Therapeutic strategies by modulating oxygen stress in cancer and inflammation

Oxygen is the essential molecule for all aerobic organisms, and plays predominant role in ATP generation, namely, oxidative phosphorylation. During this process. reactive oxygen species (ROS) including superoxide anion (O-2(center dot-)) and hydrogen peroxide (H2O2) are produced as by-products, while it seems indispensable for signal transduction pathways that regulate cell growth and reduction-oxidation (redox) status. However, during times of environmental stress ROS levels may increase dramatically, resulting in significant damage to cell structure and functions. This cumulated situation of ROS is known as oxidative stress, which may, however, be utilized for eradicating cancer cells. It is well known that oxidative stress, namely over-production of ROS, involves in the initiation and progression of many diseases and disorders, including cardiovascular diseases, inflammation, ischemia-reperfusion (1/R) injury, viral pathogenesis, drug-induced tissue injury, hypertension, formation of drug resistant mutant, etc. Thus, it is reasonable to counter balance of ROS and to treat such ROS-related diseases by inhibiting ROS production. Such therapeutic strategies are described in this article, that includes polymeric superoxide dismutase (SOD) (e.g., pyran copolymer-SOD), xanthine oxidase (XO) inhibitor as we developed water soluble form of 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP), heme oxygenase-1 (HO-1) inducers (e.g., hemin and its polymeric form), and other antioxidants or radical scavengers (e.g., canolol). On the contrary, because of its highly cytotoxic nature, ROS can also be used to kill cancer cells if one can modulate its generation selectively in cancer. To achieve this goal, a unique therapeutic strategy was developed named as "oxidation therapy", by delivering cytotoxic ROS directly to the solid tumor, or alternatively inhibiting the antioxidative enzyme system, such as HO-1 in tumor. This anticancer strategy was examined by use of O-2(center dot-) or H2O2-generating enzymes (i.e., XO and D-amino acid oxidase [DAO] respectively), and by discovering the inhibitor of HO-1 (i.e., zinc protoporphyrin [ZnPP] and its polymeric derivatives). Further for the objective of tumor targeting and thus reducing side effects, polymer conjugates or micellar drugs were prepared by use of poly(ethylene glycol) (PEG) or styrene maleic acid copolymer (SMA), which utilize EPR (enhanced permeability and retention) effect for tumor-selective delivery. These macromolecular drugs further showed superior pharmacokinetics including much longer in vivo half-life, particularly tumor targeted accumulation, and thus remarkable antitumor effects. The present review concerns primarily our own works, in the direction of "Controlling oxidative stress: Therapeutic and delivery strategy" of this volume. (C) 2009 Elsevier B.V. All rights reserved.