Reduction of alachlor-induced olfactory mucosal neoplasms by the matrix metalloproteinase inhibitor Ro 28-2653.
Chronic exposure to the chloracetanilide herbicide alachlor has been shown to cause olfactory mucosal neoplasms. Genomic analysis of olfactory mucosa from rats given alachlor (126 mg/kg/d) for from 1 day to 18 mo suggested that matrix metalloproteinases MMP-2 and MMP-9 were upregulated in the month following initiation of treatment. The present studies were designed to confirm this latter finding and to explore the potential role of MMPs in alachlor-induced olfactory carcinogenesis. Zymographic analysis of olfactory mucosal extracts confirmed that MMP-2 activity is higher in the olfactory mucosa of alachlor-treated rats. Therefore, rats were fed alachlor (126 mg/kg/d in the diet for 1 year) either with or without the MMP-2/MMP-9 inhibitor Ro 28-2653 (100 mg/kg daily by gavage for the first 2 months of alachlor treatment). The number of olfactory mucosal neoplasms was reduced by 25% after 1 year of alachlor treatment in rats that received both alachlor and Ro 28-2653. The morphology of alachlor-induced olfactory tumors was similar whether or not Ro 28-2653 had been given; the MMP inhibitor itself had no impact on olfactory mucosal histology. These data confirm that olfactory mucosal MMP-2 activity is increased following short-term alachlor exposure and show that administration of an MMP-2/9 inhibitor reduced the incidence of olfactory neoplasms in alachlor-treated rats, thereby implicating MMP-2 activity as a mediator of alachlor-induced carcinogenicity.
Genter
Mary Beth
MB
Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio 45267-0056, USA. MaryBeth.Genter@UC.edu
Warner
Blake M
BM
Krell
Hans-Willi
HW
Bolon
Brad
B
D000081:Acetamides; D000818:Animals; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009297:Nasal Mucosa / Q000187:drug effects / Q000473:pathology*; D009669:Nose Neoplasms / Q000139:chemically induced / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans
D000081:Acetamides; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; C453902:Ro 28-2653; C000188:alachlor