Early quantitative evaluation of a tumor vasculature disruptive agent AVE8062 using dynamic contrast-enhanced ultrasonography.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Lavisse
Sonia
S
UPRES EA 4040, Univ Paris-Sud, Institut Gustave Roussy, Villejuif, France.
Lejeune
Pascale
P
Rouffiac
Valérie
V
Elie
Nicolas
N
Bribes
Estelle
E
Demers
Brigitte
B
Vrignaud
Patricia
P
Bissery
Marie-Christine
MC
Brulé
Aude
A
Koscielny
Serge
S
Péronneau
Pierre
P
Lassau
Nathalie
N
D020533:Angiogenesis Inhibitors; D000818:Animals; D000970:Antineoplastic Agents; D003287:Contrast Media; D005260:Female; D008545:Melanoma / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000473:pathology; D051379:Mice; D045423:Microbubbles; D009336:Necrosis; D012867:Skin / Q000098:blood supply*; D013997:Time Factors; D014463:Ultrasonography
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003287:Contrast Media