In vivo depletion of O6-alkylguanine-DNA-alkyltransferase in lymphocytes and melanoma of patients treated with CB 10-277, a new DTIC analogue.

2.50
Hdl Handle:
http://hdl.handle.net/10541/108140
Title:
In vivo depletion of O6-alkylguanine-DNA-alkyltransferase in lymphocytes and melanoma of patients treated with CB 10-277, a new DTIC analogue.
Authors:
Lee, Siow Ming; Thatcher, Nick; Crowther, Derek; Margison, Geoffrey P
Abstract:
There is increasing evidence to suggest that alkylation of guanine residues in DNA at the O6 position is the critical cytotoxic event following treatment with dacarbazine (DTIC) and related drugs and that endogenous O6-alkylguanine-DNA alkyltransferase (ATase) gene expression may be a major factor in resistance to such agents. 1-p-Carboxyl-3,3-dimethylphenyltriazene (CB10-277) was recently selected for clinical evaluation as a DTIC analogue with improved solubility, stability and (possibly) metabolic activation. Serial ATase levels were measured in peripheral blood lymphocytes of nine patients and in biopsied melanoma samples of two patients undergoing treatment with 24-h continuous infusion of CB10-277 (12 g/m2). Wide individual variations in pre-treatment levels as well as in the post-treatment depletion of lymphocyte ATase were seen. Progressive depletion of lymphocyte ATase was seen during continuous infusion of CB10-277 in all patients. Complete suppression of lymphocyte ATase activity occurred in two patients whose pre-treatment ATase levels were low. Immediately following completion of the CB10-277 infusion, the median ATase activity was 17% of pre-treatment levels (range, 0-67%). At 24 h after the end of the infusion, no recovery of lymphocyte ATase activity was observed in six patients, but significant recovery to 50%, 100% and 102% of pre-treatment activity occurred in the other three. In three patients who returned for subsequent cycles of chemotherapy at 4 weeks after the first dose, pre-treatment ATase levels showed a 3- to 4-fold increase relative to the original pre-treatment values. A significant correlation was found between the extent of ATase depletion and the initial lymphocyte ATase levels (r = 0.725, P < 0.05). Haematological toxicity developed in two patients and was associated with low pre-treatment ATase activity. Depletion of tumour ATase activity was noted in these patients, with residual activity amounting to 8% and 11% of pre-treatment levels, respectively, in the biopsies melanoma tissues. These results indicate extensive metabolism of CB10-277 to a methylating agent capable of mediating alkylation of DNA and subsequent depletion of lymphocyte and tumour ATase levels and further indicate that the effects on lymphocytes may reflect effects on the target tumour.
Affiliation:
CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, U.K.
Citation:
In vivo depletion of O6-alkylguanine-DNA-alkyltransferase in lymphocytes and melanoma of patients treated with CB 10-277, a new DTIC analogue. 1992, 31 (3):240-6 Cancer Chemother Pharmacol
Journal:
Cancer Chemotherapy and Pharmacology
Issue Date:
1992
URI:
http://hdl.handle.net/10541/108140
PubMed ID:
1464162
Type:
Article
Language:
en
ISSN:
0344-5704
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.authorCrowther, Dereken
dc.contributor.authorMargison, Geoffrey Pen
dc.date.accessioned2010-07-22T08:59:56Z-
dc.date.available2010-07-22T08:59:56Z-
dc.date.issued1992-
dc.identifier.citationIn vivo depletion of O6-alkylguanine-DNA-alkyltransferase in lymphocytes and melanoma of patients treated with CB 10-277, a new DTIC analogue. 1992, 31 (3):240-6 Cancer Chemother Pharmacolen
dc.identifier.issn0344-5704-
dc.identifier.pmid1464162-
dc.identifier.urihttp://hdl.handle.net/10541/108140-
dc.description.abstractThere is increasing evidence to suggest that alkylation of guanine residues in DNA at the O6 position is the critical cytotoxic event following treatment with dacarbazine (DTIC) and related drugs and that endogenous O6-alkylguanine-DNA alkyltransferase (ATase) gene expression may be a major factor in resistance to such agents. 1-p-Carboxyl-3,3-dimethylphenyltriazene (CB10-277) was recently selected for clinical evaluation as a DTIC analogue with improved solubility, stability and (possibly) metabolic activation. Serial ATase levels were measured in peripheral blood lymphocytes of nine patients and in biopsied melanoma samples of two patients undergoing treatment with 24-h continuous infusion of CB10-277 (12 g/m2). Wide individual variations in pre-treatment levels as well as in the post-treatment depletion of lymphocyte ATase were seen. Progressive depletion of lymphocyte ATase was seen during continuous infusion of CB10-277 in all patients. Complete suppression of lymphocyte ATase activity occurred in two patients whose pre-treatment ATase levels were low. Immediately following completion of the CB10-277 infusion, the median ATase activity was 17% of pre-treatment levels (range, 0-67%). At 24 h after the end of the infusion, no recovery of lymphocyte ATase activity was observed in six patients, but significant recovery to 50%, 100% and 102% of pre-treatment activity occurred in the other three. In three patients who returned for subsequent cycles of chemotherapy at 4 weeks after the first dose, pre-treatment ATase levels showed a 3- to 4-fold increase relative to the original pre-treatment values. A significant correlation was found between the extent of ATase depletion and the initial lymphocyte ATase levels (r = 0.725, P < 0.05). Haematological toxicity developed in two patients and was associated with low pre-treatment ATase activity. Depletion of tumour ATase activity was noted in these patients, with residual activity amounting to 8% and 11% of pre-treatment levels, respectively, in the biopsies melanoma tissues. These results indicate extensive metabolism of CB10-277 to a methylating agent capable of mediating alkylation of DNA and subsequent depletion of lymphocyte and tumour ATase levels and further indicate that the effects on lymphocytes may reflect effects on the target tumour.en
dc.language.isoenen
dc.subjectBrain Canceren
dc.subjectLiver Canceren
dc.subjectLung Canceren
dc.subjectSkin Canceren
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshBrain Neoplasms-
dc.subject.meshDacarbazine-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshLiver Neoplasms-
dc.subject.meshLung Neoplasms-
dc.subject.meshLymphatic Metastasis-
dc.subject.meshLymphocytes-
dc.subject.meshMale-
dc.subject.meshMelanoma-
dc.subject.meshMethyltransferases-
dc.subject.meshMiddle Aged-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshSkin Neoplasms-
dc.subject.meshTriazenes-
dc.titleIn vivo depletion of O6-alkylguanine-DNA-alkyltransferase in lymphocytes and melanoma of patients treated with CB 10-277, a new DTIC analogue.en
dc.typeArticleen
dc.contributor.departmentCRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, U.K.en
dc.identifier.journalCancer Chemotherapy and Pharmacologyen
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