This study evaluated the effects of
thyroid hormone-NO interaction on
tumor development, vascularization,
vascular endothelial growth factor (
VEGF), and
aminopeptidase (AP) activity in a murine model of implanted Lewis's
carcinoma. Experiments were performed in male CBA-C57 mice. Animals were untreated (controls) or treated with: T4, the
antithyroid drug methimazole, the NO inhibitor
L-NAME, T4+L-NAME, methimazole+NAME, the αvß3
integrin antagonist
tetrac, T4+tetrac, the iNOS inhibitor
aminoguanidine (AG), and T4 + AG; all treatments were for 6 weeks except for
tetrac, administered for the last 11 days. Mice were subcutaneously inoculated with 1 × 10(6) exponentially growing Lewis
carcinoma 3LL cells into the dorsum. Study variables 9 days later were
tumor weight (TW), Hb content, an index of
tumor vascularization,
VEGF, and AP activity. T4 produced parallel increases in TW and angiogenesis.
L-NAME reduced TW and angiogenesis in control,
hyperthyroid, and hypothyroid mice, whereas AG had no effect on these variables.
Tetrac arrested TW in normal and T4-treated mice but did not decrease angiogenesis in T4-treated animals. Negative correlations were found between TW and AP activity in
tumors from control hyper- and hypothyroid groups and an inverse relationship was observed between TW and AP activities in
tetrac-treated mice. T4 enhances TW and angiogenesis, in which NO participates, but requires activation of
integrin αvß3 to promote
carcinogenesis. NO blockade reduces TW, regardless of the thyroid status.
Thyroid hormone negatively modulates AP activity in the
tumor. Accordingly, blockade of the membrane TH receptor αvß3
integrin reduces TW associated with an increase in AP activity.