K. Kitamura et al., NEW RETINOIDS AND ARSENIC COMPOUNDS FOR THE TREATMENT OF REFRACTORY ACUTE PROMYELOCYTIC LEUKEMIA - CLINICAL AND BASIC STUDIES FOR THE NEXT-GENERATION, Cancer chemotherapy and pharmacology, 40, 1997, pp. 36-41
All-trans retinoic acid (ATRA) is a potent differentiation drug for ac
ute promyelocytic leukemia (APL) and is now incorporated into first-li
ne therapy. However, ATRA resistance has become a major clinical probl
em. This limitation has prompted the development of alternative agents
with desirable pharmacologic properties. We describe (1) our recent c
linical trial using the new synthetic retinoid Am80 to overcome acquir
ed resistance to ATRA and (2) basic in vitro effects of arsenic trioxi
de, a possible alternative to ATRA, on APL cells. A total of 19 APL pa
tients who had relapsed after ATRA-induced complete remissions (CRs) r
eceived 6 mg/m(2) Am80 p.o. daily until CR; 11 (58%) patients achieved
a CR between days 20 and 58 (median day 37). The in vitro sensitivity
to Am80, based on PML immunostaining, correlated well with the clinic
al effect in all patients tested. All three patients whose blasts were
sensitive to Am80 in vitro despite a poor response to ATRA achieved C
Rs. Thus, Am80 might be an effective compound for the treatment of ref
ractory APL and is a promising alternative retinoid. Since arsenic com
pounds have reportedly induced CRs in APL patients in China, we studie
d the in vitro effect of arsenic and other metal ions on myeloid leuke
mia cell lines. The effects of arsenic were limited mainly to APL cell
s, and the arsenic concentration was critical for the APL cell line NB
4: 1 mu M As3+ induced time-dependent apoptosis, whereas 0.1 mu M As3 allowed partial NB4 cell differentiation. Arsenic trioxide was equall
y effective when used on ATRA-resistant NB4 cells. Among the clinical
leukemia samples tested, the in vitro cytotoxic effects of As3+ were o
bserved selectively in APL cells, regardless of their ATRA sensitivity
. These data suggest that APL cells are sensitive to As3+ and that As3
+ acts on APL cells via a different pathway to ATRA.