Early quantitative evaluation of a tumor vasculature disruptive agent AVE8062 using dynamic contrast-enhanced
Sonia Lavisse1, Pascale Lejeune, Valérie Rouffiac
1UPRES EA 4040, Univ Paris-Sud, Institut Gustave Roussy, Villejuif, France.
Objectives:
To evaluate the early tumor vasculature disrupting effects of the AVE8062 molecule and the feasibility of dynamic contrast-enhanced ultrasonography (DCE-US) in the quantitative assessment of these effects.
Material And Methods:
AVE8062 was administered at a single dose (41 mg/kg) to 40 melanoma-bearing nude mice, which were all imaged before and after drug administration (5 + 15 minutes, 1, 6, and 24 hours). Using an ultrasound scanner (Aplio, Toshiba), intratumor vessels were counted in power Doppler mode and tumor microvasculature was assessed in a specific harmonic mode associated with a perfusion and quantification software for contrast-uptake quantification (Sonovue, Bracco). The peak intensity (PI), time-to-PI (T PI), and full-width at half maximum (FWHM) were extracted from the time-intensity curves expressed as linear raw data. Histologic analysis evaluated microvessel density (MVD) and necrosis at each time point studied. Statistical significance was estimated (paired sum rank and Mann-Whitney tests) to evaluate drug activity and to compare its efficacy at the different time points.
Results:
In power Doppler mode, intratumoral vessels depletion started 15 minutes postinjection (32%, P = 0.004) and the decrease was maximal at 6 hours (51%, P = 0.002). PI decreased by 3.5- and 45.7-fold at 1 and 6 hours, respectively, compared with preinjection values (P = 0.016 and P = 0.008). The decrease at 6 hours was significantly different from the variation at 1 hour (P = 0.0012) and at 24 hours (P = 0.0008). T PI and FWHM showed a significant increase exclusively at 6 hours (P = 0.0034, P = 0.0039). Histology revealed significantly decreased MVD and increased necrosis at 24 hours (P < 0.01).
Conclusion:
DCE-US allowed quantitative in vivo evaluation of the functional effects of AVE8062, which was found most effective on tumoral microvasculature 6 hours after its administration. A clinical phase-1 study of AVE8062 is ongoing using the same ultrasonography methodology before and 6 and 24 hours postadministration.
Insights
Dynamic contrast-enhanced ultrasonography (DCE-US) effectively assessed AVE8062's tumor vasculature disruption. The drug showed maximal efficacy on tumoral microvasculature six hours post-administration in this study.
Area of Science:
- Oncology
- Medical Imaging
- Pharmacology
Background:
- Tumor vasculature is a key target for anti-cancer therapies.
- Assessing the early effects of anti-angiogenic drugs is crucial for treatment monitoring.
- Dynamic contrast-enhanced ultrasonography (DCE-US) offers a non-invasive method for evaluating tumor perfusion.
Purpose of the Study:
- To evaluate the early tumor vasculature disrupting effects of AVE8062.
- To assess the feasibility of using DCE-US for quantitative evaluation of these effects.
Main Methods:
- Forty nude mice with melanoma xenografts received a single dose of AVE8062 (41 mg/kg).
- Tumor imaging was performed using power Doppler and harmonic mode DCE-US before and at multiple time points after drug administration.
- Intratumoral vessels, contrast uptake parameters (Peak Intensity, Time-to-Peak, Full-Width at Half-Maximum), microvessel density (MVD), and necrosis were quantified.
Main Results:
- Intratumoral vessel depletion was observed as early as 15 minutes post-injection, peaking at 51% reduction by 6 hours.
- Peak intensity significantly decreased by 6 hours post-administration, indicating reduced blood flow.
- Histological analysis confirmed decreased MVD and increased necrosis at 24 hours.
Conclusions:
- DCE-US provides a quantitative in vivo method to assess the functional effects of AVE8062 on tumor vasculature.
- AVE8062 demonstrates significant anti-vascular effects, with maximal impact observed 6 hours after administration.
- A Phase-1 clinical trial is underway utilizing DCE-US to monitor AVE8062 treatment efficacy.
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