Inhibition of vinyl carbamate-induced lung tumors and K ras2 mutations by the garlic derivative diallyl sulfone

Abstract

Vinyl carbamate (VC) is derived from ethyl carbamate (EC), a chemical found in alcoholic beverages and fermented foods. The objectives of this study were to characterize the formation of lung tumors induced by VC in F 1 (Big Blue ® x A/J) mice, and to identify the mutations formed in the K ras2 gene. In addition, we have tested the hypothesis that pretreatment with diallyl sulfone (DASO 2) inhibits the adverse effects of VC. Mice were treated with VC (60 mg/kg, i.p.) or DASO 2 (50 mg/kg, p.o.) 2 h prior to VC (DASO 2/VC). Lung tumor multiplicity was significantly lower (21%) in mice treated with DASO 2/VC than with VC. Lung tumors induced by VC are manifested as solid or papillary tumors, with the latter being regarded as a more malignant phenotype as they demonstrate no growth restrictions. Solid (42%) and papillary tumors (58%) were found in similar proportions in VC-treated mice. The number of papillary tumors was significantly decreased (44.5%) in mice treated with DASO 2/VC, while there was a proportional increase (44.5%) in the number of solid tumors. The number of tumors with mutations in the first and second exon of K ras2 was significantly lower after treatment with DASO 2/VC (7%) than after treatment with VC (61%). The mutations were mainly found in codon 61, and were identified as A → T transversions (31%) and A → G transitions (25%) in the second base, and A → T transversions (12%) in the third base. All of these mutations were significantly reduced by DASO 2 pretreatment. The number of tumors containing K ras2 mutations was highest (38%) in the large papillary tumors. Hence, mice treated with DASO 2/VC had decreased frequencies of K ras2 mutations and reduced numbers of small and large papillary tumors, suggesting that activation of the K ras2 gene may be implicated in lung tumor formation and progression.