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dc.contributor.authorRobson, Helen
dc.contributor.authorAnderson, Elizabeth
dc.contributor.authorEden, Tim O B
dc.contributor.authorIsaksson, O
dc.contributor.authorShalet, Stephen M
dc.date.accessioned2010-02-12T15:48:45Z
dc.date.available2010-02-12T15:48:45Z
dc.date.issued1998
dc.identifier.citationGlucocorticoid pretreatment reduces the cytotoxic effects of a variety of DNA-damaging agents on rat tibial growth-plate chondrocytes in vitro. 1998, 42 (2):171-6 Cancer Chemother. Pharmacol.en
dc.identifier.issn0344-5704
dc.identifier.pmid9654119
dc.identifier.doi10.1007/s002800050802
dc.identifier.urihttp://hdl.handle.net/10541/92027
dc.description.abstractIt is apparent that cytotoxic chemotherapy used to treat childhood malignancies has a major impact on subsequent growth. Our initial studies have demonstrated a direct adverse effect of individual glucocorticoids and cytotoxic agents on the proliferative capacity of rat tibial growth-plate chondrocytes in vitro. In the present study we investigated the interaction between these classes of agents using in vitro cultures of chondrocytes and examined the potential of these cells to recover from the adverse effects of the drugs as applied either alone or in combination. The glucocorticoids prednisolone and dexamethasone significantly reduced the growth rate of chondrocytes when present in cultures for 3 days. The growth rate increased following the removal of prednisolone and dexamethasone from cultures and reached 83.9+/-0.8% and 62.4+/-4.0%, respectively, of the control values after 11 days of culture. In contrast, cell numbers were significantly reduced when the DNA-damaging agents cisplatin, carboplatin, etoposide or actinomycin-D were present in cultures for 3 days. Very little recovery of cell growth was observed after removal of the drugs from cultures, with cell loss occurring in the cisplatin- and actinomycin-D-treated cultures. However, pretreatment of chondrocytes with either of the glucocorticoids completely ameliorated the cytotoxic effects of etoposide and carboplatin and significantly reduced those of cisplatin and actinomycin-D. Recovery of the cells treated with a combination of glucocorticoid and DNA-damaging agent was demonstrated by a significant increase in their ability to form colonies in suspension culture. Colony numbers were increased by a factor of between 5 and 80 as compared with the cells receiving medium alone followed by DNA-damaging agent. The glucocorticoids offer a protective effect in terms of the reduced cytotoxicity of DNA-damaging agents and improve the subsequent clonogenicity and recovery of growth-plate chondrocytes. This has important implications for treatment schedules involving both cytotoxic agents and glucocorticoids in childhood malignancies.
dc.language.isoenen
dc.subject.meshAnimals
dc.subject.meshAnti-Inflammatory Agents
dc.subject.meshAntineoplastic Agents
dc.subject.meshCarboplatin
dc.subject.meshCell Division
dc.subject.meshChondrocytes
dc.subject.meshCisplatin
dc.subject.meshDactinomycin
dc.subject.meshDexamethasone
dc.subject.meshDrug Interactions
dc.subject.meshEtoposide
dc.subject.meshFemale
dc.subject.meshMale
dc.subject.meshPrednisolone
dc.subject.meshRats
dc.subject.meshTibia
dc.titleGlucocorticoid pretreatment reduces the cytotoxic effects of a variety of DNA-damaging agents on rat tibial growth-plate chondrocytes in vitro.en
dc.typeArticleen
dc.contributor.departmentClinical Research Department, Christie Hospital NHS Trust, Manchester, UK.en
dc.identifier.journalCancer Chemotherapy and Pharmacologyen
html.description.abstractIt is apparent that cytotoxic chemotherapy used to treat childhood malignancies has a major impact on subsequent growth. Our initial studies have demonstrated a direct adverse effect of individual glucocorticoids and cytotoxic agents on the proliferative capacity of rat tibial growth-plate chondrocytes in vitro. In the present study we investigated the interaction between these classes of agents using in vitro cultures of chondrocytes and examined the potential of these cells to recover from the adverse effects of the drugs as applied either alone or in combination. The glucocorticoids prednisolone and dexamethasone significantly reduced the growth rate of chondrocytes when present in cultures for 3 days. The growth rate increased following the removal of prednisolone and dexamethasone from cultures and reached 83.9+/-0.8% and 62.4+/-4.0%, respectively, of the control values after 11 days of culture. In contrast, cell numbers were significantly reduced when the DNA-damaging agents cisplatin, carboplatin, etoposide or actinomycin-D were present in cultures for 3 days. Very little recovery of cell growth was observed after removal of the drugs from cultures, with cell loss occurring in the cisplatin- and actinomycin-D-treated cultures. However, pretreatment of chondrocytes with either of the glucocorticoids completely ameliorated the cytotoxic effects of etoposide and carboplatin and significantly reduced those of cisplatin and actinomycin-D. Recovery of the cells treated with a combination of glucocorticoid and DNA-damaging agent was demonstrated by a significant increase in their ability to form colonies in suspension culture. Colony numbers were increased by a factor of between 5 and 80 as compared with the cells receiving medium alone followed by DNA-damaging agent. The glucocorticoids offer a protective effect in terms of the reduced cytotoxicity of DNA-damaging agents and improve the subsequent clonogenicity and recovery of growth-plate chondrocytes. This has important implications for treatment schedules involving both cytotoxic agents and glucocorticoids in childhood malignancies.


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