flunarizine and carbogen

T2*-weighted gradient-echo magnetic resonance imaging (T2*-weighted GRE MRI) was used to investigate spontaneous fluctuations in tumour vasculature non-invasively. FSa fibrosarcomas, implanted intramuscularly (i.m.) in the legs of mice, were imaged at 4.7 T, over a 30 min or 1 h sampling period. On a voxel-by-voxel basis, time courses of signal intensity were analysed using a power spectrum density (PSD) analysis to isolate voxels for which signal changes did not originate from Gaussian white noise or linear drift. Under baseline conditions, the tumours exhibited spontaneous signal fluctuations showing spatial and temporal heterogeneity over the tumour. Statistically significant fluctuations occurred at frequencies ranging from 1 cycle/3 min to 1 cycle/h. The fluctuations were independent of the scanner instabilities. Two categories of signal fluctuations were reported: (i) true fluctuations (TFV), i.e., sequential signal increase and decrease, and (ii) profound drop in signal intensity with no apparent signal recovery (SDV). No temporal correlation between tumour and contralateral muscle fluctuations was observed. Furthermore, treatments aimed at decreasing perfusion-limited hypoxia, such as carbogen combined with nicotinamide and flunarizine, decreased the incidence of tumour T2*-weighted GRE fluctuations. We also tracked dynamic changes in T2* using multiple GRE imaging. Fluctuations of T2* were observed; however, fluctuation maps using PSD analysis could not be generated reliably. An echo-time dependency of the signal fluctuations was observed, which is typical to physiological noise. Finally, at the end of T2*-weighted GRE MRI acquisition, a dynamic contrast-enhanced MRI was performed to characterize the microenvironment in which tumour signal fluctuations occurred in terms of vessel functionality, vascularity and microvascular permeability. Our data showed that TFV were predominantly located in regions with functional vessels, whereas SDV occurred in regions with no contrast enhancement as the result of vessel functional impairment. Furthermore, transient fluctuations appeared to occur preferentially in neoangiogenic hyperpermeable vessels. The present study suggests that spontaneous T2*-weighted GRE fluctuations are very likely to be related to the spontaneous fluctuations in blood flow and oxygenation associated with the pathophysiology of acute hypoxia in tumours. The disadvantage of the T2*-weighted GRE MRI technique is the complexity of signal

Topics: Animals; Biomarkers, Tumor; Carbon Dioxide; Cell Hypoxia; Cell Line, Tumor; Computer Simulation; Fibrosarcoma; Flunarizine; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C3H; Models, Biological; Niacinamide; Oxygen; Reproducibility of Results; Sensitivity and Specificity; Signal Processing, Computer-Assisted; Stochastic Processes

The perfluorochemical emulsion Fluosol-DA plus carbogen breathing has been shown to increase the effectiveness of radiation therapy in preclinical solid tumors when the emulsion was administered by i.v. bolus injection. Much of the enhancement in tumor radiation response was lost when the emulsion was administered slowly.. We hypothesized that an increase in tumor perfusion resulted when Fluosol-DA was administered rapidly.. In the present study, the alpha/beta agonist ephedrine, the Ca2+ channel blocker flunarizine and the nitric oxide producing vasodilating drug nitroprusside have been tested.. Ephedrine administration resulted in a decrease in the radiation plus Fluosol-DA +/- carbogen antitumor effects in both the Lewis lung carcinoma and FSaIIC tumor systems. In contrast, flunarizine administration resulted in an increase in the efficacy of the radiation plus carbogen and the radiation plus Fluosol-DA/carbogen in both tumor systems. Even with flunarizine administration Fluosol-DA delivered slowly was less effective than when the emulsion was given rapidly. Flunarizine with Fluosol-DA infused i.v. over 30 min followed by carbogen breathing prior to and during radiation therapy resulted in a 1.7-1.6-fold increase in response compared with 2.4-2.2-fold with Fluosol-DA administered by injection i.v. and carbogen breathing prior to and during radiation therapy using growth delay of the Lewis lung carcinoma. The effects of nitroprusside were complex. This drug had considerably more effect at 10 Gy than at higher radiation doses.. These studies suggest that Fluosol-DA given by i.v. injection may increase tumor perfusion and that a drug like flunarizine may be beneficial if the Fluosol-DA is administered slowly followed by carbogen breathing and radiation therapy.

Topics: Administration, Inhalation; Animals; Carbon Dioxide; Drug Combinations; Ephedrine; Flunarizine; Fluorocarbons; Hydroxyethyl Starch Derivatives; Injections, Intravenous; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Nitroprusside; Oxygen; Radiation-Sensitizing Agents; Time Factors