Differential activity of NO synthase inhibitors as chemopreventive agents in a primary rat tracheal epithelial cell transformation system.
A model to study the effectiveness of potential chemopreventive agents that inhibit neoplastic process by different mechanisms has been used to test the efficacy of seven nitric oxide synthase (NOS) inhibitors. Five selective inducible NOS (iNOS) inhibitors: S-methyl isothiourea (S-MITU), S-2-aminoethyl isothiourea (S-2-AEITU), S-ethyl isothiourea (S-EITU), aminoguanidine (AG), 2-amino-4-methyl pyridine (2-AMP), and two non selective general NOS inhibitors: l-N(6)-(1-iminoethyl) lysine (IEL) and N(omega)-nitro-l-arginine (NNLA), were tested for efficacy against a carcinogen, benzo[a]pyrene (B[a]P)-induced primary rat tracheal epithelial (RTE) cell transformation assay. RTE cells were treated with B[a]P alone or with five nontoxic concentrations of an NOS inhibitor and the resulting foci at the end of 30 days were scored for inhibition of transformation. The results indicate that all three isothiourea compounds inhibited B[a]P-induced RTE foci in a dose-dependent manner. S-AEITU was the most effective inhibitor with an IC(50) (the molar concentration that inhibits transformation by 50%) of 9.1 microM and 100% inhibition at the highest dose tested (30 microM). However, both S-EITU and S-MITU showed a maximum percent inhibition of 81% and 100% at 1 mM with an IC(50) of 84 and 110 microM, respectively. 2-AMP did not show any dose-dependent response, but was highly effective (57% inhibition) at an intermediate dose of 30 microM and an IC(50) of 25 microM. Similar to thiourea compounds, AG exhibited good dose-dependent inhibition with a maximum inhibition of 86% at 1 mM. NNLA and IEL were negative in this assay. Based on the IC(50) values, NOS inhibitors were rated for efficacy from high to low as follows: S-2-AEITU<2-AMP<AG<S-MITU<S-EITU. The data from this study identify NOS inhibitors as a novel class of chemopreventive agents that can be developed for lung cancer prevention.
Sharma
Sheela
S
Cellular and Molecular Toxicology Program, ManTech Environmental Technology, Inc., Research Triangle Park, NC 27709, USA. sheela.sharma@mantech.com
Wilkinson
Betty P
BP
Gao
Pu
P
Steele
Vernon E
VE
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D006146:Guanidines / Q000494:pharmacology; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000517:prevention & control*; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D010847:Picolines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013047:Specific Pathogen-Free Organisms; D014132:Trachea / Q000166:cytology*; D000338:beta-Aminoethyl Isothiourea / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D004791:Enzyme Inhibitors; D006146:Guanidines; C090663:N(6)-(1-iminoethyl)lysine; D010847:Picolines; D000338:beta-Aminoethyl Isothiourea; D019335:Nitroarginine; D007550:Isothiuronium; C007687:etiron; D001564:Benzo(a)pyrene; C015672:2-amino-4-picoline; D019001:Nitric Oxide Synthase; C027744:S-methylisothiopseudouronium; D008239:Lysine; C004479:pimagedine