The consequences of doxorubicin quinone reduction in vivo in tumour tissue.

2.50
Hdl Handle:
http://hdl.handle.net/10541/108919
Title:
The consequences of doxorubicin quinone reduction in vivo in tumour tissue.
Authors:
Cummings, J; Willmott, N; Hoey, Brigid M; Marley, E S; Smyth, J F
Abstract:
A clear role for quinone reduction in the mechanism of action of doxorubicin has still to be established. There are three possible outcomes of this form of doxorubicin metabolism: (1) drug free radical formation, redox cycling and generation of reactive oxygen species (ROS) resulting in lipid peroxidation and DNA damage; (2) covalent binding of reactive drug intermediates to DNA; and (3) formation of an inactive 7-deoxyaglycone metabolite. In this work, the occurrence of each of these pathways has been studied in vivo in a subcutaneously growing rat mammary carcinoma (Sp 107). Doxorubicin was administered by direct intratumoural injection either as the free drug or incorporated in albumin microspheres (10-40 microns diameter). There was no evidence of an increase in lipid peroxidation over background after either treatment at any time point studied. In fact, doxorubicin administration resulted in a statistically significant reduction in lipid peroxidation at the later time points studied compared to control (no drug treatment), e.g. 24 hr: control, 21.7 +/- 2.8 SD nmol malondialdehyde/g tissue; free doxorubicin (70 micrograms drug), 14.5 +/- 4.0 SD nmol/g (P < 0.01 Student's t-test) and doxorubicin microspheres (70 micrograms drug), 17.4 +/- 1.1 nmol/g (P < 0.05). Covalent binding to DNA was measured by a 32P-post-labelling technique. Low levels of four putative drug-DNA adducts were detected; however, there were no qualitative or quantitative differences in profiles between free drug and microspheres. High 7-deoxyaglycone metabolite concentrations comparable to the parent drug itself were detected after administration of microspheres (3.0 micrograms/g +/- 1.7 SD at 24 hr and 3.1 micrograms/g +/- 1.1 SD at 48 hr). In contrast, these metabolites were present at levels close to the limit of detection of our HPLC assay after free drug (0.04 microgram/g +/- 0.03 SD at 24 hr and 0.02 microgram/g +/- 0.03 SD at 48 hr). Thus, 7-deoxyaglycone metabolite formation can occur in tumour tissue (indicating active drug quinone reduction) without concomitant increases in the level of lipid peroxidation or the levels of drug-DNA adducts. In conclusion, the main biological consequence of doxorubicin quinone reduction in vivo in tumour tissue would appear to be drug inactivation to a 7-deoxyaglycone metabolite rather than drug activation to DNA reactive species or ROS.
Affiliation:
Imperial Cancer Research Fund, Western General Hospital, Edinburgh, U.K.
Citation:
The consequences of doxorubicin quinone reduction in vivo in tumour tissue. 1992, 44 (11):2165-74 Biochem. Pharmacol.
Journal:
Biochemical Pharmacology
Issue Date:
1-Dec-1992
URI:
http://hdl.handle.net/10541/108919
DOI:
10.1016/0006-2952(92)90343-H
PubMed ID:
1472081
Type:
Article
Language:
en
ISSN:
0006-2952
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorCummings, Jen
dc.contributor.authorWillmott, Nen
dc.contributor.authorHoey, Brigid Men
dc.contributor.authorMarley, E Sen
dc.contributor.authorSmyth, J Fen
dc.date.accessioned2010-08-03T10:57:37Z-
dc.date.available2010-08-03T10:57:37Z-
dc.date.issued1992-12-01-
dc.identifier.citationThe consequences of doxorubicin quinone reduction in vivo in tumour tissue. 1992, 44 (11):2165-74 Biochem. Pharmacol.en
dc.identifier.issn0006-2952-
dc.identifier.pmid1472081-
dc.identifier.doi10.1016/0006-2952(92)90343-H-
dc.identifier.urihttp://hdl.handle.net/10541/108919-
dc.description.abstractA clear role for quinone reduction in the mechanism of action of doxorubicin has still to be established. There are three possible outcomes of this form of doxorubicin metabolism: (1) drug free radical formation, redox cycling and generation of reactive oxygen species (ROS) resulting in lipid peroxidation and DNA damage; (2) covalent binding of reactive drug intermediates to DNA; and (3) formation of an inactive 7-deoxyaglycone metabolite. In this work, the occurrence of each of these pathways has been studied in vivo in a subcutaneously growing rat mammary carcinoma (Sp 107). Doxorubicin was administered by direct intratumoural injection either as the free drug or incorporated in albumin microspheres (10-40 microns diameter). There was no evidence of an increase in lipid peroxidation over background after either treatment at any time point studied. In fact, doxorubicin administration resulted in a statistically significant reduction in lipid peroxidation at the later time points studied compared to control (no drug treatment), e.g. 24 hr: control, 21.7 +/- 2.8 SD nmol malondialdehyde/g tissue; free doxorubicin (70 micrograms drug), 14.5 +/- 4.0 SD nmol/g (P < 0.01 Student's t-test) and doxorubicin microspheres (70 micrograms drug), 17.4 +/- 1.1 nmol/g (P < 0.05). Covalent binding to DNA was measured by a 32P-post-labelling technique. Low levels of four putative drug-DNA adducts were detected; however, there were no qualitative or quantitative differences in profiles between free drug and microspheres. High 7-deoxyaglycone metabolite concentrations comparable to the parent drug itself were detected after administration of microspheres (3.0 micrograms/g +/- 1.7 SD at 24 hr and 3.1 micrograms/g +/- 1.1 SD at 48 hr). In contrast, these metabolites were present at levels close to the limit of detection of our HPLC assay after free drug (0.04 microgram/g +/- 0.03 SD at 24 hr and 0.02 microgram/g +/- 0.03 SD at 48 hr). Thus, 7-deoxyaglycone metabolite formation can occur in tumour tissue (indicating active drug quinone reduction) without concomitant increases in the level of lipid peroxidation or the levels of drug-DNA adducts. In conclusion, the main biological consequence of doxorubicin quinone reduction in vivo in tumour tissue would appear to be drug inactivation to a 7-deoxyaglycone metabolite rather than drug activation to DNA reactive species or ROS.en
dc.language.isoenen
dc.subjectCancer DNAen
dc.subjectExperimental Mammary Canceren
dc.subjectCancer Transplantationen
dc.subject.meshAlbumins-
dc.subject.meshAnimals-
dc.subject.meshDNA, Neoplasm-
dc.subject.meshDoxorubicin-
dc.subject.meshFemale-
dc.subject.meshInjections, Intralesional-
dc.subject.meshIsotope Labeling-
dc.subject.meshLipid Peroxidation-
dc.subject.meshMammary Neoplasms, Experimental-
dc.subject.meshMicrospheres-
dc.subject.meshModels, Biological-
dc.subject.meshNaphthacenes-
dc.subject.meshNeoplasm Transplantation-
dc.subject.meshOxidation-Reduction-
dc.subject.meshPhosphorus Radioisotopes-
dc.subject.meshQuinones-
dc.subject.meshRats-
dc.subject.meshRats, Inbred Strains-
dc.subject.meshTissue Distribution-
dc.titleThe consequences of doxorubicin quinone reduction in vivo in tumour tissue.en
dc.typeArticleen
dc.contributor.departmentImperial Cancer Research Fund, Western General Hospital, Edinburgh, U.K.en
dc.identifier.journalBiochemical Pharmacologyen
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