ABSTRACT
Purpose: The purpose of this study was to
develop a method to quantitatively assess the effect of nitric oxide synthase
(NOS) inhibition on tumor vascular activity using dynamic contrast-enhanced
computed tomography (DCE-CT) and to investigate its usefulness using animal
experiments. Mate-rials and Methods: The DCE-CT studies were performed in
anesthetized Fisher rats bearing tumors using a 4-row multi-slice CT. The
scanning started 4 s before a bolus injection of iodinated contrast agent (CA)
(150 mgI/kg) from the tail vein using an automatic injector and lasted 60 s at
1-s in-tervals. The contrast enhancement (CE) images were generated by
subtracting the CT images before and after the administration of CA. First, the
DCE-CT studies were performed before and 15, 30, and 45 min after
administration of N-nitro-L-arginine (L-NNA) (1, 3, and 10 mg/kg) or vehicle,
and the relative CE values were calculated by normalizing the CE image at each
time point by that obtained from the first DCE-CT study. Second, we investigated
the case when L-arginine (L-ARG) (200 mg/kg) and L-NNA (1, 3, and 10 mg/kg)
were administered after the first and second DCE-CT studies, respectively.
Third, we investigated the case when L-NNA (1, 3, and 10 mg/kg) and L-ARG (200
mg/kg) were administered after the first and second DCE-CT studies,
respectively. Finally, we investigated the case when L-NNA (1, 3, and 10 mg/kg)
and L-ARG (200 mg/kg) were administered simultaneously after the first DCE-CT
study. Results: The relative CE value significantly decreased after L-NNA
administration in a dose-dependent manner (p-values = 0.0074 and <0.0001 for
0 vs. 3 mg/kg and 0 vs. 10 mg/kg, respectively, at 15 min, 0.0003 and
<0.0001 for 0 vs. 3 mg/kg and 0 vs. 10 mg/kg, respectively, at 30 min, and
0.0367 and 0.0004 for 0 vs. 3 mg/kg and 0 vs. 10 mg/kg, respectively, at 45
min). When L-ARG was administered prior to the administration of 1 mg/kg L-NNA,
the relative CE value at 45 min was significantly higher than that at 15 min.
When L-ARG was administered after L-NNA administration, there was no
significant difference between the relative CE values at 15 min and 45 min.
These results suggest that when using L-NNA in combination with L-ARG, their
effect on tumor vascular activity differs depending on the order of their
administration. When L-NNA and L-ARG were administered simultaneously, there
was a tendency for the relative CE value to be higher than that when only L-NNA
was administered, at all injected doses of L-NNA. Conclusion: Our method using
DCE-CT is useful for monitoring the effect of NOS inhibition on tumor vascular
activity and for determining the optimal injected dose and timing of NOS
inhibitors for anticancer therapy.