8-nitroguanosine and Neoplasms

This review focuses primarily on my own research, including pathogenic mechanisms of microbial infection, vascular permeability in infection and tumors, and effects of nitric oxide (NO), superoxide anion radical (O₂⁻), and 8-nitroguanosine in the enhanced permeability and retention (EPR) effect for the tumor-selective delivery of macromolecular agents (nanomedicines). Infection-induced vascular permeability is mediated by activation of the kinin-generating protease cascade (kallikrein-kinin) triggered by exogenous microbial proteases. A similar mechanism operates in cancer tissues and in carcinomatosis of the pleural and peritoneal cavities. Infection also stimulates O₂⁻ generation via activation of xanthine oxidase while generating NO by inducing NO synthase. These chemicals function in mutation and carcinogenesis and promote inflammation, in which peroxynitrite (a product of O₂⁻ and NO) activates MMP, damages DNA and RNA, and regenerates 8-nitroguanosine and 8-oxoguanosine. We showed vascular permeability by using macromolecular drugs, which are not simply extravasated through the vascular wall into the tumor interstitium but remain there for prolonged periods. We thus discovered the EPR effect, which led to the rational development of tumor-selective delivery of polymer conjugates, micellar and liposomal drugs, and genes. Our styrene-maleic acid copolymer conjugated with neocarzinostatin was the first agent of its kind used to treat hepatoma. The EPR effect occurs not only because of defective vascular architecture but also through the generation of various vascular mediators such as kinin, NO, and vascular endothelial growth factor. Although most solid tumors, including human tumors, show the EPR effect, heterogeneity of tumor tissue may impede drug delivery. This review describes the barriers and countermeasures for improved drug delivery to tumors by using nanomedicines.

Topics: Animals; Antineoplastic Agents; Capillary Permeability; Free Radicals; Guanosine; Humans; Infections; Nanomedicine; Neoplasms; Nitric Oxide; Nitro Compounds

Chronic inflammation has long been recognized as a risk factor for human cancer at various sites. Examples include Helicobacter pylori-induced gastritis for gastric cancer, inflammatory bowel disease (ulcerative colitis and Crohn's disease) for colorectal cancer and chronic viral hepatitis for liver cancer. Here we review the role in carcinogenesis of nitrative damage to nucleic acids, DNA and RNA, which occurs during inflammation through the generation of reactive nitrogen species, such as peroxynitrite, nitroxyl, and nitrogen dioxide. Enhanced formation of 8-nitroguanine, representative of nitrative damage to nucleobases, has been detected in various inflammatory conditions. The biochemical nature of DNA damage mediated by reactive nitrogen species is discussed in relation to its possible involvement in mutations, genetic instability, and cell death. Better understanding of the mechanisms and role of such nitrative damage in chronic inflammation-associated human cancer is a necessary basis to develop new strategies for cancer prevention by modulating the process of inflammation.

Topics: Chronic Disease; Disease Susceptibility; DNA Damage; DNA Repair; Guanosine; Humans; Inflammation; Mutagenesis; Neoplasms; Nitric Oxide; Nitric Oxide Synthase Type II; Nitro Compounds; Reactive Nitrogen Species; Recombination, Genetic