Radioprotectors

Chemical, Biological, and Clinical Perspectives

Edward A. Bump, Kamal Malaker

• Publisher: CRC Press
• Year: 2021
• ISBN:
  9781000141542
• Edition: 1
• Topic: Diritto
• Subtopic: Scienza forense

It is essential to minimize damage to normal tissues during radiation therapy and many strategies have been employed in finding the best methods for radioprotection. This book integrates chemical, biological, and clinical perspectives on these strategies and developments, providing a comprehensive treatise. It emphasizes new concepts in radioprotection, aiming to inspire further basic science and clinical progress in radioprotector research. Radioprotectors: Chemical, Biological, and Clinical Perspectives includes the following topics:

• Early research on radioprotectors
  
• WR-2721, an aminothiol prodrug, as a radioprotector
  
• New results with naturally occurring thiols
  
• Nitroxides as effective radioprotectors in vitro and in vivo
  
• Radioprotection observed with radical scavengers or antioxidants
  
• Bone marrow radioprotection with cytokines and biological modifiers
  
• Multiple mechanisms of altering radiation response by eicosanoids
  
• Vascular response to radiation and the importance of vascular damage to normal tissue
  
• Modifiers of radiation-induced apoptosis
  
• Survey of clinical trials with radioprotectors
  Radiation biologists and oncologists, cancer researchers, and toxicologists will benefit from the findings discussed and strategies for future research.

SECTION I Chemical Aspects of Radioprotection

Introduction

Edward A. Bump

DOI: 10.4324/9781003068181-2

CONTENTS

I.1 General Considerations in Radiation Chemistry

I.2 Radioprotection by Decreasing DNA Damage

I.2.1 Importance of DNA Damage In Radiation Cytotoxicity

I.2.2 Radioprotection by HO^• Scavenging

I.2.3 Hydrogen Donation to DNA Radicals: The Competition Model

I.3 Other Potential Mechanisms of Radioprotection

I.3.1 Lipid Peroxidation — Could It Play a Role in Some of the Effects of Ionizing Radiation?

I.3.2 Scavenging of Secondary Radicals

I.3.3 Suppression of Protracted Oxidative Stress

I.3.4 Decreasing Oxygen Concentration

I.3.5 Enhancement of DNA Repair

I.4 Amelioration of Consequential Injury That Is Not Directly Initiated by Radiolytic Products

References

The purpose of Section I is to review aspects of radioprotection from a chemical perspective, that is, the types of chemical reactions that can interfere with particular processes that participate in the production of tissue injury. This introduction will briefly summarize the types of chemical processes that can play a role in radiation injury, and the corresponding range of strategies for protection. Each chapter will then focus on a particular chemical approach to radioprotection.

I.1 GENERAL CONSIDERATIONS IN RADIATION CHEMISTRY

The biological effects of ionizing radiation can ultimately be attributed to chemical changes in biological molecules that originate with energy absorption. Electrons in matter absorb energy from the high-energy photons or electrons most commonly used in therapy, resulting in ionizations and excitations. It is the ability to cause ionizations that distinguishes these types of radiation from UV radiation, for example, which only causes excitations. Ionizations produce highly reactive species with unpaired electrons (free radicals). Free radical reactions result in changes in the structure of biomolecules, sometimes altering their biological function. Damage resulting from direct ionization of the target molecule by radiation is termed the direct effect. Damage produced in the target molecule by reaction with other radiolytic products is referred to as the indirect effect.

A typical therapeutic dose of radiation that can reduce clonogenic cell survival by about 50% (2 Gy) produces approximately 2 μM free radicals.¹ This corresponds roughly to one free radical per 10 million molecules (of molecular weight 100). This seems like a very minor chemical perturbation of the cell, particularly considering that free radical production occurs constantly in unirradiated cells, as a result of normal metabolism. It is estimated that the steady-state concentration of H₂O₂ in mammalian cells is of the order of 10⁻⁸ M, and the concentration of ${\text{O}}_2^{·-}$ is of the order of 10⁻¹¹ M, entirely as a consequence of normal aerobic metabolism.² Ames et al.³ have calculated, based on the appearance of damaged bases in urine, that we experience an average of about 10, 000 chemical attacks on our DNA per cell per day, just as a consequence of normal metabolism. This is of the same order of magnitude as the number of DNA lesions that would be produced with 2 Gy per day of ionizing radiation⁴ — obviously it does not have the same biological effect. There is something qualitatively different about the free radicals produced by ionizing radiation.

The most apparent difference between free radical damage by ionizing radiation and that produced with chemical agents is that ionizing radiation produces clusters of radicals. The nature of the physical process of energy deposition is that each eneigy absorption event produces several radicals in a very small volume.⁵ When this volume overlaps a segment of a DNA double helix, both strands of the DNA can become damaged, and a number of studies have indicated that double-strand DNA lesions can account for the cytotoxic effects of ionizing radiation.^{6, 7} It is therefore reasonable to consider all other radiation-induced lesions to be irrelevant with respect to cell killing by ionizing radiation, and for the past several decades that has been the prevailing opinion among radiation biologists. Clustered DNA lesion formation involves chemical reactions that are complete within 10 msec.

Nevertheless, there are indications that some of the biological effects of ionizing radiation may be due, at least in part, to chemical effects that are distinguishable from the formation of DNA clustered lesions. This is clearest when protection can be achieved if modifiers are added more than 10 msec after irradiation, since modification of DNA clustered lesion formation would not be possible. For example, Ramakrishnan et al.⁸ (see Chapter 11 in this volume) find that the antioxidant trolox can protect against radiation-induced apoptosis in lymphocytes, even when added after irradiation. Radiation-induced apoptosis in bovine aortic endothelial cells appears to involve signaling events triggered by ceramide formation,⁹ and reconstitution experiments have indicated that the initial target in this case is the plasma membrane.¹⁰ With respect to radioprotection, the prevention of damaging mechanisms that do not involve DNA clustered lesion formation may be more easily achieved, and could result in a therapeutic gain if the importance of the damaging mechanism to tumor control and normal tissue damage is different.

A distinction can be made between chemical events involved in DNA clustered lesion formation and all other chemical events that can contribute to the biological effects of radiation, whether they are traceable to the initial radiochemical events or not. This distinction can be made because we understand the chemistry of DNA clustered lesion formation very well:

1. DNA clustered lesion production involves only direct ionization of DNA and attack by HO^• radicals that are formed within a few nanometers of the site of the clustered lesion.^11–13 None of the other diffusible radicals produced by radiation participates in clustered lesion formation because they diffuse away from the site before they have a chance to react with the DNA.¹³
2. DNA clustered lesion formation can only be prevented during a 10 msec period following irradiation, during which DNA radicals can either react with a protector to result in restoration or with a sensitizer to result in damage fixation.¹⁴ If neither occurs, damage fixation will result from unimolecular processes that will occur within the DNA molecule. This imposes a requirement that the protective reaction occur at a rate that is at least comparable with the reaction rate of DNA radicals with sensitizer. The consequence of this is that radioprotection by concentrations of protector that are lower than required for this threshold can be interpreted to indicate a different mechanism of radioprotection. Likewise, any protector that is effective when added more than msec after irradiation must be acting by a different mechanism.

Radioprotection by a mechanism other than altering DNA clustered lesion formation would require another explanation for the high efficiency of radiation compared with free radicals produced as a consequence of normal metabolism. One possibility is that some of the free radicals produced by radiation are more effective in producing damage tha...