Differential radioprotection of normal tissues by hydrophilic chemical protectors

Brown, Darrell Q.; Yuhas, John M.; MacKenzie, Laurie; Graham, William J.; Pittock, J

doi:10.1016/0360-3016(84)90507-8

Cited by 21 publications

(2 citation statements)

References 4 publications

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“…Other antioxidants such as the thioredoxin and peroxyredoxin reductases also rely on access to abundant thiols, via the amino acid cysteine and glutathione. Although radiation protection by cysteine/thiol supplementation has been recognized since biological studies of radiation exposure were initiated [19, 20], the development of protectants for normal cells and/or specific tumor sensitizers has been stymied by the inability to separately effect tumor versus surrounding normal tissues (review: [4]).…”

Section: Introductionmentioning

confidence: 99%

xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction

et al. 2018

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About 3 million US cancer patients and 1.7 million EU cancer patients received multiple doses of radiation therapy (RT) in 2012, with treatment duration limited by normal adjacent tissue damage. Tumor-specific sensitization could allow treatment with lower radiation doses, reducing normal tissue damage. This is a longstanding, largely unrealized therapeutic goal. The cystine:glutamate exchanger xCT is expressed on poor prognosis subsets of most solid tumors, but not on most normal cells. xCT provides cells with environmental cystine for enhanced glutathione synthesis. Glutathione is used to control reactive oxygen species (ROS), which are therapeutic effectors of RT. We tested whether xCT inhibition would sensitize xCT+ tumor cells to ionizing radiation. We found that pretreatment with the xCT inhibitor erastin potently sensitized xCT+ but not xCT− cells, in vitro and in xenograft. Similarly, targeted gene inactivation also sensitized cells, and both modes of sensitization were overcome by glutathione supplementation. Sensitization prolongs DNA damage signaling, increases genome instability, and enhances cell death, revealing an unforeseen role for cysteine in genome integrity maintenance. We conclude that an xCT-specific therapeutic would provide tumor-specific sensitization to RT, allowing treatment with lower radiation doses, and producing far fewer side effects than other proposed sensitizers. Our data speaks to the need for the rapid development of such a drug.

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Section: Introductionmentioning

confidence: 99%

xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction

et al. 2018

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“…In tumors, the uptake is predominantly through passive diffusion, which is slow due to the hydrophilicity of the compound.13 This is in contrast to the dephosphorylated form of the compound, WR-1065, which is less hydrophilic and readily crosses the tumor cell membrane. In fact, Brown et al 14 suggested that the hydrophilicity of the compound could be useful for designing or selecting better differential radioprotectors. This is supported by their work that showed increases in the therapeutic gain (ratio of the dose reduction factors for the hematopoietic system and tumor) for 6 hydrophilic thiols, ranging from 1.59-2.29, in comparison to values ranging from 0.88-1.59 for 5 lipophilic thiols.…”

Section: Cell Componentsmentioning

confidence: 99%

Antioxidants Reduce Consequences of Radiation Exposure

Okunieff

Swarts

Keng

et al.

Advances in Experimental Medicine and Biology

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Antioxidants have been studied for their capacity to reduce the cytotoxic effects of radiation in normal tissues for at least 50 years. Early research identified sulfur-containing antioxidants as those with the most beneficial therapeutic ratio, even though these compounds have substantial toxicity when given in-vivo. Other antioxidant molecules (small molecules and enzymatic) have been studied for their capacity to prevent radiation toxicity both with regard to reduction of radiation-related cytotoxicity and for reduction of indirect radiation effects including long-term oxidative damage. Finally, categories of radiation protectors that are not primarily antioxidants, including those that act through acceleration of cell proliferation (e.g. growth factors), prevention of apoptosis, other cellular signaling effects (e.g. cytokine signal modifiers), or augmentation of DNA repair, all have direct or indirect effects on cellular redox state and levels of endogenous antioxidants. In this review we discuss what is known about the radioprotective properties of antioxidants, and what those properties tell us about the DNA and other cellular targets of radiation.

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Stereoisomers of cysteine and its analogs Potential effects on chemo- and radioprotection strategies

Roberts

1995

Amino Acids

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The thiol-containing amino acid, cysteine, and its analogs are useful for a variety of protective applications, including protecting normal tissues against the unwanted side effects of cancer chemotherapeutic agents and radiation treatment. The protection can result from both direct action of the amino acid and/or after its conversion to glutathione (GSH), sulfate, or other sulfur-based protective substances. Unfortunately, high GSH levels have been implicated in the problematic development of tumor cells' resistance to therapy. Due to numerous differences in the metabolic processing of the cysteine stereoisomers, chemo- and radioprotective strategies might be developed using the D-form of the amino acid, which can participate in protection directly, but which cannot be used to support GSH biosynthesis. In this way, protection of normal tissue may be achieved, while the potential development of resistance in tumor cells is minimized. Greatly enhanced therapeutic efficacy of cancer treatment regimens may be the result.

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Differential radioprotection of normal tissues by hydrophilic chemical protectors

Cited by 21 publications

References 4 publications

xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction

xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction

Antioxidants Reduce Consequences of Radiation Exposure

Stereoisomers of cysteine and its analogs Potential effects on chemo- and radioprotection strategies

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