We have investigated the effect of
N-(3-(aminomethyl)benzyl)acetamidine (1400W), a novel and highly selective inhibitor for inducible NOS (iNOS), on in vivo growth of solid
tumors expressing iNOS. For the EMT6 murine mammary
adenocarcinoma, in which iNOS is expressed in the
tumor cells, continuous infusion of 1400W for 6 days
at 10 or 12 mg/kg(-1)/h(-1) resulted in significant reduction in
tumor weight (357 +/- 46 and 466 +/- 70 mg, respectively) compared with that of controls [726 +/- 65 (P < 0.001) and 796 +/- 88 mg (P < 0.02), respectively]. Reduced growth was also observed for a human
tumor xenograft (
colon adenocarcinoma DLD-1) genetically engineered to express iNOS constitutively and treated for 13 days with 6 mg/kg(-1)/h(-1) 1400W compared with controls (
tumor weights 340 +/- 50 and 580 +/- 90 mg, respectively; P < 0.03). Growth of the parental DLD-1 clone was not altered with this treatment compared with that of controls (
tumor weights 170 +/- 10 and 240 +/- 50 mg, respectively). Inhibition of iNOS in vivo was confirmed by decreases in plasma
nitrite +
nitrate concentrations in treated animals compared with that of controls (63-83% decreases for all experiments) and was supported by plasma and
tumor concentrations of 1400W that were equivalent and 2.6-4.9 times higher than the EC50 previously reported for iNOS in a tissue assay. For the murine
colon adenocarcinoma Colon 38, in which intratumoral macrophages are the predominant source of iNOS and which had high intratumoral
arginine concentrations, 1400W treatment had no effect on growth or plasma
nitrate +
nitrate. Future studies with more potent selective iNOS inhibitors and a wider range of
tumors may determine whether iNOS inhibitors could represent a novel approach to the treatment of
cancer. These studies confirm that
nitric oxide production in
tumors plays a role in promoting their growth, rather than a role as a host defense mechanism in inhibiting growth.