The radiosensitizing and radioprotective effects of various compounds have been characterized in Chinese hamster fibroblasts growing in vitro and in a model chemical system utilizing DNA as target. The contribution to the lethal action of ionizing radiation in mammalian cells from the indirect effect of OH has been measured. The data are consistent with the “oxygen fixation hypothesis,” whereby target free radicals react either with radical-reducing species, resulting in “chemical repair,” or with radical-oxidizing species, resulting in “fixation” of radical damage to a potentially lethal form. Radical repair–fixation competition has been demonstrated in the in vitro chemical system with a sensitizer other than O2. Dimethyl sulfoxide is shown to radioprotect in both the cellular and chemical systems by scavenging OH. Cysteamine, on the other hand, is shown to protect primarily by adding to the pool of radical-reducing species, resulting in enhanced repair of free-radical damage in the targets. Electron-af...

Chemical Radioprotection and Radiosensitization of Mammalian Cells Growing in Vitro

Publisher Summary The integrity of DNA is essential for the well-being of a cell. Damage to this molecule, whether caused by reaction with chemical mutagens, by irradiation with ultraviolet (UV) light, or by ionizing radiation, has dire consequences. Thus, much effort has been expended in attempting to understand the effects of these agents on DNA. This chapter describes some of the chemical mechanisms whereby DNA is damaged by ionizing radiation. The major advances in understanding of molecular mechanisms have come from the studies of simple model systems. The chapter explains the three basic model systems that have been designed to examine radiation-induced damage to DNA. Each type of system yields useful information, but the applicability of this information to the in vivo situation is limited in all cases. The chapter also discusses the indirect effects of the free radicals produced by the radiolysis of water, in terms of both initial species and final products.

Molecular mechanisms of radiation-induced damage to nucleic acids

Acid--base properties of free radicals in solution

Publisher Summary
This chapter reviews the results and their implications for cancer therapy. The efficacy of cis-dichlorodiammineplatinum (II), or cisplatin (cis-DDP), as a broad spectrum antineoplastic agent in experimental tumor systems has rapidly promoted its introduction into a number of clinical trials. Although the results of these preliminary trials include encouraging responses in a variety of tumor types, the clinical use of cisplatin is hampered by its emetic properties, kidney toxicity, and limited activity against certain malignancies. Cisplatin is the parent complex in a family of platinum coordination complexes that includes several analogs that are less toxic and possess higher therapeutic indices. The cytotoxicity of cisplatin and studies on platinum complex binding to cellular constituents suggests both the need and the potential for combination chemotherapy. Cisplatin has been combined with a variety of chemotherapeutic agents in animal models and in clinical trials. Preclinical studies have reported enhanced effects for combination drug therapy, including synergy. The clinical efficacy of cisplatin in combination with other agents has also been encouraging, and no unusual or unpredicted toxicities have resulted from such combination therapies. Although the applied rationale for combining cisplatin with antitumor drugs also extends to its combination with ionizing radiation, only a few clinical studies have examined the effects of this latter modality.

A review of interactions between platinum coordination complexes and ionizing radiation: implications for cancer therapy

The nitroimidazoles are effective radiosensitizers for both hypoxic bacterial and mammalian cells and are currently under clinical investigation as adjuncts in radiotherapy It is known that the 2-nitroimidazoles are biologically more efficient than the 5-nitro derivatives This paper reports on some aspects of the radiation chemistry of one biologically important example of each class, together with results obtained with other related derivatives Metronidazole (a 5-nitroimidazole) and Ro-07-0582 (a 2-nitroimidazole) react rapidly with both $e{}_{{\rm aq}}{}^{-}$ and OH to produce transient absorbing species which decay by second-order kinetics Both compounds accept electrons from the radical anion of thymine at near diffusion-controlled rates, but not from neutral thymine radicals formed by H and OH attack From a study of one-electron transfer reactions involving p-nitroacetophenone as an electron acceptor it is shown that the electron affinity of the 2-nitroimidazole structure is

Electron-affinic sensitization. VI. A pulse radiolysis and ESR comparison of some 2- and 5-nitroimidazoles.

The reaction of $e_{{\rm aq}}^{-}$ , OH radicals and H atoms with N-ethylmaleimide (NEM) and N-ethylmaleamic acid (NEMA, which is produced from the hydrolysis of NEM at pH > 7) were investigated in aqueous solutions. The reaction rate constants, the transient optical absorption spectra and the decay kinetics of the resulting intermediates were obtained. The free radical sensitization reactions of NEM with model compounds were followed by pulse radiolysis. A number of organic free radicals were found to react with NEM by an electron transfer process (oxidation of free radicals) to produce $\cdot {\rm NEM}^{-}$ , and/or by addition to NEM. NEMA, being a poorer oxidizing agent, does not appear to undergo most of these reactions. Electron adducts (e.g., radical anions of pyrimidine bases) were shown to transfer an electron to NEM. Solutes with redox potentials higher than that of NEM, such as menadione and oxygen, were found to be good electron acceptors from ...

E. Hayon

Papers

Radiation Sensitization Reactions of N-Ethylmaleimide with Model Compounds