tretinoin and 1-2-bis(3-5-dioxopiperazin-1-yl)ethane

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.. 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).. 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.. These results suggest that ICRF-193 may be useful in the treatment of patients with APL.

Topics: Antineoplastic Agents; Catalysis; Cell Cycle; Cell Differentiation; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Cytarabine; Daunorubicin; Deoxycytidine; Diketopiperazines; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Inhibitors; Granulocytes; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplastic Stem Cells; Piperazines; Razoxane; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; RNA, Messenger; RNA, Neoplasm; Topoisomerase II Inhibitors; Tretinoin; Tumor Cells, Cultured; U937 Cells