Development and characterization of a cyclophosphamide-resistant subline of
acute myeloid leukemia in the Lewis x Brown Norway hybrid rat
TM Koelling, AM Yeager, J Hilton, DT Haynie and JM Wiley
Oncology Center, Johns Hopkins University School of Medicine, Baltimore,
MD.
Preclinical studies of resistance to alkylating agents in the Lewis x Brown
Norway hybrid (LBN) rat model of acute myeloid leukemia (AML) have hitherto
been limited by the sensitivity of LBN AML cells to cyclophosphamide (CY).
We developed a CY-resistant subline of LBN AML by serial intravenous (IV)
passage of AML cells followed by in vivo exposure to CY (100 mg/kg) 14 days
later. After 18 and subsequent passages, CY-treated AML cells remained
viable despite ex vivo incubation with 70 to 100 mumol/L
4-hydroperoxycyclophosphamide (4HC) or in vivo exposure to 100 to 300 mg/kg
of CY. Once established, resistance to incubation with 4HC was stable in
LBN AML cells after at least six serial in vivo passages without exposure
to CY. Nevertheless, both control and CY-treated AML cells demonstrated
similar dose- dependent sensitivity to 100 to 500 mumol/L phosphoramide
mustard (PhM), the active alkylating end-product of CY activation in vivo.
Levels of aldehyde dehydrogenase (ALDH), which inactivates CY by prevention
of formation of PhM, were significantly elevated in these CY- resistant AML
cells: cytosolic and particulate ALDH fractions from these cells were 11 to
13 times control with NAD cofactor and propanal substrate and three to four
times control with NADP cofactor and benzaldehyde substrate. Further
studies with this animal model of AML, in which resistance to CY is
mediated by elevated ALDH activity, may elucidate mechanisms for effective
elimination of drug-resistant leukemic cells ex vivo and in vivo.
Volume 76,
Issue 6,
pp. 1209-1213,
09/15/1990
Copyright © 1990 by The American Society of Hematology
