Modification of survival by DNA repair modifiers: A probable explanation for the phenomenon of increased radioresistance

B. Marples, M. C. Joiner

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Purpose: The low dose (< 1 Gy) survival curve of mammalian cells is characterized by a region of hypersensitivity (HRS) followed by increased resistance (IRR). Above 1 Gy, the survival response can be described with a smooth downward-bending curve. Indirect evidence has indicated that the IRR response might reflect an induced radioresistance triggered by DNA damage. The work reported here provides experimental evidence that consolidates this hypothesis. Materials and methods: Clonogenic survival of V79-379A cells was measured using automated microscopy (DMIPS cell analyser) in the presence or absence of three known modifiers of DNA repair processes over the X-ray dose range 0-1 Gy. Results: 3-Aminobenzamide (5 μM), a potent inhibitor of poly(ADP ribose)-polymerase, inhibited the development of increased radioresistance as indicated by a statistically significant reduction in an RBE from 3.537 (± SEM (0.139)) to 2.168 (± 0.191) at an X-ray dose of 1 Gy, implying an involvement of DNA repair pathways that require poly(ADP ribose)-polymerase in the IRR response. In contrast, novobiocin (350 μM), an inhibitor of topoisomerase II, did not inhibit the development of increased radioresistance (RBE 3.650 (± 0.192) to 3.322 ± (0.156)) but eliminated low-dose hypersensitivity as measured by an increase in RBE from 2.508 (± 0.536) to 1.135 (± 0.057) at 0.04 Gy. Ara-A (120 μM), an inhibitor of DNA polymerase, sensitized cells at all doses. Conclusion: These data support the hypothesis that DNA repair processes are likely to be involved in the development of increased radioresistance and provide further evidence against a sensitive subpopulation explanation for the biphasic low-dose survival response.

Original languageEnglish (US)
Pages (from-to)305-312
Number of pages8
JournalInternational Journal of Radiation Biology
Volume76
Issue number3
DOIs
StatePublished - Jan 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology
  • Radiology Nuclear Medicine and imaging

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