaches can be used together to provide considerably enhanced anti-tumour activity.

Several studies show that the antitumour activity of melphalan (MEL) and other alkylating agents can be enhanced by the selective inhibition of tumour blood flow, although the mechanism(s) underlying these interactions are unclear. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a new anticancer agent currently in phase I clinical trial, inhibits blood flow in murine tumours. DMXAA increased the activity of MEL against the MDAH-MCa-4 mouse mammary tumour maximally when MEL was given about 2 h after DMXAA, without compromising the maximal dose of the alkylating agent that could be given. The plasma pharmacokinetics of MEL were unchanged by DMXAA pretreatment, but the area under the concentration-time curve (AUC) for the tumour increased by 33% as a result of decreasing clearance (consistent with falling tumour blood flow). However, inhibition of tumour blood flow also leads to microenvironmental changes (e.g. acidosis and hypoxia) that might influence sensitivity to MEL. The sensitivity of KHT cells (freshly isolated from tumours) to MEL in vitro was increased by lowering of either pH or oxygen concentration (pO2), with an overall dose-modifying factor of 15 being recorded for aerobic cells at pH 7.4 versus hypoxic cells at pH 6.5. The cellular uptake of MEL by KHT cells was increased by 74% under hypoxia. Thus, This study was supported by the National Cancer Institute, USA (contract NO1-CM-47019), and the Health Research Council of New Zealand DMXAA appears to augment the antitumour activity of MEL through two different mechanisms, increased exposure (via decreased tumour clearance of MEL) and increased sensitivity resulting from changes to the tumour microenvironment, both of which result from inhibition of tumour blood flow.

The blood supply to all solid tumours consists of parasitized normal vessels and new vessels which have been induced to grow by the presence of the tumour. These vessels are inadequate in many respects, being tortuous, thin-walled, chaotically arranged, lacking innervation and with no predetermined direction of flow. The walls consist of a basement membrane lined with rapidly proliferating immature endothelial cells, and are more permeable than normal vessels. The spacing of the vessels and their average diameters are not optimal for nutrient provision. This paper focuses on the evidence that many existing therapies may already have, as part of their action, a vascular mediated process of killing tumour cells. This may result from local changes within individual vessels or from systemic alterations in blood pressure, viscosity, coagulability etc. The hallmarks of vascular injury are identified and the dangers of discarding useful anticancer agent by failing to understand their mechanism of action are highlighted.