Dosage and cycle effects of dacarbazine (DTIC) and fotemustine on O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells.

2.50
Hdl Handle:
http://hdl.handle.net/10541/100069
Title:
Dosage and cycle effects of dacarbazine (DTIC) and fotemustine on O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells.
Authors:
Lee, Siow Ming; Thatcher, Nick; Dougal, Mark; Margison, Geoffrey P
Abstract:
There is increasing experimental evidence to suggest that endogenous expression of O6-alkylguanine-DNA-alkyltransferase (ATase) is a major factor in cellular resistance to certain chemotherapeutic agents including dacarbazine (DTIC). We have recently shown wide interindividual variation in the depletion and subsequent regeneration of ATase in peripheral blood mononuclear cells (PMCs) following DTIC and this has now been extended to ascertain whether or not depletion is related to dosage of DTIC used and repeated treatment cycles of chemotherapy. ATase levels were measured in three groups of 25 patients (pts) up to 24 h after receiving DTIC at 400 mg m-2, 500 mg m-2 or 800 mg m-2. Each group also received fotemustine (100 mg m-2), 4 h after DTIC. The lowest extent of ATase depletion (highest nadir ATase) was seen in patients receiving 400 mg m-2. The mean nadir ATase, expressed as a percentage of pre-treatment ATase, was respectively 56.3%, 26.4% and 23.9% for 400 mg m-2, 500 mg m-2 and 800 mg m-2. The median nadir of ATase activity for pts receiving 800 mg m-2 pts was at 4-6 h and for pts given lower doses it was at 2-3 h. In addition, repeated measures analysis of variance of observations before chemotherapy, then at 2, 3, 4, 6 and 18 h after chemotherapy provides some evidence that ATase was depleted to a lesser extent after cycle 1 than after subsequent cycles (P = 0.025). It also provides evidence that the change in ATase activity over time varied with dose and cycle. The findings can be interpreted on the basis of a dosage-dependent metabolism of DTIC to an agent capable of methylation of DNA and subsequent depletion of PMC ATase: with higher DTIC doses, the extent of ATase depletion may be limited by the pharmacokinetics of DTIC metabolism. PMC ATase was measured in another group of 8 pts at various times after receiving only fotemustine (100 mg m-2) and in contrast to DTIC, no ATase depletion was seen suggesting that insufficient concentrations of fotemustine and/or its metabolites were available to react with DNA to produce a depletion of PMC ATase activity.
Affiliation:
CRC Dept of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK.
Citation:
Dosage and cycle effects of dacarbazine (DTIC) and fotemustine on O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells. 1993, 67 (2):216-21 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
Feb-1993
URI:
http://hdl.handle.net/10541/100069
PubMed ID:
8431354
Type:
Article
Language:
en
ISSN:
0007-0920
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorLee, Siow Mingen
dc.contributor.authorThatcher, Nicken
dc.contributor.authorDougal, Marken
dc.contributor.authorMargison, Geoffrey Pen
dc.date.accessioned2010-06-01T11:29:53Z-
dc.date.available2010-06-01T11:29:53Z-
dc.date.issued1993-02-
dc.identifier.citationDosage and cycle effects of dacarbazine (DTIC) and fotemustine on O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells. 1993, 67 (2):216-21 Br. J. Canceren
dc.identifier.issn0007-0920-
dc.identifier.pmid8431354-
dc.identifier.urihttp://hdl.handle.net/10541/100069-
dc.description.abstractThere is increasing experimental evidence to suggest that endogenous expression of O6-alkylguanine-DNA-alkyltransferase (ATase) is a major factor in cellular resistance to certain chemotherapeutic agents including dacarbazine (DTIC). We have recently shown wide interindividual variation in the depletion and subsequent regeneration of ATase in peripheral blood mononuclear cells (PMCs) following DTIC and this has now been extended to ascertain whether or not depletion is related to dosage of DTIC used and repeated treatment cycles of chemotherapy. ATase levels were measured in three groups of 25 patients (pts) up to 24 h after receiving DTIC at 400 mg m-2, 500 mg m-2 or 800 mg m-2. Each group also received fotemustine (100 mg m-2), 4 h after DTIC. The lowest extent of ATase depletion (highest nadir ATase) was seen in patients receiving 400 mg m-2. The mean nadir ATase, expressed as a percentage of pre-treatment ATase, was respectively 56.3%, 26.4% and 23.9% for 400 mg m-2, 500 mg m-2 and 800 mg m-2. The median nadir of ATase activity for pts receiving 800 mg m-2 pts was at 4-6 h and for pts given lower doses it was at 2-3 h. In addition, repeated measures analysis of variance of observations before chemotherapy, then at 2, 3, 4, 6 and 18 h after chemotherapy provides some evidence that ATase was depleted to a lesser extent after cycle 1 than after subsequent cycles (P = 0.025). It also provides evidence that the change in ATase activity over time varied with dose and cycle. The findings can be interpreted on the basis of a dosage-dependent metabolism of DTIC to an agent capable of methylation of DNA and subsequent depletion of PMC ATase: with higher DTIC doses, the extent of ATase depletion may be limited by the pharmacokinetics of DTIC metabolism. PMC ATase was measured in another group of 8 pts at various times after receiving only fotemustine (100 mg m-2) and in contrast to DTIC, no ATase depletion was seen suggesting that insufficient concentrations of fotemustine and/or its metabolites were available to react with DNA to produce a depletion of PMC ATase activity.en
dc.language.isoenen
dc.subject.meshDacarbazine-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshDrug Administration Schedule-
dc.subject.meshDrug Resistance-
dc.subject.meshHumans-
dc.subject.meshLeukocytes, Mononuclear-
dc.subject.meshMelanoma-
dc.subject.meshMethyltransferases-
dc.subject.meshNitrosourea Compounds-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshOrganophosphorus Compounds-
dc.titleDosage and cycle effects of dacarbazine (DTIC) and fotemustine on O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells.en
dc.typeArticleen
dc.contributor.departmentCRC Dept of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK.en
dc.identifier.journalBritish Journal of Canceren
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