zd-6126 and Colonic-Neoplasms

Magnetic resonance elastography (MRE) is an emerging imaging technique that affords non-invasive quantitative assessment and visualization of tissue mechanical properties in vivo.. 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.. 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<0.01), Gd (P<0.01) and Gl (P<0.05), and this was associated with histologically confirmed central necrosis. This reduction in tumour viscoelasticity occurred at a time when no significant change in tumour apparent diffusion coefficient (ADC) was observed.. These data demonstrate that MRE can provide early imaging biomarkers for treatment-induced tumour necrosis.

Topics: Angiogenesis Inhibitors; Animals; Biomechanical Phenomena; Colonic Neoplasms; Elasticity; Elasticity Imaging Techniques; Female; Humans; Mice; Mice, Nude; Necrosis; Organophosphorus Compounds; Shear Strength; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Tumours derived from DLD-1 colon adenocarcinoma cells, transfected to either overexpress inducible nitric oxide synthase (clone iNOS-19) or with empty vector (pBAN2R), were utilised to test the hypothesis that tumour expression of iNOS (a) increases tumour angiogenesis and (b) modulates the anti-tumour activity of the vascular disrupting agent ZD6126. Overexpression of iNOS by clone iNOS-19 cells and murine xenografts was confirmed by the Griess assay and western blot analysis respectively. Clone iNOS-19 tumours grew more rapidly than pBAN2R tumours. Tumour perfusion, assessed by Hoechst 33342 uptake, was significantly greater in the clone iNOS-19 tumours (P < 0.001). A significant reduction in the perfusion of only the pBAN2R tumours, compared with control, was obtained 24 h after treatment with an intermediate dose of 100 mg/kg ZD6126 (P < 0.001), whereas 200 mg/kg significantly reduced the perfusion of both tumour types (P < 0.001). Whilst pBAN2R tumour necrosis increased in a dose-dependent manner, significant at 100 and 200 mg/kg ZD6126 (P < 0.05), intermediate doses did not induce a similar degree of necrosis in clone iNOS-19 tumours. A significant reduction in splenic perfusion was found 24 h after treatment with 100 mg/kg ZD6126, primarily associated with the red pulp. Overexpression of iNOS increases tumour growth, the degree of functionally perfused vasculature and angiogenesis, and also confers resistance to the vascular disrupting agent ZD6126.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Culture Techniques; Cell Line, Tumor; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Resistance; Humans; Injections, Subcutaneous; Male; Mice; Mice, Inbred Strains; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Nitric Oxide Synthase Type II; Organophosphorus Compounds; Time Factors; Transplantation, Heterologous