O2- oxidizes the [4Fe-4S] clusters of dehydratases, such as aconitase, causing-inactivation and release of Fe(II), which may then reduce H2O2 to OH- +OH.. SODs inhibit such HO. production by scavengingO2-, but Cu, ZnSODs, by virtue of a nonspecific peroxidase activity, may peroxidize spin trapping agents and thus give the appearance of catalyzing OH. production from H2O2. There is a glycosylated, tetrameric Cu, ZnSOD in the extracellular space that binds to acidic glycosamino-glycans. It minimizes the reaction of O2- with NO. E. coli, and other gram negative microorganisms, contain a periplasmic Cu, ZnSOD that may serve to protect against extracellular O2-. Mn(III) complexes of multidentate macrocyclic nitrogenous ligands catalyze the dismutation of O2- and are being explored as potential pharmaceutical agents. SOD-null mutants have been prepared to reveal the biological effects of O2-. SodA, sodB E. coli exhibit dioxygen-dependent auxotrophies and enhanced mutagenesis, reflecting O2(-)-sensitive biosynthetic pathways and DNA damage. Yeast, lacking either Cu, ZnSOD or MnSOD, are oxygen intolerant, and the double mutant was hypermutable and defective in sporulation and exhibited requirements for methionine and lysine. A Cu, ZnSOD-null Drosophila exhibited a shortened lifespan.

Superoxide Radical and Superoxide Dismutases

Diminished amounts of manganese-containing superoxide dismutase have been found in all the tumors examined to date. Lowered amounts of the copper-zinc-containing superoxide dismutase have been found in many, but not all, tumors. At the same time, tumors have been shown to produce superoxide radicals. It is shown how diminished enzyme activities along with radical production may lead to many of the observed properties of cancer cells. The apparent exploitation of the differences between normal and cancer cell superoxide dismutase activity in the treatment of cancer is discussed.

/pdf/role-of-superoxide-dismutase-in-cancer-a-review-5c4fusvkkr.pdf

Role of Superoxide dismutase in cancer: a review.

The highly active, quinone-containing anticancer drugs, Adriamycin, daunorubicin, carminomycin, rubidazone, nogalamycin, aclacinomycin A, and steffimycin (benzanthraquinones); mitomycin C and streptonigrin (N-heterocyclic quinones); and lapachol (naphthoquinone) interact with mammalian microsomes and function as free radical carriers. These quinone drugs augment the flow of electrons from reduced nicotinamide adenine dinucleotide phosphate to molecular oxygen as measured by enhanced reduced nicotinamide adenine dinucleotide phosphate oxidation and oxygen consumption. This reaction is catalyzed by microsomal protein and produces a free radical intermediate form of the drugs as determined by electron paramagnetic resonance spectroscopy. Microsomes from mouse and rat liver, heart, lung, and spleen and mouse L1210 and P388 tumors all catalyze the augmented oxygen consumption. Apparent Km values determined with normal rat liver microsomes range from 0.49 × 10-4m for steffimycin to 13.4 × 10-4m for lapachol. Since SKF 525A and carbon monoxide have little effect on this reaction, cytochrome P-450 is probably not involved. Several nonquinone anticancer agents were tested and were found inactive in the system. Since quinone anticancer drugs are associated with chromosomal damage that appears to be dependent on metabolic activation of these drugs, we propose that the intracellular activation of these drugs to a free radical state may be primary to their cytotoxic activity. As free radicals, these drugs, because of their high affinity and selective binding to nucleic acids, have the potential to be “site-specific free radicals” that bind to DNA or RNA and either react directly or generate oxygen-dependent free radicals such as superoxide radical or hydroxyl radical to cause the damage associated with their cytotoxic actions.

https://cancerres.aacrjournals.org/content/canres/38/6/1745.full.pdf

A general mechanism for microsomal activation of quinone anticancer agents to free radicals.

The cytotoxicities of a number of antineoplastic agents to oxygenated and hypoxic EMT6 mouse mammary tumor cells in culture were examined. Based on the relative sensitivities of cells under aerobic and hypoxic conditions, drugs were placed into three categories. Drugs that were preferentially toxic to cells under oxygenated conditions were classified as type 1 agents; this group includes bleomycin, procarbazine, streptonigrin, actinomycin D, and vincristine. Type 2 agents were those preferentially toxic to cells under hypoxic conditions. These include mitomycin C and Adriamycin. On the basis of other published reports, the glucose analogs, 5-thio-D-glucose and 2-deoxy-D-glucose, and the radiosensitizers, misonidazole and metronidazole, can also be placed in this category. Several antineoplastic agents showed no major preferential toxicity to cells under the conditions of oxygenation or hypoxia used in these experiments and were placed in a third class. This group (type 3) includes 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, cis-diamminedichloroplatinum(II), 5-fluorouracil, and methotrexate. The success of many combination chemotherapy and combined modality treatments may be due to their ability to kill both the hypoxic and aerobic cell populations of solid tumors. Future chemotherapeutic regimens for the treatment of solid tumors should include agents and modalities directed toward the hypoxic cell population of the tumor, as well as toward the proliferating and nonproliferating tumor cell compartments; a therapeutic approach to the selection of antineoplastic agents for use in combination based upon physiological considerations of the architecture of solid tumors is presented.

https://cancerres.aacrjournals.org/content/canres/41/1/73.full.pdf

Classification of Antineoplastic Agents by their Selective Toxicities toward Oxygenated and Hypoxic Tumor Cells

Liposome oxidation and erythrocyte lysis by enzymically generated superoxide and hydrogen peroxide.

The production of single strand cleavage in covalently-closed circular-DNA by the antitumour agent streptonigrin (reduced in situ by NADH) is demonstrated using the ethidium bromide fluorescence assay described previously. The degradation dependent on oxygen is completely inhibited by superoxide dismutase (EC 1.15.1.1) suggesting the intermediacy of the superoxide radical anion in the degradation. However similar complete inhibition of DNA strand breakage by catalase (EC 1.11.1.6) indicates that the hydroxyl radical (formed by interaction of superoxide with hydrogen peroxide) is the primary reactive species. Cupric ion stimulates the cleavage reaction and cobaltous ion has no effect in keeping with model studies using quinolinequinones.

S. K. Hasan

Papers

The mechanism of the degradation of DNA by streptonigrin.