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dc.contributor.authorClemons, Mark
dc.contributor.authorWatson, Amanda J
dc.contributor.authorHowell, Anthony
dc.contributor.authorChang, James
dc.contributor.authorHeyworth, Clare M
dc.contributor.authorLord, Brian I
dc.contributor.authorTesta, Nydia G
dc.contributor.authorDexter, T Michael
dc.contributor.authorMargison, Geoffrey P
dc.date.accessioned2009-11-23T11:32:06Z
dc.date.available2009-11-23T11:32:06Z
dc.date.issued2000-03
dc.identifier.citationMacrophage inflammatory protein 1alpha attenuates the toxic effects of temozolomide in human bone marrow granulocyte-macrophage colony-forming cells. 2000, 6 (3):966-70 Clin. Cancer Res.en
dc.identifier.issn1078-0432
dc.identifier.pmid10741722
dc.identifier.urihttp://hdl.handle.net/10541/86665
dc.description.abstractMacrophage inflammatory protein 1alpha (MIP-1alpha) is a chemokine that may act principally by preventing hemopoietic cells from entering G1, thereby attenuating the cytotoxic effects of cell cycle-specific chemotherapeutic agents. Here we examine the effect of MIP-1alpha on the sensitivity of human granulocyte-macrophage hemopoietic progenitor cells (granulocyte-macrophage colony-forming cells; GM-CFCs) with the cytotoxic effects of antitumor agents that act mainly via alkylation at the O6 position of guanine in DNA. Mononuclear cell preparations from human bone marrow were used in an in vitro GM-CFC colony-forming assay. The GM-CFC survival from individual patients displayed a range of sensitivities to the methylating agent temozolomide [(Tz) 20-55% survival at 10 microg/ml Tz]. However, in all 16 cases, MIP-1alpha (50 ng/ml) protected against GM-CFC killing: survival in the presence of MIP-1alpha ranged from 65-97% at 10 microg/ml Tz, with GM-CFCs being 1.5-4.5-fold more resistant than control cells from the same patient. The highest levels of protection were seen in the GM-CFCs with the highest sensitivity in the absence of MIP-1alpha. Similar degrees of protection were seen for the methylating agent streptozotocin, but no protection was detected for the chloroethylating agents carmustine or mitozolomide in the samples for which there was protection against the toxic effects of Tz. Whereas the mechanism of this effect remains to be established, the results may have potential immediate clinical application in the attenuation of hematological toxicity after administration of methylating antitumor agents.
dc.language.isoenen
dc.subjectHaematopoietic Stem Cellsen
dc.subject.meshAntineoplastic Agents, Alkylating
dc.subject.meshBone Marrow Cells
dc.subject.meshCell Division
dc.subject.meshCell Survival
dc.subject.meshChemokine CCL3
dc.subject.meshChemokine CCL4
dc.subject.meshColony-Forming Units Assay
dc.subject.meshDacarbazine
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshHematopoietic Stem Cells
dc.subject.meshHumans
dc.subject.meshMacrophage Inflammatory Proteins
dc.subject.meshStreptozocin
dc.titleMacrophage inflammatory protein 1alpha attenuates the toxic effects of temozolomide in human bone marrow granulocyte-macrophage colony-forming cells.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign Department of Medical Oncology, Manchester, United Kingdom. markclemons@sprint.caen
dc.identifier.journalClinical Cancer Researchen
html.description.abstractMacrophage inflammatory protein 1alpha (MIP-1alpha) is a chemokine that may act principally by preventing hemopoietic cells from entering G1, thereby attenuating the cytotoxic effects of cell cycle-specific chemotherapeutic agents. Here we examine the effect of MIP-1alpha on the sensitivity of human granulocyte-macrophage hemopoietic progenitor cells (granulocyte-macrophage colony-forming cells; GM-CFCs) with the cytotoxic effects of antitumor agents that act mainly via alkylation at the O6 position of guanine in DNA. Mononuclear cell preparations from human bone marrow were used in an in vitro GM-CFC colony-forming assay. The GM-CFC survival from individual patients displayed a range of sensitivities to the methylating agent temozolomide [(Tz) 20-55% survival at 10 microg/ml Tz]. However, in all 16 cases, MIP-1alpha (50 ng/ml) protected against GM-CFC killing: survival in the presence of MIP-1alpha ranged from 65-97% at 10 microg/ml Tz, with GM-CFCs being 1.5-4.5-fold more resistant than control cells from the same patient. The highest levels of protection were seen in the GM-CFCs with the highest sensitivity in the absence of MIP-1alpha. Similar degrees of protection were seen for the methylating agent streptozotocin, but no protection was detected for the chloroethylating agents carmustine or mitozolomide in the samples for which there was protection against the toxic effects of Tz. Whereas the mechanism of this effect remains to be established, the results may have potential immediate clinical application in the attenuation of hematological toxicity after administration of methylating antitumor agents.


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