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Blood, 1 January 2001, Vol. 97, No. 1, pp. 264-269
NEOPLASIA
Combined effect of all-trans retinoic acid and arsenic
trioxide in acute promyelocytic leukemia cells in vitro and in
vivo
Yongkui Jing,
Long Wang,
Lijuan Xia,
Guo-qiang Chen,
Zhu Chen,
Wilson H. Miller, and
Samuel Waxman
From the Department of Medicine, Division of Medical
Oncology, Mount Sinai School of Medicine, New York, NY; the Shanghai
Institute of Hematology, Shanghai Second Medical University, Shanghai,
China; and Lady Davis Institute for Medical Research, McGill
University, Montreal, QC, Canada.
All-trans retinoic acid (tRA) and arsenic trioxide
(As2O3) induce non-cross-resistant complete
clinical remission in patients with acute promyelocytic leukemia with
t(15;17) translocation and target PML-RAR , the leukemogenic protein,
by different pathways suggesting a possible therapeutic synergism. To
evaluate this possibility, this study examined the effect of
As2O3 on tRA-induced differentiation and,
conversely, the effect of tRA on As2O3-induced apoptosis. As2O3 at subapoptotic concentrations
(0.5 µM) decreased tRA-induced differentiation in NB4 cells but
synergized with atRA to induce differentiation in tRA-resistant NB4
subclones MR-2 and R4 cells as measured by nitroblue
tetrazolium reduction and tRA-inducible genes
(TTGII, RAR , RIG-E). tRA cleaved PML-RAR into distinct fragments in NB4 but not in tRA-resistant MR-2 or R4
cells, whereas As2O3 completely degraded
PML-RAR in all 3 cell lines. As2O3-induced
apoptosis was decreased by tRA pretreatment of NB4 cells but not of R4
cells and was associated with a strong induction of Bfl-1/A1
expression, a Bcl-2 protein family member. Severe combined
immunodeficient mice bearing NB4 cells showed an additive survival
effect after sequential treatment, but a toxic effect was observed
after simultaneous treatment with tRA and
As2O3. These data suggest that combined
As2O3 and tRA treatment may be more effective
than single agents in tRA-resistant patients. Although in vitro data do
not always translate to in vivo response, toxicity and potential drug
antagonism may be diminished by decreasing the concentration of
As2O3 when given at the same time with
therapeutic levels of tRA.
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