Selective inhibition of inducible nitric oxide synthase inhibits tumor growth in vivo: studies with 1400W, a novel inhibitor.
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.
Thomsen
L L
LL
Glaxo Wellcome Research and Development, Medicines Research Centre, Ware, Hertfordshire, United Kingdom. LLT36851@ggr.co.uk
Scott
J M
JM
Topley
P
P
Knowles
R G
RG
Keerie
A J
AJ
Frend
A J
AJ
D000230:Adenocarcinoma / Q000201:enzymology*; D000578:Amidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000032:analysis; D001596:Benzylamines / Q000493:pharmacokinetics / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D009573:Nitrites / Q000097:blood; D014183:Transplantation, Heterologous
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009566:Nitrates; D009573:Nitrites; D001120:Arginine; D019001:Nitric Oxide Synthase