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Cancer Chemother Pharmacol. 2000;45(2):111-9.

Evaluation of the alkaline comet assay and urinary 3-methyladenine excretion for monitoring DNA damage in melanoma patients treated with dacarbazine and tamoxifen.

Author information

1
Imperial Cancer Research Fund Medical Oncology Unit, Churchill Hospital, Oxford OX3 7LJ, UK.

Abstract

PURPOSE:

To develop, using dacarbazine as a model, reliable techniques for measuring DNA damage and repair as pharmacodynamic endpoints for patients receiving chemotherapy.

METHODS:

A group of 39 patients with malignant melanoma were treated with dacarbazine 1 g/m(2) i.v. every 21 days. Tamoxifen 20 mg daily was commenced 24 h after the first infusion and continued until 3 weeks after the last cycle of chemotherapy. DNA strand breaks formed during dacarbazine-induced DNA damage and repair were measured in individual cells by the alkaline comet assay. DNA methyl adducts were quantified by measuring urinary 3-methyladenine (3-MeA) excretion using immunoaffinity ELISA. Venous blood was taken on cycles 1 and 2 for separation of peripheral blood lymphocytes (PBLs) for measurement of DNA strand breaks.

RESULTS:

Wide interpatient variation in PBL DNA strand breaks occurred following chemotherapy, with a peak at 4 h (median 26.6 h, interquartile range 14.75-40.5 h) and incomplete repair by 24 h. Similarly, there was a range of 3-MeA excretion with peak levels 4-10 h after chemotherapy (median 33 nmol/h, interquartile range 20.4-48.65 nmol/h). Peak 3-MeA excretion was positively correlated with DNA strand breaks at 4 h (Spearman's correlation coefficient, r=0.39, P=0.036) and 24 h (r=0.46, P=0.01). Drug-induced emesis correlated with PBL DNA strand breaks (Mann Whitney U-test, P=0.03) but not with peak 3-MeA excretion.

CONCLUSIONS:

DNA damage and repair following cytotoxic chemotherapy can be measured in vivo by the alkaline comet assay and by urinary 3-MeA excretion in patients receiving chemotherapy.

PMID:
10663625
DOI:
10.1007/s002800050018
[Indexed for MEDLINE]

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