Danae Christodoulou

Redox generation of nitric oxide to radiosensitize hypoxic cells

PURPOSE Previous studies have shown that nitric oxide (NO) delivered from NO donor agents sensitizes hypoxic cells to ionizing radiation. In the present study, nitroxyl (NO-), a potential precursor to endogenous NO production, was evaluated for hypoxic cell radiosensitization, either alone or in combination with electron acceptor agents. METHODS AND MATERIALS Radiation survival curves of Chinese hamster V79 lung fibroblasts under aerobic and hypoxic conditions were assessed by clonogenic assay. Hypoxia induction was achieved by metabolism-mediated oxygen depletion in dense cell suspensions. Cells were treated with NO- produced from the nitroxyl donor Angelis salt (AS, Na2N2O3, sodium trioxodinitrate), in the absence or presence of electron acceptor agents, ferricyanide, or tempol. NO concentrations resulting from the combination of AS and ferricyanide or tempol were measured under hypoxic conditions using an NO-sensitive electrode. RESULTS Treatment of V79 cells under hypoxic conditions with AS alone did not result in radiosensitization; however, the combination of AS with ferricyanide or tempol resulted in significant hypoxic radiosensitization with SERs of 2.5 and 2.1, respectively. Neither AS alone nor AS in combination with ferricyanide or tempol influenced aerobic radiosensitivity. The presence of NO generated under hypoxic conditions from the combination of AS with ferricyanide or tempol was confirmed using an NO-sensitive electrode. CONCLUSION Combining NO- generated from AS with electron acceptors results in NO generation and substantial hypoxic cell radiosensitization. NO- derived from donor agents or endogenously produced in tumors, combined with electron acceptors, may provide an important strategy for radiosensitizing hypoxic cells and warrants in vivo evaluation.

An unusual Bi–Tri–binuclear sandwich complex formed in the reaction of CuCl2 with the Et2N–N2O2– ion

Reaction of the Et2N–N2O2– ligand with CuII ions in methanol produces a mixed complex, shown by X-ray crystallography to consist of simple, alkoxo-bridged bi- and tri-nuclear units held together in a discrete triple-decker array.

Mixed-Ligand, Non-Nitrosyl Cu(II) Complexes as Potential Pharmacological Agents via NO Release

Nitric oxide (NO) has recently been established as a key bioregulatory agent1. Its multifaceted nature has been demonstrated in vascular relaxation, antiplatelet action, macrophage induced cytostasis and cytotoxicity, and neurotransmission. NO is produced endogenously from the amino acid L-arginine2–3 by the enzyme NO synthase (Fig. 1). Several forms of this enzyme have been isolated. The NO produced can activate soluble guanylate cyclase, and thereby influence cellular concentration of another secondary messenger, cyclic GMP, resulting in different physiological responses. Another type of NO synthase, which is induced by activated macrophages and other cells, synthesizes NO which acts as a cytotoxic agent against tumor cells and bacteria. A number of cofactors are involved in the action of the enzyme, such as Ca2+/calmodulin, tetrahydrobiopterin, FMN, FAD and NADPH. NO synthase has high homology to cytochrome P450 reductase.4–5 Inhibitors of NO synthase activity include hemoglobin, the superoxide radical, and glucocorticoids. Analogues of L-arginine, where the guanidino NH2 group has been replaced with groups such as MeNH (L-NMMA), Me (L-NIO), O2N-NH (L-NA), or H2N-NH (L-NAA) act as inhibitors6 of the endothelial NO synthase in vivo.