Cilengitide-Induced Temporal Variations in Transvascular Transfer Parameters of Tumor Vasculature in a Rat Glioma Model: Identifying Potential MRI Biomarkers of Acute Effects

Abstract

Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (v p), forward volume transfer constant (K trans) and interstitial volume fraction (v e) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for K trans (p = 0.0001 and v e (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities.

Acute Temporal Changes of MRI-Tracked Tumor Vascular Parameters after Combined Anti-angiogenic and Radiation Treatments in a Rat Glioma Model: Identifying Signatures of Synergism

“…Our choice of the intervals between Cilengitide treatment and irradiation was based on a knowledge of the temporal profile of acute changes in the tumor vascular parameters after Cilengitide treatment alone reported by Nagaraja et al . (7), and of irradiation alone reported by Brown et al . (8).…”

“…Timing-dependent outcomes appear to be related to acute changes in the tumor vascular physiology in the hours after a monotreatment or combined treatments (4, 5, 7, 8, 19). Furthermore, by tracking short-term changes in tumor vascular physiology, a beneficial timing of the combined therapies can be identified, leading to better treatment outcome and OS.…”

“…Since these potential “synergies” are short-term with respect to tumor response, and many of the agents affect tumor vasculature, it might be expected that the short-term changes in tumor physiology which occur in response to combined treatments could be used as biomarkers of response. Indeed, studies in preclinical models (7, 8) showed that tumor physiology changes profoundly in the hours after either anti-angiogenic treatment or irradiation. In current clinical practice, short-term anatomical changes don’t occur and short-term physiological responses are not usually assessed.…”

“…Nagaraja et al . observed short-term effects of Cilengitide on the tumor vasculature of U-251 cerebral glioma in athymic rats, demonstrating that it exerted a short-term effect on transvascular transfer parameters of the tumor vasculature, causing vascular normalization at approximately 8 h after treatment (7). It has been suggested that normalization of the vasculature increased radiosensitivity and enhanced treatment efficacy (14).…”

“…The importance of optimizing the timing and sequence of combined therapies such as radiotherapy with anti-angiogenic drugs has become increasingly recognized (15–18), as has the importance of acute tumor responses to therapies (4, 5, 7, 8, 19). In this study, we investigated the timing between Cilengitide and radiation exposure to determine the vascular signature corresponding to increased tumor response to combined treatments.…”