aclarubicin and Leukemia--Myeloid

Tumor cells, and particularly leukemic cells, can be considered as maturation-arrested cells which have escaped some normal control and continue to proliferate. This maturation arrest can be reversed by differentiation agents such as antitumor drugs currently used in conventional cytotoxic chemotherapy. In this respect, anthracyclines have been shown to trigger the differentiation of leukemic and solid tumor cells, but the molecular mechanisms by which such drugs lead to the differentiating phenotype are still poorly understood. Using human leukemic multipotent K562 cells, we have demonstrated that subtoxic concentrations of aclacinomycin (ACLA) and doxorubicin (DOX) preferentially stimulate the hemoglobinic pathway (globins and heme synthesis) and the expression of mRNAs of globins and of porphobilinogen deaminase (PBGD). However, our results indicate that both drugs exert this differentiating effect along distinct regulatory pathways. Indeed, only ACLA and not DOX induces the expression of erythropoietin receptor (EpoR) mRNAs and of membrane EpoR, as well as an overexpression of the erythroid transcription factors GATA-1 and NF-E2 known to play a central role in erythroid gene regulation. Similarly, using transfection assays, ACLA but not DOX activates the regulatory regions (promoters and enhancers) of GATA-1, EpoR, PBGD, epsilon- and gamma-globin genes. Finally, results of run-on assays indicate that ACLA induces an enhancement of the transcription rate of these erythroid genes whereas DOX preferentially increases stability of GATA-1, NF-E2 and PBGD mRNAs. In conclusion, ACLA mainly acts at the transcriptional level via specific activation of erythroid regulatory regions whereas DOX rather acts at the posttranscriptional level by increasing the half-lives of erythroid mRNAs.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Carbohydrate Sequence; Cell Differentiation; Doxorubicin; Erythroid Precursor Cells; Gene Expression Regulation, Leukemic; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Molecular Sequence Data

Currently, the treatment decisions in elderly patients with acute myeloid leukemia (AML) are difficult and remain controversial. This study aims to evaluate the effect of thalidomide plus chemotherapy on elderly patients with AML.. 70 elderly AML patients (median age 71 years) were enrolled into this prospective study and randomly assigned to either the control arm (PC, n = 35) or the investigational arm (TPC, n = 35). Patients in the PC arm received a non-intensive regimen composed of cytarabine, aclarubicin and G-CSF (CAG) chemotherapy for induction of remission, and patients in the TPC arm received in addition thalidomide at a maximum dose of 200 mg/day.. After 2 courses of induction therapy, complete response rate of TPC and PC arms was 54.3% and 57.1%, respectively (p = 0.810). At the last follow-up, the Kaplan-Meier estimate showed that the median overall survival (OS) and event-free survival (EFS) in patients in the PC arm was inferior to those of patients in the TPC arm. Using a stratified Cox model adjusted for randomized treatment, patients receiving thalidomide plus chemotherapy were shown to derive some survival benefit in both OS and EFS. Overall, the hematological and non-hematological toxicity were similar between the 2 treatment arms.. Thalidomide in combination with chemotherapy is an alternative treatment option for elderly patients with AML.

Topics: Aclarubicin; Acute Disease; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy-Induced Febrile Neutropenia; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Middle Aged; Outcome Assessment, Health Care; Proportional Hazards Models; Prospective Studies; Remission Induction; Thalidomide

The aim of this study was to evaluate the efficacy and toxicity of low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (G-CSF) protocol in elderly patients with acute myeloid leukemia (AML). A total of 50 elderly patients including 8 aged over 70 years were enrolled. All patients were treated with CAG regimen including low-dose cytarabine (10mg/m(2) every 12h, days 1-14), aclarubicin (10mg every day, days 1-8), and G-CSF (200 microg/m(2) every day, days 1-14) priming. The overall response rate was 72.0%, and 29 of 50 (58.0%) patients achieved complete remission, including 23 of 35 (65.8%) with previously untreated AML, 6 of 15 (40.0%) with refractory, relapsed or secondary AML, 4 of 8 (50.0%) aged over 70 years, 4 of 10 (40.0%) with unfavorable cytogenetic aberrations. The early death rate was 7.6%. The median overall survival was 14 months. Myelosuppression was mild to moderate, severe nonhematologic toxicity was not observed. Thus CAG priming regimen as the induction therapy is well tolerated and effective in elderly patients with AML.

Topics: Aclarubicin; Acute Disease; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Middle Aged; Treatment Outcome

One hundred twelve patients with geriatric acute myeloid leukemia (AML), refractory or relapsed AML, or myelodysplastic syndrome and refractory anemia with excess of blasts in transformation (MDS-RAEBt) were entered into this study to receive CAG (aclarubicin and low-dose cytosine arabinoside [Ara-C]in combination with granulocyte colony-stimulating factor [G-CSF]) with the objective of evaluating the efficacy and tolerance of this regimen. Low-dose Ara-C was given subcutaneously at a dosage of 10 mg/m2 every 12 hours on days 1 to 14. Aclarubicin was administered intravenously at a dosage of 14 mg/m2 per day on days 1 to 4 (CAG regimen A) or 7 mg/m2 on days 1 to 8 (CAG regimen B). Recombinant G-CSF was given subcutaneously at a dosage of 200 3g/m2 per day on days 1 to 14. We demonstrated comparable overall complete remission rates for the 4 groups of patients: 30.8% (8/26) in the elderly patients, 48.4% (30/62) in the refractory AML patients, 44.4% (8/18) in the relapsed AML patients, and 38.5% (5/13) in the MDS-RAEBt patients. Of the 52 patients followed up, the 12-month progression-free survival (PFS) and overall survival (OS) rates estimated by the Kaplan-Meier method were 40.73% 3 8.15% and 42.85% 3 8.23%, respectively. The median PFS and OS times were 9.0 3 2.2 months and 11.0 3 1.6 months, respectively. Toxic effects were very rare and mainly consisted of neutropenia and thrombocytopenia due to myelosuppression; approximately 70% to 80% of patients had neutropenia or thrombocytopenia that exceeded National Cancer Institute grade II. Nonhematologic toxicities were not observed in this study. The CAG regimen seems promising, with acceptable toxicity, for the treatment of various categories of poor-prognosis AML and MDS-RAEBt.

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Dose-Response Relationship, Drug; Female; Granulocyte Colony-Stimulating Factor; Humans; Injections, Subcutaneous; Leukemia, Myeloid; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Survival Analysis; Thrombocytopenia; Treatment Outcome

In 1991 we reported the results from a prospective randomised phase 3 trial comparing 7 days continuous infusion of cytosine arabinoside (ara-C) combined with either daunorubicin (DNR) or aclarubicin (ACR) as direct i.v. injection for 3 days as induction chemotherapy (CT) for patients with de novo acute myeloid leukemia (AML) followed by early intensive consolidation CT with two alternating cycles of high-dose ara-C and two cycles of amsacrine plus etoposide, and finally 3 days of daunomycin plus 7 days of ara-C as administered for induction of remission. A total of 174 patients with de novo AML in the age group 17-65 years were included. The patients have now been followed till death or for at least 7 years, and an evaluation of the long-term survival and the risk of developing secondary neoplasms has been made. The overall survival rate 5-years after diagnosis was 23%, and after 10 years 19%. No difference was found between the two treatment regimens in overall survival or disease-free survival (DFS). For the subgroup of 99 patients who achieved complete remission after one or two induction courses, 5- and 10-year survival rates were 35% and 31% respectively, with the highest survival rates in the age group 17-39 years (57% at 5 years) as compared with 27% in patients aged 40-60 years (P= 0.007). Seven secondary neoplasms were diagnosed simultaneously with or after the diagnosis of AML indicating a standardized incidence ratio (SIR) of 3.41, (95% CI: 1.60-7.26). In three cases the secondary neoplasms were diagnosed simultaneously with the AML diagnosis and were for that reason completely unrelated to the chemotherapy administered for AML, as the psammomatous meningeoma diagnosed after only 8 months. The remaining three neoplasms which developed subsequently did not significantly exceed the expected number, with a SIR = 1.46 (0.47-4.57). Thus, no increased risk of solid tumors causally related to the intensive chemotherapy for de novo AML was observed. However, a generally increased risk of solid tumors in patients diagnosed simultaneously with the AML diagnosis seems likely. Over 20% of the patients were alive and in complete remission 5 years after the AML diagnosis, and they have a high probability of surviving the next 5-year period.

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Age Factors; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Etoposide; Female; Follow-Up Studies; Humans; Leukemia, Myeloid; Male; Middle Aged; Neoplasms, Second Primary; Recurrence; Remission Induction; Survival Rate; Survivors

Aclarubicin was evaluated in combination chemotherapy for adult acute myeloid leukemia in a randomized trial involving 58 institutions throughout Japan. Behenoyl cytosine arabinoside (BH-AC).daunorubicin, 6-mercaptopurine, and prednisolone (DMP) was compared with BH-AC.aclarubicin, 6-mercaptopurine, and prednisolone (AMP). In the 360 evaluable cases among the 433 cases enrolled, complete remission (CR) rates were 63.7% (116/182) for BH-AC.DMP and 53.9% (96/178) for BH-AC.AMP (P = 0.0587). Median survival periods and 7-year survival rates were 15.8 months and 19.3% for BH-AC.DMP and 9.5 months and 20.2% for BH-AC.AMP (P = 0.0091 according to the generalized Wilcoxon test [GW], P = 0.196 according the log-rank test [LR]). Median disease-free survival periods were 15.4 months for BH-AC.DMP and 14.1 months for BH-AC.AMP (P = 0.851 by GW, P = 0.439 by LR). Among the 346 cases of extramurally confirmed FAB subtypes, CR rates were 67.9% (19/28) with BH-AC.DMP and 31.8% (7/22) with BH-AC.AMP for subtype M3 (P = 0.011) and 63.3% (93/147) with BH-AC.DMP and 56.8% (84/148) with BH-AC.AMP (P = 0.254) for subtypes M1, M2, M4, and M5. Diarrhea, ileus, pneumonia, and renal failure were more frequent with BH-AC.AMP than with BH-AC.DMP. The results indicate, at least on the basis of the long-term outcome, that BH-AC.AMP has antileukemic effects on subtypes M1, M2, M4, and M5 that are comparable with those of BH-AC.DMP.

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid; Male; Mercaptopurine; Middle Aged; Prednisolone; Prospective Studies; Survival Analysis

Topics: Aclarubicin; Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Autoimmune Diseases; Cytarabine; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypothyroidism; Iodide Peroxidase; Leukemia, Myeloid; Male; Recombinant Proteins; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine

Low-dose cytarabine and calcitriol (LDCA + VD3) combination therapy was performed in two adult patients with acute myeloid leukemia (AML) that relapsed within 1 yr after unrelated donor cord blood transplantation (URD CBT) performed in a relapse or non-remission stage. Concomitant aclarubicin was also administered in one patient. Remission because of recovery of donor cord blood hematopoiesis was obtained in both patients. The treatment was low intensive, and neither adverse effects in terms of digestive symptoms nor hypercalcemia was observed. Activity of daily life was maintained. The patients were followed as outpatients after remission, and the remission duration was approximately 6 months in both patients. Although LDCA + VD3 therapy is minimally intensive chemotherapy, it may prolong the survival time of patients with relapsed AML after URD CBT.

Topics: Aclarubicin; Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Calcitriol; Cord Blood Stem Cell Transplantation; Cytarabine; Dose-Response Relationship, Drug; Female; Humans; Leukemia, Myeloid; Middle Aged; Recurrence; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction

In 85 adult patients diagnosed with acute myeloid leukaemia (AML) and treated at the same institution during a 5-yr period, the clinical significance of in vitro cellular drug resistance to the anthracyclines aclarubicin (Acla) and daunorubicin (Dau) as well as the nucleoside analogue cytarabine (Ara-C) was investigated using a 4-d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. In 59 patients of whom 40 were treated by the combination of Acla and Ara-C we found that leukaemia cell drug resistance towards Acla was higher (by a factor 2.80) in patients who failed to enter complete remission (CR) after the first cycle of induction chemotherapy as compared to patients who entered complete remission. The relationship was significant in univariate as well as multivariate analysis (p=0.02 and 0.03, respectively). By contrast, no in vitro single drug resistance values were consistently correlated to other parameters of clinical outcome (overall CR rate, overall survival (OS), or continuous complete remission (CCR)), whereas the combined Acla and Ara-C drug resistance profile (Acla/Ara-C DRP) was of prognostic significance to overall survival of all 85 patients (p=0.004) as well as to the CCR of 39 complete responders (p=0.04). These findings remained statistically significant in multivariate analyses correcting for other variables influencing clinical outcome including patient age, leukocyte count, karyotype, FAB-subtype, and presence/absence of secondary AML. We conclude that the in vitro drug resistance of leukaemia cells at time of disease presentation appears to be independent of prognostic significance to short- and long-term clinical outcome in AML.

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Etoposide; Female; Humans; Idarubicin; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Neoplastic Stem Cells; Prognosis; Remission Induction; Survival Analysis; Thioguanine; Treatment Outcome; Tumor Cells, Cultured

In 145 adult patients diagnosed with non-M3 acute myeloid leukaemia (AML) the relevance of FAB-subtype and immunophenotype to in vitro cellular drug resistance towards the anthracyclines aclarubicin (Acla) and daunorubicin (Dau), and the nucleoside analogue cytarabine (Ara-C), as well as other antileukaemic drugs, was investigated using a 4-d MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. We demonstrate that high CD14 expression is highly significantly associated with high cellular Ara-C and Dau resistance in univariate as well as multivariate analyses. FAB subtypes with highest and lowest cellular Ara-C resistance were M4 and M5, respectively (P < 0.01, one-way anova), whereas FAB subtypes with highest and lowest cellular Dau resistance were M4 and M1, respectively (P < 0.01, one-way anova). By contrast, no significant differences in cellular drug resistance towards Acla could be demonstrated among FAB subtypes. Furthermore, in two cohorts of AML patients treated by two different regimens for remission induction over a period of 15 yr (1985-94, n = 159 and 1995-99, n = 76, respectively) we demonstrate in univariate analyses a significance of CD14 expression with respect to clinical outcome. With the exception of significance to probability of obtaining complete remission in the first cohort (P = 0.03, logistic regression), this significance was, however, lost in multivariate analyses. It was demonstrated that FAB-M4 patients were older than M5 patients and that high CD14 expression was associated with the presence of secondary AML and older age. We conclude that although cases with high blast cell CD14 expression (and FAB-M4 cases) were more resistant to Ara-C as well as Dau in vitro, the clinical and biological significance of this may be debatable because of interactions with major prognostic factors in AML.

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Amsacrine; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Cohort Studies; Cytarabine; Daunorubicin; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Idarubicin; Leukemia, Myeloid; Leukemia, Myelomonocytic, Acute; Lipopolysaccharide Receptors; Male; Middle Aged; Mitoxantrone; Multivariate Analysis; Neoplastic Stem Cells; Thioguanine; Treatment Outcome

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 examined the cellular effects of topo II inhibitors in two human myeloid cell lines, HL-60 and KG-1 cells, with the purpose of finding molecular markers for the sensitivity of leukemia cells to topo II inhibitors. These cell lines are widely used, well characterized and they differ in their sensitivities to topo II inhibitors. Despite the fact that HL-60 cells are p53-negative, they are much more sensitive than KG-1 cells. Three different topo II inhibitors with distinct molecular ways of action have been used. Daunorubicin and aclarubicin are DNA intercalators that secondarily interact with topo II; etoposide, on the other hand, directly binds to the enzyme. In contrast to daunorubicin, which induces protein-associated DNA double-strand breaks due to the blockage of topo II action, aclarubicin inhibits the access of DNA by topo II. No correlation could be established between the drug-induced DNA damage and apoptosis. In fact, the amount and pattern of DNA damage examined with the 'comet assay' was characteristic for each drug in both cell lines. The DNA binding of daunorubicin was slightly higher in HL-60 cells, but there was no notable variance between the cell lines for aclarubicin. The most striking difference could be found for the nuclear topo II activity, which was about half in KG-1 cells and, additionally, less than 1% of the nuclear topo II activity was bound to the DNA in KG-1 cells when compared to HL-60 cells. This fraction of topo II interacts with the inhibitors; subsequently these findings might well explain the variance in the cellular sensitivity. Additional factors are alterations of the apoptotic pathways, eg loss of p53 in HL-60 cells. Although we found no differences in the quantity of DNA damage between the cell lines after drug treatment, the quality of DNA damage appeared to be distinct for each topo II inhibitor. The morphological appearance of the comet tails after treatment was characteristic for each drug. Further studies are necessary to decide whether these in vitro data are compatible with the clinical situation.

Topics: Aclarubicin; Acute Disease; Antineoplastic Agents; Apoptosis; Cell Nucleus; Comet Assay; Daunorubicin; DNA; DNA Damage; DNA Topoisomerases, Type II; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Etoposide; fas Receptor; Genes, p53; Humans; Intercalating Agents; Leukemia, Myeloid; Mitochondria; Topoisomerase II Inhibitors; Tumor Cells, Cultured

We investigated the cellular drug resistance to aclarubicin (Acla), cytosine arabinoside (Ara-C), daunorubicin (Dau), doxorubicin (Dox), etoposide (Etop) and mitoxantrone (Mitox) using the MTT assay at time of disease presentation in 93 cases of acute myeloid leukaemia (AML). In 31 cases we concomitantly investigated MDR1 (multiple drug resistance 1 gene) expression (semi-quantitative competitive RT-PCR) of the leukaemic cells. Drug resistance towards Dau, Dox and Etop was correlated to the MDR1 expression of the AML cells (P<0.05) with high MDR1 expression being associated with high drug resistance towards these drugs. Although the data did not allow firm conclusions to be drawn on the correlation between MDR1 expression and drug resistance towards Ara-C and Mitox, the drug resistance towards Acla clearly was not correlated to, or dependent on, the MDR1 expression level of the AML blast cells. In addition, when examining the cross-activities among the six drugs distinct patterns emerged. Thus, high to very high degrees of cross-activity were found to exist between Dau, Dox, Etop and Mitox, whereas Ara-C had moderate cross-activity with the other drugs except Acla, which showed absent to moderate cross-activity with the other drugs. We conclude that MDR1 gene expression is of significance for cellular drug resistance towards specific (MDR1-related) drugs in AML, whereas it is not of significance regarding drug resistance towards other drugs, which is the case with the anthracycline Acla. We suggest that in the place of other more or less complicated ways to circumvent MDR1-mediated drug resistance, Acla may be used to replace Dau, Dox and other MDR1-related drugs if proven as potent as the drug it is to substitute.

Topics: Aclarubicin; Acute Disease; Antineoplastic Agents; Cytarabine; Daunorubicin; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Gene Expression; Genes, MDR; Humans; Lethal Dose 50; Leukemia, Myeloid; Mitoxantrone; Tumor Cells, Cultured

We have investigated the in vitro blast cell survival (viability) and drug resistance to cytosine arabinoside (Ara-C), daunorubicin (Dau), mitoxantrone (Mitox) and aclarubicin (Acla) of fresh leukaemic blast cells from 80 patients with newly diagnosed acute myeloid leukaemia (AML) employing the semiautomated colourimetric MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)-assay. In 15 cases we concurrently investigated the relation between in vitro blast cell survival (MTT assay) and blast cell proliferation (3H-thymidine incorporation) in the presence and absence of myeloid growth factors (GFs) G-CSF, GM-CSF and IL-3 (individually and in combination). A highly significant correlation was found between blast cell survival and blast cell proliferation (r = 0.87, P < 1 x 10(-4). Furthermore, in 40 evaluable adult patients who completed intravenous induction chemotherapy and were evaluable for response to chemotherapy we found a positive correlation between in vitro blast survival (MTT assay) and response to chemotherapy with high blast survival being associated with poor response to chemotherapy (P = 0.05). Moreover, in a multivariate analysis, high blast cell survival was significantly associated with high CD13 expression and monocytic phenotype (P = 0.0003 and P = 0.02, respectively). Furthermore, we found an inverse relationship between the baseline proliferation of the blasts and the magnitude of response to the GFs (P < 0.02), indicating that cells with low baseline proliferation were more readily stimulated by growth factors. Finally, we found a significant correlation between leukaemic cell survival and cellular drug resistance towards Dau (P = 0.001) and Mitox (P = 0.03), but not towards Ara-C (P = 0.68) and Acla (P = 0.13). We conclude that high in vitro leukaemic cell survival is associated with drug resistance in vivo and in vitro, and furthermore is correlated with high blast cell proliferation and some adverse prognostic factors previously identified in AML.

Topics: Aclarubicin; Adolescent; Adult; Aged; Antineoplastic Agents; Cell Differentiation; Cell Survival; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Female; Humans; Infant; Infant, Newborn; Leukemia, Myeloid; Leukocyte Count; Male; Middle Aged; Mitoxantrone; Treatment Outcome; Tumor Cells, Cultured

We herein report a case of acute myeloid leukaemia (AML, FAB:M0) who showed upregulation of T-lymphoid antigens (CD2, CD7) and adhesion molecules (CD11a, CD11b, CD18) on leukaemic cells after in vivo administration of granulocyte colony-stimulating factor (G-CSF). To our knowledge, this is the first report which describes in vivo changes of cell surface antigen expression on AML cells after the administration of G-CSF.

Topics: Aclarubicin; Acute Disease; Aged; Antigens, CD; Antigens, Surface; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Cells; Cell Adhesion Molecules; Cell Separation; Cytarabine; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid; T-Lymphocytes; Up-Regulation

The effect of stimulating acute myeloid leukemia blast cells with a combination of growth factors (G-CSF, GM-CSF, and IL-3) on cellular resistance to the antileukemia drugs Ara-C, daunorubicin, aclarubicin, and mitoxantrone was studied. For assessment of in vitro cellular drug resistance the MTT assay was employed. Stimulated cells showed enhanced sensitivity to Ara-C (p < 0.02), whereas a significant increase in cellular drug resistance to daunorubicin (p < 0.02) was observed. Variable and statistically non-significant changes in drug resistance to aclarubicin and mitoxantrone was induced by stimulation of the blast cells. We conclude on the basis of these observations that myeloid growth factors should be used with caution in combination with daunorubicin in AML treatment until further confirmatory evidence has been presented by other investigators.

Topics: Aclarubicin; Acute Disease; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Death; Cell Survival; Coloring Agents; Cytarabine; Daunorubicin; Drug Antagonism; Drug Screening Assays, Antitumor; Drug Synergism; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-3; Leukemia, Myeloid; Male; Middle Aged; Prospective Studies; Remission Induction

Topics: Aclarubicin; Acute Disease; Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Etoposide; Humans; Idarubicin; Leukemia, Myeloid; Mitoxantrone; Prognosis; Remission Induction; Time Factors

The purpose of the study was to evaluate the effect of a mouthrinse regimen comprising both chemical plaque control and mechanical plaque removal. 20 adult patients with acute myeloid leukaemia were assigned to one of the following 2 regimens: (1) (group 1) mouthrinse twice daily with a 0.1% chlorhexidine solution; or (2) (group 2) the same regimen, but preceded by mechanical removal of plaque and calculus on day 1. All patients were followed for 28 days from the initiation of remission-induction therapy. In group 2, the plaque scores remained lower than those of group 1 throughout the study, although only 3 patients remained completely free of plaque after 28 days. Gingival inflammation as judged by bleeding scores remained unchanged in group 1, whereas in group 2, the degree of inflammation was reduced from 52% (median value) on day 1 to 31% (median value) on day 28. The bleeding scores were also lower in group 2 (31%) than in group 1 (60%) on day 28. No differences were found between the 2 groups with respect to the occurrence of other oral infections. It is concluded that chemical plaque control with chlorhexidine should be preceded by mechanical removal of plaque and calculus, when used in patients with acute myeloid leukaemia and thrombocytopenia.

Topics: Aclarubicin; Acute Disease; Adolescent; Aged; Antineoplastic Combined Chemotherapy Protocols; Bacterial Infections; Chlorhexidine; Cytarabine; Dental Calculus; Dental Plaque; Dental Scaling; Female; Gingival Hemorrhage; Gingivitis; Humans; Leukemia, Myeloid; Leukopenia; Male; Middle Aged; Mouthwashes; Netilmicin; Piperacillin; Premedication; Thrombocytopenia

For the purpose of establishing a method for reasonable clinical use of anthracyclines in leukemia chemotherapy, we examined the pharmacokinetics and the mode of action with five anthracyclines such as daunorubicin (DNR), doxorubicin (DOX), aclarubicin (ACR), THP adriamycin (THP), idarubicin (IDA). In the patients with AML, blood ACR or IDA level increased and then disappeared very rapidly after iv bolus injection. In contrast, their metabolites (M1 or IDAol) increased for up to 2 or 4 hrs and remained much longer than ACR or IDA. The concentration of ACR, IDA or their metabolites were found to be much higher in the leukocyte fraction than in erythrocyte fraction or plasma. In HL60 cell suspension, anthracyclines were rapidly accumulated into the cells, and the uptake of IDA or THP were higher than the other agents. In HL60 cells, anthracyclines accumulated in the nuclear fraction but ACR was accumulated markedly in the cytosol fraction. From the result of DNA binding assay, binding at excess to calf thymus DNA of ACR was suggested to be approximately 2 times higher than that of other agents. DNA strand brakes in HL60 cells treated with anthracyclines were shown by pulse field gel electrophoresis, and IDA was found to have stronger activity to cause the DNA strand breaks. In conclusion, it seemed that anthracyclines showed similar action mechanisms, but in some respects quantitative differences were existed among them. Anthracyclines should be given to patients based on their pharmacological characteristics to obtain higher remission rate and suppress resistant cells.

Topics: Aclarubicin; Acute Disease; Antibiotics, Antineoplastic; Daunorubicin; DNA; DNA Damage; DNA Replication; Doxorubicin; Humans; Leukemia, Myeloid

Topics: Aclarubicin; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Humans; Leukemia, Myeloid; Lymph Nodes; Mercaptopurine; Prednisolone

WEHI-3B D+ monomyelocytic leukemia cells were induced to differentiate to mature granulocytes when treated with either 30 nM aclacinomycin A or 7 microM retinoic acid. Differentiation was assessed by the appearance of mature granulocytic phenotypes, as measured by the ability to reduce nitro blue tetrazolium, morphological changes, an increase in cell surface Fc receptors, as well as the loss of proliferative capacity. Maximum differentiation occurred 3 days after drug exposure. Analysis of DNA histograms of treated cells indicated that cells accumulated in the G1 phase of the cell cycle after 8 h of exposure to either inducer, with maximum accumulation occurring by 20 h; this arrest was observed prior to the phenotypic appearance of mature cells. The minimum interval of time necessary to commit cells to a differentiation pathway, which was less than one doubling time (9.2 h), closely paralleled the initial accumulation of cells in the G1 phase of the cell cycle. Since drug exposure for more than one cell division was required for maximum differentiation, the observed kinetics of maturation is consistent with a stochastic model. These studies support the idea that this cell line would be a particularly good model for extrapolation of findings with differentiating agents in culture to therapeutic monitoring in animals, since WEHI-3B D+ leukemia cells can be readily propagated in vivo in BALB/c mice.

Topics: Aclarubicin; Animals; Cell Cycle; Cell Differentiation; Cell Line; Dose-Response Relationship, Drug; Leukemia, Myeloid; Mice; Naphthacenes; Neutrophils; Receptors, Fc; Time Factors; Tretinoin

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

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Cytarabine; Humans; Leukemia, Myeloid; Male; Naphthacenes

Topics: Aclarubicin; Animals; Cells, Cultured; Combined Modality Therapy; Immunization; Leukemia, Experimental; Leukemia, Myeloid; Mice; Naphthacenes; Neoplastic Stem Cells; Spleen; Splenectomy