CHEMOPREVENTIVE ACTIVITY OF THIOL CONJUGATES OF ISOTHIOCYANATES FOR LUNG TUMORIGENESIS

A series of L-cysteine (L-Cys), glutathione (GSH), and N-acetyl-L-cyst eine (NAG) conjugates of phenethyl (PEITC), benzyl (BITC), and 6-pheny lhexyl isothiocyanate (PHITC) were studied for their inhibitory activi ty toward metabolic activation of the tobacco-specific nitrosamine 4-( methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mouse lung micro somes. Selected compounds, PEITC, PEITC -GSH, PEITC -NAC and PHITC -NA C, were also assayed for the potential chemopreventive activity toward NNK-induced lung tumorigenesis in A/J mice, Results showed that PEITC and its conjugates inhibited NNK metabolism with decreasing potency: PEITC < PEITC-GSH > PEITC-Cys > PEITC -NAC, PHITC and its GSH and NAC conjugates exhibited nearly 10 times higher inhibitory activity toward NNK metabolism than the PEITC counterparts,In the tumor bioassay, as expected, the conjugates exhibited inhibitory activity against lung tu morigenesis induced by NNK, PEITC -GSH was not inhibitory at 4 mu mol/ mouse, but it inhibited similar to 32% of lung tumor multiplicity at 8 mu mol/mouse. PEITC-NAC at 5 and 20 mu mol/mouse both inhibited simil ar to 30% tumor multiplicity, Among all the conjugates examined, PHITC -NAC was the most potent, At a 5-mu mol dose, it completely inhibited tumor multiplicity and incidence to the background level observed in t he control group, These results revealed that the structure-activity r elationships of the conjugates are similar to those found with their p arent isothiocyanates (ITCs), i.e., the potency increased with the inc reasing alkyl chain length from two to six carbons in arylalkyl ITCs, suggesting that a common active species is involved, The inhibitory ac tivity of ITC conjugates and the expected low toxicity make thiol conj ugates of ITC a promising new series of chemopreventive agents.