Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several new cytostatic drugs have entered clinical phase I-II studies for the treatment of leukemia: the most promising are pyrimidine analogs such as 5-aza-cytidine, 5-aza-2'-deoxycytidine, 5-aza-cytosine arabinoside, and 2',2'-difluorodeoxycytidine. Fludarabine, a fluorinated purine analog, appears to be active in CLL and multiple myeloma. Deoxycoformycin, an adenosine analog, showed good activity in the treatment of hairy cell leukemia and T-cell neoplasias. 2-chloro-deoxyadenosine has recently been introduced into the treatment of CLL and hairy-cell leukemia refractory to deoxycoformicin. Tiazofurin, an antimetabolite which interferes with nicotine-adenine-dinucleotide (NAD) metabolism, has been applied in CML blast crisis. Other agents include 13-cis retinoic acid and 1, 25-dihydroxy vitamin D3 as differentiation inducers, and homoharringtonine, an alkylating agent which is widely used for ANLL treatment in China. Among new anthracyclines, aclarubicin, idarubicin, THP-adriamycin and fluoro-adriamycin should be mentioned. Mitoxantrone, a substituted anthraquinone, has successfully been applied in the treatment of relapsed and refractory ANLL. Amsacrine (m-AMSA), finally, is a synthetic aminoacridine which intercalates into DNA and inhibits DNA topoisomerase II. m-AMSA is not cross-resistant to anthracyclines and has been particularly active in ANLL treatment. Studies using m-AMSA alone or in combination revealed comparable results to anthracycline--containing regimens. Cardiotoxicity of the anthracycline congestive type has not been observed with m-AMSA. The EORTC Leukemia Cooperative Group has successfully used m-AMSA in several trials prepositioning this drug stepwise: from relapsed and refractory ANLL, into intensive maintenance treatment during first remission in ANLL, and, still on-going, into intensive consolidation.
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PMID:New drugs in the treatment of acute and chronic leukemia with some emphasis on m-AMSA. 206 23

Seventy-seven patients with relapsed or refractory acute leukemia and three with acute blastic chronic myeloid leukemia (CML) were treated in an open Phase II study using mitoxantrone 12 mg/m2 intravenously daily X 5 days. Complete remission (CR) was achieved in 32 of 80 (40%), including 23/45 (52%) with relapsed acute nonlymmphocytic leukemia (ANLL), four of 12 (33%) with relapsed acute lymphocytic leukemia ALL, four of 17 (24%) with ANLL refractory to daunorubicin + cytosine arabinoside, and one of three (33%) with refractory ALL. None of the patients with acute blastic CML achieved CR. Median survival time for all patients was 121 days. Median duration of complete response was 303 days with ten of 32 patients in continuing CR for periods varying from 44+ to 1210+ days. Apart from moderately prolonged hematologic suppression toxicity was mild and subjective side effects were tolerable. Mitoxantrone is an active agent in the treatment of acute leukemia and demonstrates incomplete cross resistance with duanorubicin. Mitoxantrone should be considered for first-line therapy in ANLL.
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PMID:Mitoxantrone for refractory and relapsed acute leukemia. 219 40

Mitoxantrone is a substituted anthraquinone with considerable activity against human acute leukemia. The authors' goal was to treat patients with continuous infusion mitoxantrone in order to maintain cytotoxic steady state levels with acceptable toxicity and to assess the results. Daily mitoxantrone levels showed a mean steady state plasma level of 16.8 +/- 1.4 ng/ml (range, 9.1-25.1) with a systemic clearance of 519 +/- 47 ml/minute/m2. No drug accumulation occurred. Mitoxantrone was undetectable 24 hours postinfusion. All patients, including two patients with chronic myelogenous leukemia in blast phase, had greater than 90% reduction in leukemia cell mass (marrow cellularity X percent leukemia cells) by day 6. However, six patients received 3 days of etoposide at that point because of residual acute nonlymphocytic leukemia (ANLL). Overall four patients (36%) had a complete remission; one additional patient had a bone marrow remission but also had a persistent granulocytic sarcoma. Toxicities included severe but tolerable myelosuppression, mucositis, and hepatic dysfunction. There was no correlation between mitoxantrone levels, toxicity, or clinical response. Continuous infusion produces cytotoxic plasma mitoxantrone levels and rapid clearing of ANLL from bone marrow. Further dose escalation may be possible.
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PMID:Continuous infusion mitoxantrone in relapsed acute nonlymphocytic leukemia. 234 Apr 63

Recently, treatment of leukemia has shown remarkable progress. Development of new antileukemic drugs, improvements in supportive care and rapid progress in bone marrow transplantation have resulted in considerable changes in responses in refractory leukemia. Chemotherapy for Acute leukemia: By the introduction of Mitoxantrone and etoposide and a new combination chemotherapy including them, a high remission rate of acute leukemia is obtained, but because of the high relapse rate the 5-year survival rates in our center were 20% for adult ALL and 18% for ANL. In order to reduce the relapse rate, a new regimen containing intensive consolidation treatments is now being studied in a nation-wide cooperative study. BMT: In 1987, 160 BMTs including 75 acute leukemia and 28 CML, were registered in Japan. The improvements in the management of graft versus host disease (GVHD) and infections in the granulocytopenic period has contributed to the marked increase in the long-term survival rate after BMT. In our center the long-term survival rate rose from 20% before 1984 to 85% after 1985. Colony stimulating factor: Macrophage-colony stimulating factor (M-CSF) and granulocyte colony stimulating factor (G-CSF) were studied in Japan. In the double-blind placebo controlled study of M-CSF, a significantly shorter duration of granulocytopenia, as well as a significantly lower rate of failure of BMT (i.e., death or retransplant) was observed. In the phase II study of G-CSF, a rapid recovery of granulocytes after chemotherapy or BMT and marked efficacy on infection in granulocytopenic patients were observed.
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PMID:[Multidisciplinary treatment of leukemia]. 265 20

Calcium channel-blocking agent verapamil has been established to be an effective drug to modulate the action of many anticancer drugs. In this study, we examined the effect of verapamil on the cytotoxicity of mitoxantrone in human chronic myeloid leukemia (CML) cells. Mitoxantrone alone exhibited dose-dependent inhibition of DNA biosynthesis in CML cells. The addition of verapamil (3.3 microM) enhanced the responsiveness of CML cells to mitoxantrone (1 microgram/ml) cytotoxicity indicated by significant increased inhibition of thymidine incorporation (p less than 0.001). The present study demonstrates the possible efficacy of verapamil in the chemotherapy of CML with mitoxantrone.
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PMID:Modulation of mitoxantrone cytotoxicity by verapamil in human chronic myeloid leukemia cells. 271 Apr 77

Mitoxantrone, a new anticancer drug has DNA-binding properties similar to anthracycline antibiotics. In the present studies, effect of the drug has been tested in vitro on human chronic myeloid leukemia cells at 37 degrees C and 42 degrees C. Inhibition of 3H-tritiated thymidine incorporation in the drug-treated cells compared with untreated cells has been used as the parameter of cytotoxicity of the drug and hyperthermia. Cell samples from 11 CML patients who did not receive any chemotherapy showed less response to the drug at 0.5 micrograms/ml and 1 microgram/ml at 37 degrees C. Exposure of CML cells to 42 degrees C for 2 h indicated 13 to 44% inhibition in 3H-TdR incorporation. However, when CML cells were exposed to mitoxantrone for 2 h at 42 degrees C the 3H-thymidine incorporation was inhibited to the extent of 27 to 71%, indicating greater cellular damage with this combination.
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PMID:Effect of mitoxantrone on human chronic myeloid leukemia cells in vitro, combined with hyperthermia. 346 80

Mitoxantrone, a new anthracenedione, was administered to thirty-nine patients with relapsed and refractory acute leukemia and to 12 patients with blastic crisis of chronic myelogenous leukemia between August 1981 and September 1984. Eleven patients were not evaluable and 40 were analysed. There were 24 males and 16 females with a median age of 37 yrs (range 6-73 yrs). Three of these were less than 15 yrs and 7 more than 60 yrs. The initial dose employed was 1.9 mg/m2/day X 5. Although eventually a starting dose of 12.3 mg/m2/day X 5 was used, about one half of cases were given more than 5 mg/m2/day X 5 by i.v. bolus. Among 25 patients with acute non-lymphocytic leukemia, there were 4 complete and 6 partial remissions. Among 7 patients with acute lymphocytic leukemia there was one complete remission and one partial remission. All patients except one who attained remissions had received prior anthracyclines. One of 8 patients with blastic crisis of chronic myelogenous leukemia had a partial remission. The durations of complete remission were 1, 1, 5+, 13+ and 17 weeks, respectively. Side-effects showed expected bone marrow depression. Mucositis occurred in ten patients. Gastrointestinal symptoms were noted in approximately 50%, but were mostly mild. Mild alopecia occurred occasionally. The trials were too short to allow evaluation of possible cardiac toxicity. These data indicate that mitoxantrone is non-toxic but hematological and a promising single drug for use in treating relapsed and refractory acute leukemia and suggest that further study would be worthwhile in order to identify its role in the first-line therapy of acute leukemia.
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PMID:[Phase II trial of mitoxantrone in patients with relapsed and refractory acute leukemia]. 346 30

Mitoxantrone was evaluated in a multi-institution trial to define the effective dose for treating acute leukemia, to evaluate its toxicity, and to assess the induction rates for the different types of acute leukemia. Fifty-seven patients have been treated. Of the 24 patients receiving mitoxantrone (10 mg/m2/day X 5), one of nine with acute nonlymphoblastic leukemia (ANLL) in relapse, one of five with acute lymphoblastic leukemia in relapse, and one of seven with blastic chronic myelogenous leukemia achieved remission. At a dose of 12 mg/m2/day X 5, seven of 16 patients with ANLL in relapse, none of six with acute lymphoblastic leukemia in relapse, and one of five with blastic chronic myelogenous leukemia achieved remission. At both dose levels, there was no response in patients who had failed to achieve a prior remission. Toxic effects included nausea/vomiting, stomatitis, and hepatic dysfunction. Nine of the 57 patients treated experienced cardiac events but cardiac toxicity seemed clinically significant in only three. We conclude that mitoxantrone, at a dose of 12 mg/m2/day X 5, is effective therapy for ANLL. Trials combining mitoxantrone with other agents are needed.
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PMID:Phase I-II trial of mitoxantrone in acute leukemia. 385 86

Twenty-four patients with acute leukemia or blast crisis (BC) of chronic myelocytic leukemia (CML) in relapse or refractory to standard chemotherapy, were eligible for treatment with mitoxantrone. Mitoxantrone (Novantrone; dihydroxyanthracenedione) was administered in a dose of 8-13 mg/m2 on five consecutive days. Five of 20 evaluable patients were induced into complete remission, one patient achieved a partial remission. Side-effects included moderate to severe bone marrow suppression, moderate mucositis and hair loss. No cardiotoxicity was observed. We believe that mitoxantrone is an active agent in the treatment of acute leukemia and suggest further studies in combination chemotherapy.
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PMID:Mitoxantrone in the treatment of relapsed and refractory acute leukemia. 386 Apr 90

Mitoxantrone (Novantrone; 1, 4-dihydroxy-5, 8-bis [[2-[(2-hydroxyethyl) amino]ethyl]amino-] 9, 10 anthracenedione dihydrochloride (NSC 301739] is a synthetic anthracenedione with intercalating properties. Activity has been shown in preclinical studies in mice bearing intraperitoneal P388 and L1210 leukaemias, ADJ-Pc6 plasmacytoma and a variety of solid tumours. In a phase I/II collaborative study fourteen consecutive patients with relapsed or primarily refractory acute leukaemia received a single infusion of mitoxantrone (20-32 mg/m2) at fourteen-day intervals. Antileukaemic activity was seen but there were no complete remissions and toxicity was minimal. Mitoxantrone was subsequently given in a five-day schedule at a dose of 10mg/m2 daily to twenty-one patients with relapsed or refractory acute leukaemia or chronic myeloid leukaemia in blast crisis (CML-BC). Four of five patients in first relapse of acute non-lymphoblastic leukaemia (ANLL) achieved a complete remission (CR). The overall response rate (CR + partial remission (PR] was 48%. In an ongoing phase III study the same (5-day) mitoxantrone treatment has been given in conjunction with a 7-day continuous infusion of cytosine arabinoside (Ara-C) in a kinetically designed schedule based upon the preclinical studies of the Mount Sinai group.
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PMID:Sequential studies on the role of mitoxantrone in the treatment of acute leukemia. 389 80


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