The catalytic DNA topoisomerase II inhibitor ICRF-193 and all-trans retinoic acid cooperatively induce granulocytic differentiation of acute promyelocytic leukemia cells: candidate drugs for chemo-differentiation therapy against acute promyelocytic leukemia.
OBJECTIVE
Although all-trans retinoic acid (ATRA) can bring about complete remission of acute promyelocytic leukemia (APL), the incidence of early recurrence is considerably high. Thus, chemotherapeutic agents, such as anthracycline agents or cytosine arabinoside (AraC), are generally co-administered with ATRA. The therapeutic outcome of APL patients has significantly improved by chemo-differentiation therapy. Late-phase toxicities, such as cardiotoxicity and secondary carcinogenesis, are becoming clinically important. Therefore, we must identify the most suitable chemotherapeutic agents for the treatment of APL.


METHODS
We examined the effects of ICRF-193 and several other anticancer drugs on the growth and differentiation of APL cell lines (NB4 and HT-93) and other myeloid leukemia cell lines (HL-60 and U937).


RESULTS
If anticancer agents were available that not only inhibited the proliferation of APL cells but also induced their differentiation, they would be very useful for the treatment of APL. DNR slightly induced the differentiation of APL cells. On the other hand, other DNA topoisomerase II inhibitors, such as ICRF-154 and ICRF-193, significantly induced the differentiation of APL cell lines and leukemia cells freshly isolated from APL patients. These drugs effectively cooperated with ATRA in inhibiting the growth and inducing the differentiation of APL cells, whereas DNR did not. The incidence of cardiotoxicity and secondary carcinogenesis associated with ICRF-193 are much lower than that with DNR.


CONCLUSIONS
These results suggest that ICRF-193 may be useful in the treatment of patients with APL.
Niitsu
Nozomi
N
Department of Hematology and Internal Medicine IV, Kitasato University School of Medicine, Kanagawa, Japan. nniitsu@med.kitasato-u.ac.jp
Higashihara
Masaaki
M
Honma
Yoshio
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002384:Catalysis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D054659:Diketopiperazines; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006098:Granulocytes / Q000166:cytology; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D011929:Razoxane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D059005:Topoisomerase II Inhibitors; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D020298:U937 Cells / Q000166:cytology / Q000187:drug effects
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D010879:Piperazines; C000607071:RARA protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D059005:Topoisomerase II Inhibitors; C082925:retinoic acid receptor beta; D003561:Cytarabine; D003841:Deoxycytidine; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D014212:Tretinoin; D011929:Razoxane; C056034:2'-deoxy-2'-methylenecytidine; C000283:1,2-bis(3,5-dioxopiperazin-1-yl)ethane; D003630:Daunorubicin