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Introduction: Hypoxic tumor cells are radioresistant, therefore, identification of hypoxia is crucial. Hyperpolarized magnetic resonance spectroscopy (HPMRS) allows real time measurements of the conversion of pyruvate to lactate, the final step of anaerobic energy production, and may thus allow non-invasive identification of hypoxia or treatment-induced changes in oxygenation. The aim of the study was to investigate the usefulness of HPMRS as a means to assess tumor hypoxia and its dynamics during intervention., Material and Methods: C3H mammary carcinomas grown in CDF1 mice were used. To manipulate with tumor oxygenation, non-anaesthetized mice were gassed with air, 10% or 100% oxygen prior to administration of hyperpolarized [1-¹³C]pyruvate and HPMRS analysis. A direct assessment of tumor oxygen partial pressure (pO2) distributions were made using the Eppendorf oxygen electrode in a separate, but similarly treated, group of mice., Results: Even though breathing 100% oxygen improved tumor oxygenation as evidenced by pO2 measurements, the mean (with 1 S.E.) [1-¹³C]lactate/[1-¹³C]pyruvate ratio was unaffected by this intervention, being 34 (30-37) in mice breathing air and 37 (33-42) in mice breathing 100% oxygen. In contrast, and in accordance with pO2 measurements, a significant increase in the [1-¹³C]lactate/[1-¹³C]pyruvate ratio was seen in 10% oxygen-breathing mice with a ratio of 46 (42-50)., Conclusions: Although, no metabolic change was observed during 100% O2 breathing using HPMRS, the significant increase in the [1-¹³C]lactate/[1-¹³C]pyruvate ratio during 10% oxygen breathing suggests, that HPMRS can detect hypoxia-driven changes in the metabolic fate of pyruvate. To what extent and for what purposes HPMRS may best supplement or complement established techniques like hypoxia PET needs to be unraveled in future research.

Purpose: This study investigated the anti-tumour effects of the novel vascular disrupting agent plinabulin (NPI-2358) when given alone or combined with radiation., Materials and Methods: Foot implanted C3H mammary carcinomas or leg implanted KHT sarcomas were used, with plinabulin injected intraperitoneally. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements were made with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) on a 7-tesla magnet. Treatment response was assessed using regrowth delay (C3H tumours), clonogenic survival (KHT sarcomas) or histological estimates of necrosis for both models., Results: Plinabulin (7.5 mg/kg) significantly reduced the initial area under curve (IAUC) and the transfer constant (K(trans)) within 1 hour after injection, reaching a nadir at 3 h, but returning to normal within 24 h. A dose-dependent decrease in IAUC and K(trans), was seen at 3 h. No significant anti-tumour effects were observed in the C3H tumours until doses of 12.5 mg/kg were achieved, but started at 1.5 mg/kg in the KHT sarcoma. Irradiating tumours 1 h after injecting plinabulin enhanced response in both models., Conclusions: Plinabulin induced a time- and dose-dependent decrease in tumour perfusion. The KHT sarcoma was more sensitive than the C3H tumour to the anti-tumour effects of plinabulin, while radiation response was enhanced in both models.

Introduction: The efficacy of the vascular disrupting agent combretastatin A-4 phosphate (CA4P) depends on several factors including tumor size, nitric oxide level, interstitial fluid pressure, and vascular permeability. These factors vary among tumor types. The aim of this study was to investigate all these factors in two tumor models that respond differently to CA4P., Material and Methods: Mice bearing C3H mammary carcinomas or KHT sarcomas (200 to 800 mm(3)) were intraperitoneally injected with CA4P (100 mg/kg). Tumor size and the effect of a nitric oxide inhibitor nitro-L-arginine (NLA) administered intravenously were evaluated by necrotic fraction histologically assessed at 24 hours. Interstitial fluid pressure (IFP) was measured using the wick-in-needle technique, and vascular characteristics were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)., Results: Initial necrotic fraction was about 10% in both tumor models at 200 mm(3), but only increased significantly with tumor size in the C3H mammary carcinoma. In this tumor, CA4P significantly induced further necrosis by about 15% at all sizes, but in the KHT tumor, the induced necrotic fraction depended on tumor size. For both tumor types, NLA with CA4P significantly increased necrotic fraction above that for each drug alone. CA4P significantly decreased IFP in all tumors except in the 800 mm(3) C3H tumor, which had an initially non-significant lower value. Interstitial volume estimated by DCE-MRI increased in all groups, except the 800 mm(3) C3H tumors. DCE-MRI vascular parameters showed different initial characteristics and general significant reductions following CA4P treatment., Conclusions: Both tumor models showed differences in all factors before treatment, and in their response to CA4P. Perfusion and permeability as estimated by DCE-MRI play a central role in the CA4P response, and interstitial volume and IFP seemed related. These factors may be of clinical value in the planning of CA4P treatments.

Purpose: To determine how combretastatin A-4 disodium phosphate (CA4DP) dose-dependent changes in radiation response of a C3H mouse mammary carcinoma relate to measurements of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and how those mouse DCE-MRI results compare with published clinical DCE-MRI data., Methods and Materials: C3H mammary carcinomas grown in female CDF(1) mice were treated when at 200 mm(3) in size. Groups of mice were given graded radiation doses, either alone or followed 30 min later by an intraperitoneal injection of CA4DP, administered at doses of 10-250 mg/kg. The radiation dose producing local tumor control in 50% of treated animals at 90 days (TCD(50)) was calculated for each CA4DP dose. DCE-MRI was performed before and 3 h after CA4DP administration, and parameters describing vascularity and interstitial volume were estimated., Results: TCD(50) showed a dose-dependent decrease reaching significance at 25 mg/kg. At greater doses of 50 and 100 mg/kg, the TCD(50) increased slightly and was not significantly different from that of controls. TCD(50) significantly decreased again at 250 mg/kg. The drug dose-response curves for all post-treatment vascular DCE-MRI parameters showed a shape similar to that of the TCD(50) curve. A similar dose dependency was seen with previously published clinical data., Conclusion: Our preclinical DCE-MRI data could predict the CA4DP enhancement of the tumor radiation response and suggest the clinical CA4DP doses necessary to improve the radiation response in patients.

Introduction: Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) allows in vivo characterization of tumour vasculature. As such, it is applicable for monitoring the effects of treatments targeting vasculature. The aims of this study were to evaluate the properties of tumour areas segmented-out by DCE-MRI parameters and to evaluate the changes induced by the vascular disrupting agent (VDA) combretastatin A-4 disodium phosphate (CA4DP), a leading VDA in clinical trials, in these areas., Material and Methods: Two tumour models previously shown to respond differently to CA4DP were chosen. The C3H mammary carcinoma and the KHT sarcoma were grown in the right rear foot of CDF(1) and C3H/km mice, respectively, and treated when at 200 or 800 mm(3) in size. DCE-MRI, using the contrast agent Gd-DTPA, was performed on a 7 T spectroscopy/imaging system before and 3 hours after i.p. CA4DP administration at a dose of 100 mg/kg. From the voxel concentration-time curves, the semiquantitative parameter of initial area under the curve (IAUC), the model parameters transfer constant K(trans), interstitial volume v(e), and blood plasma volume v(p), were calculated. Tumour images were segmented into three groups based on the DCE-MRI model parameters using the K-means algorithm, and the groups were ranked by IAUC., Results: The resulting voxels of the tumour segments were mainly spatially connected structures. Initial DCE-MRI parameter values showed different dependencies on tumour model and size in the regions. For all regions in all tumour groups, the treatment reduced IAUC by 36-51%, whereas the model parameters showed more dependencies on tumour model and size., Discussion: This segmentation technique identifies tumour regions with different microenvironmental characteristics responding differently to CA4DP and may be valuable in the optimization of combined VDA with radiotherapy or chemotherapy. The method may also prove useful for optimization and monitoring of local treatment such as radiotherapy.

Purpose: To evaluate the effect of the vascular disrupting drugs combretastatin A-4 disodium phosphate (CA4DP) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on the intra/extracellular volume fraction of water and blood perfusion in tumours using MRI., Methods and Materials: Mice with C3H mammary carcinomas underwent repeated MRI T2-weighted imaging, water-diffusion and perfusion measurements before and up to 6-hours following CA4DP and DMXAA treatment., Results: CA4DP treatment caused an increase in water diffusion in those tumour areas that presented the lowest blood perfusion, however this appeared only after five hours. The blood perfusion in highly perfused tumour regions decreased immediately after administration of CA4DP. DMXAA treatment caused an early decrease in water diffusion in the low-perfused tumour segments and followed by a subsequent decrease in the remaining part of the tumour. The blood perfusion decreased early in all parts of the tumour., Conclusion: The effect of CA4DP and DMXAA on tumour blood flow was comparable. The reduction in regional blood flow caused by CA4DP in the whole tumour segment occurred early, however, changes in ADC after DMXAA appeared more extended and earlier than after CA4DP treatment, especially in tumour areas already suffering from a low blood perfusion.

Background: Texture analysis can be used to identify and discriminate between objects in an image and has already been used for the characterization of diseases. The present study evaluated the potential of texture analysis for monitoring tumor cell viability during treatment with an anti-vascular drug., Materials and Methods: Texture analysis of T2-weighted magnetic resonance images of C3H mammary carcinomas in mice was used to study tumor cell viability during treatment with the anti-vascular drug combretastatin A-4 disodium phosphate (CA4DP). Texture analysis was done by MaZda, and boot strap statistics were used to analyze the results., Results: The results revealed significant differences in the textures of T2-weighted images when non-tumor tissue and tumor tissue were compared. Furthermore, selected texture parameters were significantly different when image data from before and after CA4DP administration were analyzed., Conclusion: Texture analysis is helpful in the diagnosis of different types of tissues, especially when these tissues can not be recognized by human observers. Some functional changes, such as perfusion changes in the tumor, can also be detected by texture analysis.