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Induction of Differentiation in Acute Promyelocytic Leukemia Cells by
9-cis Retinoic Acid  -Tocopherol Ester (9-cis
Tretinoin Tocoferil)
Makoto Makishima,
Kazuhiko Umesono,
Koichi Shudo,
Tomoki Naoe,
Kenji Kishi, and
Yoshio Honma
From the Department of Chemotherapy, Saitama Cancer Center Research
Institute, Saitama, Japan; the Institute for Virus Research, Kyoto
University, Kyoto, Japan; the Faculty of Pharmaceutical Sciences,
University of Tokyo, Tokyo, Japan; the Department of Infectious
Diseases, Nagoya University School of Medicine, Nagoya, Japan; and the
First Department of Internal Medicine, Niigata University School of
Medicine, Niigata, Japan.
Acute promyelocytic leukemia (APL) has a specific genetic
rearrangement between the retinoic acid receptor (RAR)- gene
and the pml nuclear protein gene. All-trans retinoic
acid (ATRA) induces granulocytic differentiation of APL-derived cells
and is used to treat APL patients. However, ATRA interacts with normal
cells with RAR throughout the entire body, and when used at high doses or over a long duration, it induces several adverse effects. The development of drugs that selectively act on APL cells may contribute to increasing the therapeutic efficacy of APL treatment as well as
elucidating the mechanisms of response to ATRA. In this study, 9-cis retinoic acid -tocopherol ester (9CTT) inhibited the
proliferation of APL-derived NB4 and HT93 cells and induced
differentiation markers, such as granulocytic maturation, nitroblue
tetrazolium reduction, and CD11b expression, in these cells. The
effects of 9CTT on non-APL cells, including HL-60 and U937 cells, were
much weaker than those on APL cells, and tretinoin tocoferil (TT), which is an -tocopherol ester of ATRA, did not induce the
differentiation of APL cells as effectively as 9CTT. The
differentiation-inducing effects of 9CTT were inhibited by RAR
antagonists. 9CTT and TT similarly induced the transactivating activity
of RARs, but were not effective on RXRs. 9CTT downregulated the
expression of PML/RAR- protein more effectively than TT, which
suggests that it may be involved in the selectivity of 9CTT against APL
cells. Interestingly, 9CTT enhanced the differentiation of APL cells
induced by ATRA, 9-cis retinoic acid, and synthetic
retinobenzoic acids. Combined with 1,25-dihydroxyvitamin
D3 (VD3), 9CTT also more than additively induced the differentiation of APL cells. Thus, 9CTT, alone or in
combination with other retinoids or VD3, may be useful for the treatment of APL.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4715-4726
© 1998 by The American Society of Hematology.
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