ATM as a target for novel radiosensitizers

Jann N Sarkaria, Jeffrey S. Eshleman

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

DNA damage checkpoints are complex signal transduction pathways that are critical for normal cellular recovery following potentially lethal genotoxic insults. The ataxia-telangiectasia mutated (ATM) protein kinase is a critical component in these pathways and integrates the cellular response to damage by phosphorylating key proteins involved in cell cycle regulation and DNA repair. Lack of normal ATM function in the inherited ataxia-telangiectasia (A-T) syndrome results in a pleiotropic clinical syndrome characterized by a marked increased risk of cancer and profound hypersensitivity to ionizing radiation. Cells derived from patients with A-T share some of these attributes with genomic instability, loss of normal cell cycle arrest pathways, defects in DNA repair and increased radiation sensitivity. The radiosensitivity of A-T cells suggests that pharmacological inhibitors of the ATM kinase should be effective radiosensitizing agents. In fact, caffeine inhibits ATM kinase activity at concentrations that result in an A-T-like phenotype with loss of cell cycle checkpoints and hypersensitivity to ionizing radiation. Although the clinical use of caffeine as a radiosensitizer is limited by potentially lethal systemic toxicities, more potent methyl xanthines may selectively inhibit the ATM pathway at clinically achievable levels. Interestingly, caffeine and other methyl xanthines preferentially radiosensitize cells that lack normal p53 function. Because p53 is commonly inactivated in epithelial malignancies, this suggests that small molecule inhibitors of ATM might selectively sensitize the majority of tumors to the lethal effects of ionizing radiation while sparing normal tissues.

Original languageEnglish (US)
Pages (from-to)316-327
Number of pages12
JournalSeminars in Radiation Oncology
Volume11
Issue number4
StatePublished - 2001

Fingerprint

ataxia
Ataxia Telangiectasia
caffeine
Ionizing Radiation
Caffeine
Xanthines
xanthines
ionizing radiation
Radiation Tolerance
Cell Cycle Checkpoints
deoxyribonucleic acid
DNA Repair
Hypersensitivity
inhibitors
Phosphotransferases
cycles
Ataxia Telangiectasia Mutated Proteins
Radiation-Sensitizing Agents
Neoplasms
damage

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology
  • Radiation

Cite this

ATM as a target for novel radiosensitizers. / Sarkaria, Jann N; Eshleman, Jeffrey S.

In: Seminars in Radiation Oncology, Vol. 11, No. 4, 2001, p. 316-327.

Research output: Contribution to journalArticle

Sarkaria, JN & Eshleman, JS 2001, 'ATM as a target for novel radiosensitizers', Seminars in Radiation Oncology, vol. 11, no. 4, pp. 316-327.
Sarkaria, Jann N ; Eshleman, Jeffrey S. / ATM as a target for novel radiosensitizers. In: Seminars in Radiation Oncology. 2001 ; Vol. 11, No. 4. pp. 316-327.
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