Reduction of Alachlor-Induced Olfactory Mucosal Neoplasms by the Matrix Metalloproteinase Inhibitor Ro 28-2653

Abstract

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.

Recent advances in MMP inhibitor design

“…This compound inhibits the MT1-MMP, MT-3-MMP, MMP-2, MMP-8 and MMP-9 subtypes (IC 50 values of 10-20 nM) while sparing the MMP-1 activity. It has been shown to reduce tumor growth in chronic arachlor exposure-induced nasal cancer in rats [145], in prostate cancer cell culture and xenograft models [146][147][148], and in a breast cancer xenograft model [149]. In this latter assay Ro 28-2653 reduced tumor vascularization, inhibited the tumor-promoting effects of fibroblasts, and did not upregulate MMP-9 angiogenic activity (as was observed with Batimastat).…”

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

“…X‐ray crystallography revealed a binding mode of the pyrimidinetrione group in which nearly all possible interactions from the core to the protein are saturated and sum up to more interactions than those found for hydroxamates . Compound 20 performed well in in vivo examinations, in which it reduced tumor growth and prolonged survival in a prostate cancer rat model, reduced alachlor‐induced olfactory mucosal neoplasm in rats, and reduced tumor growth on breast adenocarcinoma, as well as tumor vascularization in a rat aortic ring assay…”

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

“…With dosing for up to 1 month, 148 genes and expressed sequence tags (ESTs) were up-regulated. A major subgroup of these was genes related to control of extracellular matrix including metalloproteinase genes, whose products appear to be important in nasal tumor progression (Genter et al, 2005). Other up-regulated genes included several related to cell cycle and proliferation.…”