zd-6126 and Pituitary-Neoplasms

To assess tumor fractional blood volume (xi), determined in vivo by susceptibility contrast magnetic resonance imaging (MRI) as a noninvasive imaging biomarker of tumor response to the vascular disrupting agent ZD6126.. The transverse MRI relaxation rate R(2)( *) of rat GH3 prolactinomas was quantified prior to and following injection of 2.5 mgFe/kg feruglose, an ultrasmall superparamagnetic iron oxide intravascular contrast agent, and xi (%) was determined from the change in R(2)( *). The rats were then treated with either saline or 50 mg/kg ZD6126, and xi measured again 24 hours later. Following posttreatment MRI, Hoechst 33342 (15 mg/kg) was administered to the rats and histological correlates from composite images of tumor perfusion and necrosis sought.. Irrespective of treatment, tumor volume significantly increased over 24 hours. Saline-treated tumors showed no statistically significant change in xi, whereas a significant (p = 0.002) 70% reduction in xi of the ZD6126-treated cohort was determined. Hoechst 33342 uptake was associated with viable tumor tissue and was significantly (p = 0.004) reduced and restricted to the rim of the ZD6126-treated tumors. A significant positive correlation between posttreatment xi and Hoechst 33342 uptake was obtained (r = 0.83, p = 0.002), providing validation of the MRI-derived measurements of fractional tumor blood volume.. These data clearly highlight the potential of susceptibility contrast MRI with ultrasmall superparamagnetic iron oxide contrast agents to provide quantitative imaging biomarkers of fractional tumor blood volume at high spatial resolution to assess tumor vascular status and response to vascular disrupting agents.

Topics: Animals; Benzimidazoles; Blood Volume; Contrast Media; Dextrans; Female; Ferrosoferric Oxide; Fluorescent Dyes; Iron; Magnetic Resonance Imaging; Magnetite Nanoparticles; Organophosphorus Compounds; Oxides; Pituitary Neoplasms; Prolactinoma; Rats

ZD6126 is a vascular targeting agent that disrupts the tubulin cytoskeleton of proliferating neo-endothelial cells. This leads to the selective destruction and congestion of tumour blood vessels in experimental tumours, resulting in extensive haemorrhagic necrosis. In this study, the dose-dependent activity of ZD6126 in rat GH3 prolactinomas and murine RIF-1 fibrosarcomas was assessed using two magnetic resonance imaging (MRI) methods. Dynamic contrast-enhanced (DCE) MRI, quantified by an initial area under the time-concentration product curve (IAUC) method, gives values related to tumour perfusion and vascular permeability. Multigradient recalled echo MRI measures the transverse relaxation rate T(2)*, which is sensitive to tissue (deoxyhaemoglobin). Tumour IAUC and R(2)* (=1/T(2)*) decreased post-treatment with ZD6126 in a dose-dependent manner. In the rat model, lower doses of ZD6126 reduced the IAUC close to zero within restricted areas of the tumour, typically in the centre, while the highest dose reduced the IAUC to zero over the majority of the tumour. A decrease in both MRI end points was associated with the induction of massive central tumour necrosis measured histologically, which increased in a dose-dependent manner. Magnetic resonance imaging may be of value in evaluation of the acute clinical effects of ZD6126 in solid tumours. In particular, measurement of IAUC by DCE MRI should provide an unambiguous measure of biological activity of antivascular therapies for clinical trial.

Topics: Animals; Area Under Curve; Biomarkers, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrosarcoma; Magnetic Resonance Imaging; Mice; Necrosis; Organophosphorus Compounds; Pituitary Neoplasms; Prolactinoma; Rats; Regional Blood Flow