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(Received for publication, September 15, 1995; and in revised form, February
20, 1996) Human class 1 aldehyde dehydrogenase (hALDH-1) can oxidize
aldophosphamide, a key aldehyde intermediate in the activation pathway
of cyclophosphamide and other oxazaphosphorine (OAP) anti-cancer
alkylating agents. Overexpression of class 1 ALDH (ALDH-1) has been
observed in cells selected for survival in the presence of OAPs. We
used transfection to induce de novo expression of human ALDH-1
in V79/SD1 Chinese hamster cells to clearly quantitate the role of
hALDH-1 expression in OAP resistance. Messenger RNA levels correlated
well with hALDH-1 protein levels and enzyme activities (1.5-13.6
milliunits/mg with propionaldehyde/NAD
Volume 271,
Number 20,
Issue of May 17, 1996 pp. 11884-11890
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
ELEVATED CLASS 1 ALDH ACTIVITY IS CLOSELY CORRELATED WITH REDUCTION
IN DNA INTERSTRAND CROSS-LINKING AND LETHALITY
substrate,
compared to < 1 milliunit/mg in controls) in individual clonal
transfectant lines, and slot blot analysis confirmed the presence of
the transfected cDNA. Expressed ALDH activity was closely correlated (r = 0.99) with resistance to mafosfamide, up to
21-fold relative to controls. Transfectants were cross-resistant to
other OAPs but not to phosphoramide mustard, ifosfamide mustard,
melphalan, or acrolein. Resistance was completely reversed by
pretreatment with 25 µM diethylaminobenzaldehyde, a potent
ALDH inhibitor. Alkaline elution studies showed that expression of
ALDH-1 reduced the number of DNA cross-links commensurate with
mafosfamide resistance, and this reduction in cross-links was fully
reversed by the inhibitor. Thus, overexpression of human class 1 ALDH
alone is sufficient to confer OAP-specific drug resistance.
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