PULMONARY FIBROSIS INDUCED BY ANTICANCER DRUGS-ITS MECHANISM AND PROPHYLAXIS

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To prevent pulmonary fibrosis (PF) in cancer chemotherapy, we examined the mechanism of peplomycin (PLM)-induced PF and obtained following results.1. Both in and ex vivo, PLM enhanced cytokine generation by lymphocytes, macrophages, neutrophils and fibroblasts (Fb).2. In and ex vivo PLM enhanced proliferation and collagen synthesis of Fb.3. In Fb, lymphocytes and neutrophils, PLM enhanced phosphorylation of inositols protein and tyrosine residues and activated^<ras> p21 and MAPK,inducing activation of NF-kappaB with c-myc expression.4. PLM activated p47^<phox> and p67^<phox> (components of NADPH) and increased reactive oxygen generation by neutrophils and macrophages.5. Azelastine hydrochloride (Azeptin, an anti-allergic drug) inhibited these PLM activities and suppressed PLM-induced pulmonary fibrosis in mice.6. PLM-induced fibrosis begun in the periphery of the lung and advanced to the central region, especially around the bronchi. Immunohistochemically and electromicroscopically. Fb in the lung with fibrosis expressed vimentin, desmin and alpha-smooth muscle (alpha-SM) actin. The change of Fb to myofibroblasts was ascertained by in situ hybridization of alpha-SM and blotting for alpha-SM-mRNA and its protein.These results indicate that PLM-induced fibrosis is resulted from enhanced signal transduction which induces cytokine and reactive oxygen generation, that Azeptin is expected to prohibit pulmonary fibrosis in cancer therapy and that with advance of fibrosis, Fb, become myofibroblasts expressing alpha-SM.Therefore, it is important to investigate the intracellular signals associated with the expression of alpha-SM.