Abstract
BackgroundGene expression profiling of the transcriptional response of human dermal fibroblasts to in vitro radiation has shown promise as a predictive test of radiosensitivity. This study tested if treatment with the radiomimetic drug bleomycin sulphate could be used to differentiate radiation sensitive patients and controls in patients who had previously received radiotherapy for early breast cancer.FindingsEight patients who developed marked late radiation change assessed by photographic breast appearance and 8 matched patients without any change were selected from women entered in a prospective randomised trial of breast radiotherapy fractionation. Gene expression profiling of primary skin fibroblasts exposed in vitro to bleomycin sulphate and mock treated fibroblast controls was performed. 973 genes were up-regulated and 923 down-reguated in bleomycin sulphate treated compared to mock treated control fibroblasts. Gene ontology analysis revealed enriched groups were cellular localisation, apoptosis, cell cycle and DNA damage response for the deregulated genes. No transcriptional differences were identified between fibroblasts from radiation sensitive cases and control patients; subgroup analysis using cases exhibiting severe radiation sensitivity or with high risk alleles present in TGF β1 also showed no difference.ConclusionsThe transcriptional response of human dermal fibroblasts to bleomycin sulphate has been characterised. No differences between clinically radiation sensitive and control patients were detected using this approach.
Highlights
Gene expression profiling of in vitro cellular responses of human fibroblasts and lymphocytes to radiation has demonstrated that cells undergo complex early transcriptional responses of a wide spectrum of genes from different gene ontologies [1,2,3,4]
The spectrum of DNA damage caused by bleomycin sulphate is similar but not identical to that caused by ionising radiation, its definition as a radiomimetic agent [8]
Transcriptional response of cultured fibroblasts exposed to bleomycin sulphate
Summary
Gene expression profiling of in vitro cellular responses of human fibroblasts and lymphocytes to radiation has demonstrated that cells undergo complex early transcriptional responses of a wide spectrum of genes from different gene ontologies [1,2,3,4]. The molecular and clinical responses after bleomycin sulphate and radiation are similar: both induce post-mitotic differentiation of fibroblasts inducing a senescent phenotype associated with increased collagen production [9,10,11], activate cascades of profibrotic chemokines and cytokines and cause skin and pulmonary fibrosis in animal models and in the clinic [12,13,14]. On this basis, the potential of using bleomycin. This study tested if treatment with the radiomimetic drug bleomycin sulphate could be used to differentiate radiation sensitive patients and controls in patients who had previously received radiotherapy for early breast cancer
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