tretinoin and 2--deoxy-2--methylenecytidine

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

Since the establishment of all-trans retinoic acid (ATRA) differentiation therapy, the prognosis of acute promyelocytic leukemia (APL) has improved, and APL has become a curable subtype of acute myelocytic leukemia. Complete remission can be achieved with ATRA alone, but disease-free survival is still too short because of relapse. To overcome this drawback, ATRA has been used in combination with chemotherapeutic agents such as 1-beta-D-arabinofuranosylcytosine (araC) and daunorubicin. However, growth of the APL cell lines NB4 and HT93 is less sensitive to araC than to that of other myeloid leukemia cell lines such as HL-60 and U937. ATRA effectively induced granulocytic differentiation of NB4 and HT93 cells, whereas araC did not, even in a high concentration. A cytidine deaminase-resistant analogue of araC, 1-(2-deoxy-2-methylene-beta-D-erythro-pentofuranosyl)cytidine (DMDC), inhibited the growth of NB4 and HT-93 cells and was also effective on HL-60 and U937 cells. The promyelocytic cell lines were induced to differentiate by DMDC and other cytidine deaminase-resistant analogues. Among them, DMDC was the most potent in inducing differentiation and inhibiting the growth of NB4 cells. The ATRA-induced differentiation of NB4 cells was not augmented by araC, whereas combined treatment with ATRA and DMDC had more than additive effects in inducing the differentiation of NB4 cells. Similar results were observed in a primary culture of leukemia cells that had been freshly isolated from APL patients. These results suggest that DMDC may play a role in the treatment of APL.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Cell Division; Cytarabine; Cytidine Deaminase; Deoxycytidine; Drug Resistance, Neoplasm; Drug Synergism; Female; Growth Inhibitors; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Tretinoin; Tumor Cells, Cultured; U937 Cells