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First published on August 12, 2004; DOI: 10.1124/mol.104.000596

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Received for publication May 12, 2004.
Revised July 8, 2004.
Accepted for publication August 11, 2004.

p53 elevation in relation to levels and cytotoxicity of mono- and bi-functional melphalan DNA adducts

Katherine A. Gould 1, Cally Nixon 1, Michael J. Tilby 1*

1 Northern Institute for Cancer Research

* Address correspondence to: E-mail: m.j.tilby{at}ncl.ac.uk

Abstract

The hypothesis tested was that bifunctional DNA adducts formed by a nitrogen mustard-based anti-cancer drug were more efficient than monofunctional adducts at causing elevation of p53, consistent with the difference in cytotoxicity. Human leukaemia cell line ML-1 was exposed for 1 hour to melphalan, or its monofunctional derivative, monohydroxymelphalan. Levels of DNA-adducts, measured by specific immunoassay, were linearly related to concentration of alkylating agent. Monohydroxymelphalan formed twice as many adducts as did equal concentrations of melphalan. After removal of alkylating agent, adduct levels were maintained or increased slightly up to 8 h and then declined by 27-44 % by 24 h. Alkaline elution analyses confirmed the absence of detectable DNA inter-strand cross-links in cells exposed to monohydroxymelphalan. DNA single strand breaks were detected following monohydroxymelphalan but not melphalan. Levels of p53 were quantified by sensitive fluorogenic ELISA at intervals up to 24 h after exposure of cells to various concentrations of melphalan and monohydroxymelphalan. The level of initially formed DNA adducts needed to cause elevation of p53 from a base-line level of 0.5 ng/mg total protein to 2 ng/mg were 5 to 8-fold higher for monohydroxymelphalan than melphalan. The concentrations of melphalan and monohydroxymelphalan (±S.D.) causing 50 % growth inhibition were 1.2 ±0.4 and 28.1 ±1.6 µg/ml respectively, a difference of 23-fold. The adduct levels induced by these exposures were 9.3 and 420 nmoles / g DNA for melphalan and monohydroxymelphalan respectively, a difference of 45-fold which is considerably greater than the difference in efficacy at elevating p53.


Key words: DNA damage and repair, Mechanisms of cell killing/apoptosis, Tumor suppressors


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