New retinoids and arsenic compounds for the treatment of refractory acute promyelocytic leukemia: clinical and basic studies for the next generation.
All-trans retinoic acid (ATRA) is a potent differentiation drug for acute promyelocytic leukemia (APL) and is now incorporated into first-line therapy. However, ATRA resistance has become a major clinical problem. This limitation has prompted the development of alternative agents with desirable pharmacologic properties. We describe (1) our recent clinical trial using the new synthetic retinoid Am80 to overcome acquired resistance to ATRA and (2) basic in vitro effects of arsenic trioxide, a possible alternative to ATRA, on APL cells. A total of 19 APL patients who had relapsed after ATRA-induced complete remissions (CRs) received 6 mg/m2 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 clinical effect in all patients tested. All three patients whose blasts were sensitive to Am80 in vitro despite a poor response to ATRA achieved CRs. Thus, Am80 might be an effective compound for the treatment of refractory APL and is a promising alternative retinoid. Since arsenic compounds have reportedly induced CRs in APL patients in China, we studied the in vitro effect of arsenic and other metal ions on myeloid leukemia cell lines. The effects of arsenic were limited mainly to APL cells, and the arsenic concentration was critical for the APL cell line NB4: 1 microM As3+ induced time-dependent apoptosis, whereas 0.1 microM As3+ allowed partial NB4 cell differentiation. Arsenic trioxide was equally effective when used on ATRA-resistant NB4 cells. Among the clinical leukemia samples tested, the in vitro cytotoxic effects of As3+ were observed 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.
Kitamura
K
K
Department of Medicine, Nagoya University School of Medicine Branch Hospital, Japan.
Kiyoi
H
H
Yoshida
H
H
Tobita
T
T
Takeshita
A
A
Ohno
R
R
Naoe
T
T
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use*; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use*; D012008:Recurrence; D012074:Remission Induction; D012176:Retinoids / Q000494:pharmacology* / Q000627:therapeutic use*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; D001565:Benzoates; D010087:Oxides; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D000077237:Arsenic Trioxide