aclarubicin and Blast-Crisis

Ten patients with refractory and relapsed acute myelogenous leukaemia (AML) and one patient with CML in blast crisis were treated with aclacinomycin A (ACA, 60 mg/m2/day for 5 days) and etoposide (VP-16, 100 mg/m2/day for 5 days) and analysed retrospectively. Of 11 patients, seven (63%) achieved an objective response including four CRs (36%). Most impressively, two patients experienced consecutive CRs (second, third, and fourth) following relapses. Only two patients (18%) were primary resistant with persisting leukaemia. In conclusion, the combination of ACA and VP-16 is an active regimen in refractory and relapsed AML with a toxicity comparable with other salvage regimens.

Topics: Aclarubicin; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Etoposide; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Recurrence; Retrospective Studies

The clinical efficacy of aclarubicin, an anthracycline antibiotic, was studied in 48 patients with leukemia. The antibiotic was used in the following combinations with cytarabine: "7 + 7", "5 + 5" and "7 & 3". A complete remission was stated in 14 (42.4 per cent) out of 33 patients with acute nonlymphoid leukemia, 6 (43 per cent) out of the 14 patients having relapses. The combined therapy was effective in 4 out of 5 pre-resistant patients. The "7 + 3" scheme was the most beneficial. The most common adverse reactions were nausea and vomiting.

Topics: Aclarubicin; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Cytarabine; Humans; Leukemia; Leukemia, Monocytic, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction

DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage response, is also evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair. Histone eviction deregulates the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy.

Topics: Aclarubicin; Animals; Anthracyclines; Antineoplastic Agents; Apoptosis; Blast Crisis; Cell Line, Tumor; Cell Survival; Chromatin; DNA; DNA Damage; Doxorubicin; Etoposide; Heart; Histones; Humans; Intercalating Agents; Leukemia, Myeloid, Acute; Mice; Mice, Nude; Nucleic Acid Conformation; Nucleosomes; Organ Specificity; Transcriptome

In 93 cases of acute myeloid leukaemia (AML) the extent to which prognostic factors mirrored the in vitro cellular chemotherapy resistance (to anthracyclines aclarubicin (Acla) and daunorubicin (Dau) as well as nucleoside analogue cytarabine (Ara-C)) was investigated using a 4-d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. We found that age at presentation and presence of secondary AML were significantly correlated to leukaemia cell Ara-C resistance. Thus, analysis of in vitro drug resistance data revealed that age at presentation and presence of secondary leukaemia were both independently correlated to cellular drug resistance, with older age being associated with higher Ara-C resistance in vitro (p=0.02 and 0.01 in univariate and multivariate analyses, respectively) and with secondary leukaemia being associated with higher Ara-C resistance (p=0.04 and 0.059 in univariate and multivariate analysis, respectively). Median LC-50 values (Ara-C) were: 178 ng/ml in paediatric cases, 356 ng/ml in younger adult cases, and 584 ng/ml in elderly (age > or = 60 yr) cases giving a resistance ratio between these age subgroups of 1:2.0:3.3. Median LC-50 values (Ara-C) was 381 ng/ml in de novo cases as opposed to 891 ng/ml (resistance ratio 1:2.3) in secondary cases. By contrast, cytogenetic findings, presenting leucocyte count, FAB-subtype, and gender were not consistently correlated to in vitro drug resistance to any of the three drugs. We conclude that at least two major adverse prognostic factors in AML (advanced age at presentation and presence of secondary leukaemia) are associated with increased leukaemia cell Ara-C resistance. High leucocyte count is not associated with increased cellular drug resistance towards Acla, Ara-C or Dau.

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Blast Crisis; Child; Child, Preschool; Cytarabine; Cytogenetic Analysis; Daunorubicin; Drug Resistance, Neoplasm; Female; Humans; Infant; Leukemia, Myeloid; Male; Middle Aged; Multivariate Analysis; Prognosis; Tetrazolium Salts

We attempted treatment with low-dose aclarubicin (ACR), a new anthracycline, in a 66-year-old man with blastic transformation of essential thrombocythemia (ET). Two courses of ACR (20 mg/day x 7 days) were given intravenously. He showed a good response to this therapy without severe side effects. He has since maintained a state of prolonged remission. These observations indicate that low-dose ACR may be beneficial for management of the blastic transformation of ET.

Topics: Aclarubicin; Blast Crisis; Granulocytes; Humans; Male; Middle Aged; Thrombocythemia, Essential

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.

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Aged; Blast Crisis; Child; Daunorubicin; Drug Evaluation; Drug Resistance; Female; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Naphthacenes