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dc.contributor.authorLee, Siow Ming
dc.contributor.authorCrowther, Derek
dc.contributor.authorScarffe, J Howard
dc.contributor.authorDougal, Mark
dc.contributor.authorElder, Rhoderick H
dc.contributor.authorRafferty, Joseph A
dc.contributor.authorMargison, Geoffrey P
dc.date.accessioned2010-08-16T14:42:43Z
dc.date.available2010-08-16T14:42:43Z
dc.date.issued1992-08
dc.identifier.citationCyclophosphamide decreases O6-alkylguanine-DNA alkyltransferase activity in peripheral lymphocytes of patients undergoing bone marrow transplantation. 1992, 66 (2):331-6 Br. J. Canceren
dc.identifier.issn0007-0920
dc.identifier.pmid1387001
dc.identifier.urihttp://hdl.handle.net/10541/109650
dc.description.abstractO6-alkylguanine-DNA-alkyltransferase (ATase) levels were measured in extracts of peripheral blood lymphocytes taken at various times during chemotherapy from 19 patients with various haematological malignancies. Seven patients with advanced Hodgkin's disease received preparative treatment consisting of cyclophosphamide (1.5 g m-2, daily) administered on days 1 to 4 and BCNU (600 mg m-2) on day 5 prior to autologous bone marrow rescue (ABMR) delivered on day 7. Treatment in the remaining 12 patients consisted of cyclophosphamide (1.8 g m-2, daily) given on days 1 and 2 followed at day 4 with total body irradiation (TBI) administered in six fractions over the subsequent 3 days to a total dose of 1200 cGy prior to bone marrow transplantation. In the Hodgkin's group, significant decreases in ATase activity were seen during the cyclophosphamide treatment, and the median ATase nadir was 32% (range 0% to 57%) of pretreatment levels following 4 days of cyclophosphamide. In one patient, no ATase activity was detectable following the 4th cyclophosphamide treatment. ATase activities decreased further after BCNU administration to a median of 19% (range 0% to 32%) of pretreatment levels. Extensive cyclophosphamide-induced reduction of lymphocyte ATase levels was also seen in the other group of 12 patients treated with cyclophosphamide/TBI: postcyclophosphamide median ATase nadir was 35% (range 12% to 78%) of the pretreatment levels. No ATase depletion was seen when cyclophosphamide (up to 10 mM) was incubated for 2 h with pure recombinant human ATase in vitro whereas ATase activity was reduced by 90% on preincubation with 100 microns acrolein or with greater than 1 mM phosphoramide mustard. This suggests that a cyclophosphamide-induced decrease in ATase levels in human peripheral lymphocytes in vivo may be due to depletion mediated by the production of intracellular acrolein. Since ATase appears to be a principal mechanism in cellular resistance to the cytotoxic effects of BCNU and related alkylating agents, these observations suggest that a cyclophosphamide-induced reduction in ATase activity may be an additional factor in the effectiveness of the combined sequential therapy.
dc.language.isoenen
dc.subjectLeukaemiaen
dc.subject.meshAcrolein
dc.subject.meshAdenosine Triphosphatases
dc.subject.meshAdolescent
dc.subject.meshAdult
dc.subject.meshBone Marrow Transplantation
dc.subject.meshCarmustine
dc.subject.meshCyclophosphamide
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshKinetics
dc.subject.meshLeukemia
dc.subject.meshLymphocytes
dc.subject.meshLymphoma, Non-Hodgkin
dc.subject.meshMale
dc.subject.meshMethyltransferases
dc.subject.meshMiddle Aged
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase
dc.subject.meshPhosphoramide Mustards
dc.subject.meshRecombinant Proteins
dc.subject.meshTransplantation, Autologous
dc.titleCyclophosphamide decreases O6-alkylguanine-DNA alkyltransferase activity in peripheral lymphocytes of patients undergoing bone marrow transplantation.en
dc.typeArticleen
dc.contributor.departmentCRC Department of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK.en
dc.identifier.journalBritish Journal of Canceren
html.description.abstractO6-alkylguanine-DNA-alkyltransferase (ATase) levels were measured in extracts of peripheral blood lymphocytes taken at various times during chemotherapy from 19 patients with various haematological malignancies. Seven patients with advanced Hodgkin's disease received preparative treatment consisting of cyclophosphamide (1.5 g m-2, daily) administered on days 1 to 4 and BCNU (600 mg m-2) on day 5 prior to autologous bone marrow rescue (ABMR) delivered on day 7. Treatment in the remaining 12 patients consisted of cyclophosphamide (1.8 g m-2, daily) given on days 1 and 2 followed at day 4 with total body irradiation (TBI) administered in six fractions over the subsequent 3 days to a total dose of 1200 cGy prior to bone marrow transplantation. In the Hodgkin's group, significant decreases in ATase activity were seen during the cyclophosphamide treatment, and the median ATase nadir was 32% (range 0% to 57%) of pretreatment levels following 4 days of cyclophosphamide. In one patient, no ATase activity was detectable following the 4th cyclophosphamide treatment. ATase activities decreased further after BCNU administration to a median of 19% (range 0% to 32%) of pretreatment levels. Extensive cyclophosphamide-induced reduction of lymphocyte ATase levels was also seen in the other group of 12 patients treated with cyclophosphamide/TBI: postcyclophosphamide median ATase nadir was 35% (range 12% to 78%) of the pretreatment levels. No ATase depletion was seen when cyclophosphamide (up to 10 mM) was incubated for 2 h with pure recombinant human ATase in vitro whereas ATase activity was reduced by 90% on preincubation with 100 microns acrolein or with greater than 1 mM phosphoramide mustard. This suggests that a cyclophosphamide-induced decrease in ATase levels in human peripheral lymphocytes in vivo may be due to depletion mediated by the production of intracellular acrolein. Since ATase appears to be a principal mechanism in cellular resistance to the cytotoxic effects of BCNU and related alkylating agents, these observations suggest that a cyclophosphamide-induced reduction in ATase activity may be an additional factor in the effectiveness of the combined sequential therapy.


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