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Theoretical implications of incorporating relative biological effectiveness into radiobiological equivalence relationships.

ABSTRACT: OBJECTIVE: Earlier radiobiological equivalence relationships as derived for low-linear energy transfer (LET) radiations are revisited in the light of newer radiobiological models that incorporate an allowance for relative biological effectiveness (RBE). METHODS: Linear-quadratic (LQ) radiobiological equations for calculating biologically effective dose at both low- and high-LET radiations are used to derive new conditions of equivalence between a variety of radiation delivery techniques. The theoretical implications are discussed. RESULTS: The original (pre-LQ) concept of equivalence between fractionated and continuous radiotherapy schedules, in which the same physical dose is delivered in each schedule, inherently assumed that low-LET radiation would be used in both schedules. LQ-based equivalence relationships that allow for RBE and are derived assuming equal total physical dose between schedules are shown to be valid only in limited circumstances. Removing the constraint of equality of total physical dose allows the identification of more general (and more practical) relationships. CONCLUSION: If the respective schedules under consideration for equivalence both involve radiations of identical LET, then the original equivalence relationships remain valid. However, if the compared schedules involve radiations of differing LET, then new (and more restrictive) equivalence relationships are found to apply. ADVANCES IN KNOWLEDGE: Theoretically derived equivalence relationships based on the LQ model provide a framework for the design and intercomparison of a wide range of clinical techniques including those involving high- and/or low-LET radiations. They also provide a means of testing for the validity of variously assumed tissue repair kinetics.

SUBMITTER: Holloway RP

PROVIDER: S-EPMC3608045 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Project description:PURPOSE:Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of ?1.1. However, emerging data have suggested that Fanconi anemia (FA) and homologous recombination pathway defects can lead to a variable RBE, at least in vitro. We investigated the role of SLX4 (FANCP), which acts as a docking platform for the assembly of multiple structure-specific endonucleases, in the response to proton irradiation. METHODS AND MATERIALS:Isogenic cell pairs for the study of SLX4, XPF/ERCC1, MUS81, and SLX1 were irradiated at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer 2.5 keV/?m) or with 250 kVp x-rays, and the clonogenic survival fractions were determined. To estimate the RBE of the protons relative to cobalt-60 photons (Co60Eq), we assigned a RBE(Co60Eq) of 1.1 to x-rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor the damage responses, and the cell cycle distributions were assessed by flow cytometry. The poly(ADP-ribose) polymerase inhibitor olaparib was used for comparison. RESULTS:Loss of SLX4 function resulted in an enhanced proton RBE(Co60Eq) of 1.42 compared with 1.11 for wild-type cells (at a survival fraction of 0.1; P<.05), which correlated with increased persistent DNA double-strand breaks in cells in the S/G2 phase. Genetic analysis identified the SLX4-binding partner MUS81 as a mediator of resistance to proton radiation. Both proton irradiation and olaparib treatment resulted in a similar prolonged accumulation of RAD51 foci in SLX4/MUS81-deficient cells, suggesting a common defect in the repair of DNA replication fork-associated damage. CONCLUSIONS:A defect in the FA pathway at the level of SLX4 results in hypersensitivity to proton radiation, which is, at least in part, due to impaired MUS81-mediated processing of replication forks that stall at clustered DNA damage. In vivo and clinical studies are needed to confirm these findings in human cancers.

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Theoretical implications of incorporating relative biological effectiveness into radiobiological equivalence relationships.

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