aclarubicin and Leukemia--Erythroblastic--Acute

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

A female patient in whom acute nonlymphocytic leukemia (ANLL, FAB-M6) developed during treatment of hepatocellular carcinoma (HCC) is described. Two years after partial hepatectomy and subsequent chemotherapy, leukemia developed following a 2 month preleukemic stage. Chromosomal analysis revealed an abnormal karyotype, 46,XX,-5, + der(5)t(3;5)(q25;q31). The balanced translocation t(3;5) has been observed in all types of ANLL and MDS except for ANLL M3 subtype. We summarize patients with ANLL M6 and t(3;5).

Topics: Aclarubicin; Adolescent; Adult; Aged; Anemia, Refractory, with Excess of Blasts; Carcinoma, Hepatocellular; Child; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 5; Cytarabine; Daunorubicin; Doxorubicin; Female; Hepatectomy; Hepatitis B; Humans; Leukemia, Erythroblastic, Acute; Liver Neoplasms; Male; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Prednisolone; Remission Induction; Translocation, Genetic

Patients with myelodysplastic syndrome (MDS) show a relatively high incidence of developing cancers. However, it is extremely rare that synchronous double cancers develop in an MDS patient. We report a case of MDS that progressed rapidly into erythroleukemia (M6 by French-American-British classification) complicated by gastric cancer and carcinoma of the papilla of Vater. A 66-year-old man was admitted because of pancytopenia with peripheral blasts. A diagnosis of MDS (with refractory anemia with excess of blasts in transformation [RAEB-T]) was made by bone marrow examination. Chromosome analysis revealed 46,XY. An early gastric cancer was also diagnosed by endoscopic examination. The peripheral blasts gradually proliferated and the disease progressed to M6. A chromosome abnormality 46,XY,del(1)(q42) was detected at the leukemic transformation. A CAG (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor) regimen was started as a remission-induction therapy. However, obstructive jaundice developed and a marked dilatation of bile ducts was observed by abdominal computed tomography (CT). A carcinoma of the papilla of Vater was detected by endoscopy. As remission was achieved and the pancytopenia improved, the patient subsequently underwent a surgical jejuno-choledochostomy to manage the jaundice. However, the leukemia relapsed thereafter and additional chromosome abnormalities including der(5)t(5;10)(p15:q11) were observed.

Topics: Aclarubicin; Adenocarcinoma; Aged; Ampulla of Vater; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cholestasis, Extrahepatic; Chromosome Aberrations; Chromosome Disorders; Common Bile Duct Neoplasms; Cytarabine; Disease Progression; Granulocyte Colony-Stimulating Factor; Humans; Karyotyping; Leukemia, Erythroblastic, Acute; Male; Neoplasms, Multiple Primary; Neoplasms, Second Primary; Pancytopenia; Stomach Neoplasms

Human erythroleukemic K 562 cells were induced to were induced to differentiate along the erythroid lineage by anthracycline antitumor drugs, such as aclacinomycin (ACLA) and doxorubicin (DOX). Subsequent stimulation of heme and globin synthesis led to a differential quantitative expression of hemoglobins. Gower 1 (epsilon2, zeta2) was the major type for ACLA and X (epsilon2, gamma2) for DOX. Although ACLA and DOX increased both the expression of gamma-globin and porphobilinogen deaminase mRNAs, striking differences were observed in the expression of erythropoietin receptor mRNAs and in erythroid transcription factors GATA-1 and NF-E2, known to play a key role in erythroid gene regulation. Indeed, ACLA induces an increase either in the binding capacity of GATA-1 and NF-E2 or in the accumulation of erythropoietin receptor, GATA-1 and NF-E2 transcripts. In contrast, their expression with DOX was not significantly modified compared to uninduced cells, except for a slight decrease in NF-E2 expression on day 3. In conclusion, these data show that: 1. increased expression of erythroid transcription factors and erythroid genes are associated only with ACLA treatment, and 2. although cytotoxicity of both ACLA and DOX is certainly dependent on DNA intercalation, regulation of differentiation processes by these two drugs involves distinct mechanisms.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Base Sequence; Cell Differentiation; DNA-Binding Proteins; Doxorubicin; Erythroid-Specific DNA-Binding Factors; GATA1 Transcription Factor; Gene Expression; Globins; Hemoglobins; Humans; Hydroxymethylbilane Synthase; Leukemia, Erythroblastic, Acute; Molecular Sequence Data; NF-E2 Transcription Factor; NF-E2 Transcription Factor, p45 Subunit; Receptors, Erythropoietin; RNA, Messenger; Transcription Factors; Tumor Cells, Cultured

Anthracycline antitumor drugs such as aclacinomycin (ACM) and doxorubicin (DOX) used in subtoxic concentrations induce erythroid differentiation of the erythroleukemic cell line K562. To elucidate the possible role of erythroid genes of the erythropoietin receptor (EpoR) and the transcription factor GATA-1 in this effect, the regulatory regions of the above genes and human epsilon- and gamma-globin and porphobilinogen deaminase (PBGD) genes were fused to the firefly luciferase gene. The resulting reporter constructs were tested in a transfection assay of the erythroleukemic cell line K562 stimulated to differentiate by treatment with the anthracycline drugs ACM and DOX or hemin (HEM). The results showed activation of the tested promoters after cell treatment with ACM, but not with DOX or HEM. In contrast to the mouse EpoR gene promoter, the activity of the human EpoR gene promoter (-659/-60) in the reporter construct was not modified by addition of the first intron sequence. In ACM-treated K562 cells, EpoR gene promoter activity completely correlated with EpoR and GATA-1 mRNA levels and the degree of erythroid maturation. In addition, ACM strongly activated the erythroid gene promoters that contain GATA binding sites. Nevertheless, less activation was also observed for the GATA-1 gene promoter (-312/-31) lacking any known GATA binding sites. Insertion of the GATA-1 gene enhancer with two canonic GATA binding sites, stimulated the ACM activation effect for EpoR and GATA-1 promoter-containing constructs. Mutation of the enhancer GATA binding sites abolished this effect. All the regulatory regions tested (except gamma-globin promoter) were completely inactive in nonerythroid COS7 cells. These data indicate that (1) two structurally different anthracycline analogues, DOX and ACM, differ in their differentiation mechanisms, and (2) ACM switches on the erythroid program of K562 cells, at least in part because of interaction with a factor(s) that recognizes the GATA binding sites in the promoter region of erythroid genes leading to their activation.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Base Sequence; Cell Differentiation; Doxorubicin; Erythropoiesis; Humans; Leukemia, Erythroblastic, Acute; Molecular Sequence Data; Promoter Regions, Genetic; Tumor Cells, Cultured

Anthracycline antitumor drugs, particularly aclacinomycin (ACM) have been shown to be potent inducers of erythroid differentiation in human leukemic K562 cells. Here we report that such an event is associated with an overexpression of the erythroid-specific transcription factors GATA-1 and NFE-2. Using the electrophoretic mobility shift assay, during differentiation over 3 days of culture, we have observed an increase in the binding either of GATA-1 to the promoter of the gamma-globin gene (region -201 to -156) or NFE-2 to the promotor of the porphobilinogen deaminase gene (region -170 to -142). Both events were paralleled by a recruitment of hemoglobinized cells and a stimulation of heme synthesis. Enhanced binding capacity of GATA-1 was confirmed by an increase in its mRNAs. Moreover, GATA-1 and NFE-2 overexpression has been shown to be specific of the differentiating effect of the drug and not of its growth inhibitory effect. In contrast, no change was observed in the binding of the ubiquitous factors OTF-1 and AP-1, except on day 3, where AP-1 decreased. Although ACM is a DNA-intercalating agent, it did not directly affect transcription factors binding to their cis-sequences as assessed by the preincubation of the oligonucleotides probes with increasing concentrations of ACM. Taken together, these results strongly suggest that ACM could exert their erythroid-differentiating activity by modulating the expression of transcription factors which specifically regulate the transcription of erythroid genes.

Topics: Aclarubicin; Adjuvants, Immunologic; Base Sequence; Binding Sites; Cell Differentiation; DNA Probes; DNA-Binding Proteins; Erythroid-Specific DNA-Binding Factors; GATA1 Transcription Factor; Gene Expression; Globins; HeLa Cells; Humans; Hydroxymethylbilane Synthase; Leukemia, Erythroblastic, Acute; Molecular Sequence Data; Promoter Regions, Genetic; RNA, Messenger; Sensitivity and Specificity; Transcription Factors

Target molecules for NK cells are unknown. Numerous studies have proposed putative target molecules, but have examined their role in the modulation of sensitivity to NK-mediated lysis one independently of each other. We examined the simultaneous expression of various surface molecules and the susceptibility of K562 cells to NK attack. We have previously shown that adriamycin (40 nM) and aclacinomycin (15 nM) can induce, in vitro, an increase of glycophorin A (GPA) on K562 cells, a modulation of transferrin receptor (TfR) and CD15 antigen expression and a significant resistance of cells to NK-mediated lysis. In the present work, Fc gamma receptor II (CD32) expression at the K562 cell membrane was clearly decreased after aclacinomycin-treatment but was unaltered by adriamycin-treatment. Four K562 cell clones were studied. Two clones (F and G) expressed a higher level of CD32 at the membrane (62% and 70% of erythrocyte antibody (EA) rosettes respectively) and two clones (9 and 19) expressed lower a level (18% and 7% EA rosettes respectively) than the original population (43%). The sensitivity to lysis by NK cells was increased in clones F, G and 9 but decreased in clone 19 (without alteration in the binding capacity). Relationships between the sensitivity to NK attack and the levels of simultaneous expression of CD32, TfR, CD15, glycophorin A (GPA) and MHC class I monomorphic antigens were studied. In addition, the presence at the membrane of some cellular adhesion molecules (CD54, CD58, CD29, CD18, CD56) was examined in anthracyclin-treated cells and in the four clones. The difference in the sensitivity of target cells to NK attack is not strictly related to variation of one or other of these molecules. Our previous and present data suggest that the resistance of K562 cells to NK cells may correlate with the level of erythroid maturation at the cell membrane, involving simultaneous variations in expression of several molecules such as a decrease of TfR, CD15 and CD32 and an increase of GPA.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Antigens, CD; Antigens, Surface; Cell Adhesion Molecules; Clone Cells; Cytotoxicity, Immunologic; Flow Cytometry; Glycophorins; Histocompatibility Antigens Class I; Humans; Killer Cells, Natural; Leukemia, Erythroblastic, Acute; Lewis X Antigen; Receptors, IgG; Receptors, Transferrin; Rosette Formation; Tumor Cells, Cultured

Fluorescence-emission spectra from anthracycline-treated cells suspended in buffer have been used to measure the uptake of three anthracycline derivatives: adriamycin, 4'-O-tetrahydropyranyladriamycin and aclacinomycin in drug-sensitive and drug-resistant K562 cells. The initial rate of uptake and the kinetics of active efflux under the effect of an integral membrane glycoprotein, P-glycoprotein, have been measured as a function of temperature. The activation energies for the passage of the drugs through the plasma membrane have been calculated. In the case of 4'-O-tetrahydropyranyladriamycin, the activation energies for the passive diffusion of the drug equal 45 kJ.mol-1 and 37 kJ.mol-1 for sensitive and resistant cells, respectively. The activation energy for the active efflux of 4'-O-tetrahydropyranyladriamycin equal 25 kJ.mol-1.

Topics: Aclarubicin; Biological Transport; Cell Line; Cell Membrane; Doxorubicin; Drug Resistance; Fluorescence Polarization; Kinetics; Leukemia, Erythroblastic, Acute; Membrane Fluidity; Temperature

Chemical inducers of the differentiation are known to cause an early transient decrease in c-myc and c-myb mRNA levels in Friend erythroleukemia cells preceding the down-regulation of c-myc and c-myb expression in the course of irreversible terminal differentiation. We therefore investigated the early effect of the potent differentiation-inducing anthracycline antitumor antibiotic, aclacinomycin A, on the c-myc and c-myb mRNA levels in the Friend cell line, F4-6, using Northern blot analysis. Aclacinomycin A induced a rapid decrease in the levels of c-myc and c-myb transcripts within 0.5-1 h and 2-3 h, respectively. The time course of decline in c-myc and c-myb expression was similar to that observed with dimethylsulfoxide or after transcription blockage brought about by a high concentration of actinomycin D. By 12 to 18 h after aclacinomycin A exposure, the c-myc and c-myb mRNA levels had returned to about pretreatment levels. When the cells were treated with adriamycin, an anthracycline that reduces cell proliferation in F4-6 cells without increasing differentiation, an early decrease in c-myc and c-myb expression was not observed. These results suggest that the transient decrease in c-myc and c-myb mRNA levels in F4-6 cells may be an early differentiation-related biochemical effect of aclacinomycin A.

Topics: Aclarubicin; Animals; Cell Differentiation; Dimethyl Sulfoxide; Doxorubicin; Friend murine leukemia virus; Gene Expression; Genes, myc; Hemoglobins; Kinetics; Leukemia, Erythroblastic, Acute; Mice; Oncogenes; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured

Human K562 leukemia cells have been induced to differentiate along the erythroid lineage by aclacinomycin (ACM), an anthracyclic antitumor drug. During differentiation over 3 days in culture, the expression and the nature of erythropoietin (EPO) receptors have been analyzed using 125I-labeled bioactive recombinant human EPO. Aclacinomycin at 20 nM, the concentration inducing optimum differentiation, progressively increased EPO-specific binding. On day 3, EPO binding was nine-fold higher than that of the controls (1031 +/- 101 cpm/5 x 10(6) cells versus 112 +/- 15 cpm); with various concentrations of ACM, the increase in EPO binding appeared to parallel the recruitment of hemoglobin-producing cells. However, at 95% of growth inhibition, EPO binding remained constant while the percentage of differentiated cells decreased. Specific binding was reversible, saturable, and proportional to cell number; bound EPO was displaced by unlabeled EPO. Scatchard analysis of the equilibrium binding data suggested the existence of a single class of EPO receptors with an apparent Kd of 867 +/- 458 pM, corresponding to 400 +/- 142 receptors per cell. Affinity cross-linking of 125I-EPO using disuccinimidyl suberate followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions demonstrated that EPO was preferentially cross-linked to a protein of approximately 116 kD. Taken together, these results demonstrate that, in addition to cytostatic properties, antitumor drugs such as ACM can modulate the expression of differentiation factor receptors on the surface of leukemic cells.

Topics: Aclarubicin; Adjuvants, Immunologic; Binding Sites; Cell Differentiation; Erythroid Precursor Cells; Erythropoietin; Hemoglobins; Humans; Leukemia, Erythroblastic, Acute; Receptors, Cell Surface; Receptors, Erythropoietin

Simultaneous exposure to 30 microM hemin and 3 x 10(-8) M aclacinomycin (ACL) or mussetamycin for 6 days led to terminal differentiation of K562 cells. The number of hemoglobinized cells and the total hemoglobin content of cells treated with both ACL and hemin exceeded the sum of the corresponding values induced in response to each of these two agents when used alone. Although neither ACL nor hemin alone induced substantial morphological maturation, 40%-45% of cells treated with both agents developed the morphological characteristics of orthochromatophilic normoblasts, a level of maturation not previously reported for this highly malignant cell line. Subcloning of K562 cells that had been treated with both ACL and hemin in inducer-free plasma clots revealed a 50% decrease in the clonogenic potential of these cells, even though the cells in the original cultures were still growing at only a moderately decreased rate. Despite the apparent terminal maturation of K562 cells induced with both ACL and hemin, with an advanced level of morphologic maturation and hemoglobin synthesis accompanied by a loss of proliferative capacity, these cells remained incapable of producing beta-globin chains and hence hemoglobin A.

Topics: Aclarubicin; Benzidines; Cell Differentiation; Drug Synergism; Erythroid Precursor Cells; Hemin; Hemoglobins; Humans; Leukemia, Erythroblastic, Acute; Tumor Cells, Cultured

The effect of adriamycin, daunomycin, N,N-dimethyladriamycin, N,N-dimethyldaunomycin, pyrromycin, marcellomycin, and aclacinomycin A on erythroid differentiation and glycoprotein synthesis in Friend erythroleukemia cells, clone F4-6 was investigated. Whereas N-dimethylated natural anthracyclines, pyrromycin, marcellomycin, and aclacinomycin A stimulated erythroid differentiation (induction of hemoglobin synthesis), this was not seen with adriamycin, daunomycin and their N-dimethylated derivatives. The incorporation of 3H-mannose in glycoprotein was inhibited by the N-alkylated natural anthracyclines at a concentration at which they induced erythroid differentiation. N,N-Dimethyladriamycin and N,N-dimethyldaunomycin only inhibited 3H-mannose incorporation into glycoprotein at cytotoxic concentrations. However, adriamycin and daunomycin did not inhibit glycoprotein synthesis, even at high cytotoxic concentrations. Aclacinomycin A decreased the incorporation of 3H-mannose into proteins earlier than the incorporation into dolichol-linked oligosaccharide intermediates. Tunicamycin, a specific inhibitor of glycoprotein synthesis, failed to stimulate differentiation in Friend erythroleukemia cells. These results indicate a structure-specific induction of the differentiation and inhibition of glycoprotein synthesis in Friend cells by N-alkylated anthracyclines. The inhibition of glycoprotein synthesis may be involved in the induction of differentiation by N-alkylated anthracyclines, but it cannot be the only target for the differentiation-inducing effect of these substances.

Topics: Aclarubicin; Animals; Anthracyclines; Antibiotics, Antineoplastic; Cell Differentiation; Cell Line; Cell Survival; Daunorubicin; Dose-Response Relationship, Drug; Doxorubicin; Friend murine leukemia virus; Glycoproteins; Hemoglobins; Leukemia, Erythroblastic, Acute; Mannose; Mice; Tunicamycin

Little is known about membrane target antigens for natural killer (NK) cells. Transferrin receptor and CD15 antigen might be two of these target structures. A novel antileukemic alkaloid, fagaronine, is able to induce hemoglobin synthesis in the K562 cell line. Numerous reports suggest relations between the expression of natural killer target structures and the differentiation stage of malignant cells. Effects of fagaronine on the expression of glycophorin A, transferrin receptor and CD15 antigen and susceptibility to NK-mediated lysis have been investigated in K562 cells and compared to those of two anthracyclines (Adriamycin and aclacinomycin A) known to be erythroid-differentiation inducers. When comparing the balance of differentiating effect and toxicity, the dose and time-dependent effects of the drugs, fagaronine and aclacinomycin, are equivalent on K562 cells. In experimental conditions where fagaronine (3500 nM), Adriamycin (40 nM) and aclacinomycin (15 nM) recruit the same percentage of hemoglobin-containing cells (40%-50%), glycophorin A expression increases and transferrin receptor expression decreases. Only Adriamycin treatment decreases CD15 antigen expression. In addition, Adriamycin and aclacinomycin, but not fagaronine, induce resistance to NK-mediated lysis. These data suggest that (a) it is unlikely that CD15 antigen and transferrin receptor, separately considered, can be unique target structures for NK cells; and (b) fagaronine is a potent erythroid inducer which, in our system, has similar effects to aclacinomycin without induced resistance to NK attack.

Topics: Aclarubicin; Alkaloids; Antigens, CD; Antineoplastic Agents; Benzophenanthridines; Cell Line; Cytotoxicity, Immunologic; Doxorubicin; Glycophorins; Hemoglobins; Humans; Immunity, Innate; Killer Cells, Natural; Leukemia, Erythroblastic, Acute; Phenanthridines; Receptors, Transferrin; Tumor Cells, Cultured

Treatment of Friend erythroleukemia cells with aclacinomycin A caused a concomitant inhibition of the uptake of 14C-alpha-aminoisobutyric acid (AIB) and of the incorporation of 3H-alanine into proteins. The decrease in amino acid uptake and incorporation into proteins was dose-dependent and reached a maximum of 60% within 3 hours at the concentration of aclacinomycin A, 200 ng/ml. A comparison of the effect on protein incorporation of 3H-alanine and cell proliferation by various anthracycline antitumor antibiotics in a concentration range of 50-200 ng/ml revealed that two other N-alkylated anthracyclines, pyrromycin and marcellomycin, are also potent inhibitors of the incorporation of amino acids into proteins. Inhibition of amino acid incorporation into proteins correlated well with the reduction of cell number at a later time. In contrast, adriamycin and daunomycin inhibited the incorporation of 3H-alanine into proteins only weakly, although these substances were highly active at inhibiting cell proliferation. Studies with an inhibitor of RNA synthesis, actinomycin D, suggest that the concomitant inhibition of amino acid uptake and incorporation into proteins observed with aclacinomycin A is not due to a reduced RNA synthesis. In addition, aclacinomycin A, up to a concentration of 10 micrograms/ml, did not inhibit protein synthesis in a cell-free translational system from rabbit reticulocytes. These results indicate that the reduction of amino acid incorporation into proteins after treatment of Friend erythroleukemia cells with aclacinomycin A may be due to a reduced uptake of amino acids. Inhibition of the transport of 14C-AIB may be indicative for an interaction of aclacinomycin A with the plasma membrane.

Topics: Aclarubicin; Alanine; Amino Acids; Aminoisobutyric Acids; Animals; Antibiotics, Antineoplastic; Cell Division; Dactinomycin; Dose-Response Relationship, Drug; Friend murine leukemia virus; Leukemia, Erythroblastic, Acute; Naphthacenes; Protein Biosynthesis; Rabbits; Tumor Cells, Cultured

The oligosaccharide-anthracyclines, aclacinomycin A, marcellomycin and musettamycin, are potent inducers of erythroid differentiation in hemopoietic cells lines of rodent and human origin. The present studies revealed that pyrromycin, a closely related monosaccharide-anthracycline, induced erythroid differentiation in Friend leukemia cells and in the human leukemia cell line K 562. Pyrromycin, marcellomycin and musettamycin, which possess an identical aglycone structure containing a Cl-hydroxyl group, exhibited relatively low optimal inductive concentrations. In contrast, the optimal inductive concentration of aclacinomycin A, which lacks the Cl-hydroxyl group, was markedly higher, i.e., the differentiation inducing capacity was lower. It should be noted, however, that the yield of differentiated cells following treatment with the monosaccharide-anthracycline pyrromycin was distinctly lower than that after treatment with the oligo-saccharide-anthracyclines, aclacinomycin A, marcellomycin or musettamycin. Thus, our data indicate that the efficacy of anthracyclines to induce erythroid differentiation is related to a) the presence of a Cl-hydroxyl group in the aglycone and b) the presence of an oligosaccharide side chain.

Topics: Aclarubicin; Animals; Anthracyclines; Antibiotics, Antineoplastic; Cell Line; Doxorubicin; Erythropoiesis; Friend murine leukemia virus; Humans; Leukemia, Erythroblastic, Acute; Mice

The clastogenic effect of the anthracycline antitumor antibiotics, N,N-dimethyldaunomycin and aclarcinomycin A, was studied in a murine hemopoietic cell line (Friend leukemia cells). A dose-dependent increase in chromatid lesions, i.e., achromatic lesions, chromatid breaks, chromatid deletions and triradial or quandriradial chromosomal exchange fiqures, was found. It appears that the clastogenicity of N,N-dimethyldaunomycin and aclacinomycin A is lower than that of the classic anthracycline, daunomycin, which is also a potent mutagen and carcinogen. The data demonstrate that the capacity of chemicals to induce point mutations and chromosomal aberrations may not necessarily be correlated: aclacinomycin A is devoid of mutagenic activity in bacterial (Salmonella typh.) and mammalian cell (HGPRT) mutagenesis assays, and is non-carcinogenic in rats. Nevertheless, it was now found to possess clastogenic activity.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Cell Line; Chromosome Aberrations; Daunorubicin; Leukemia, Erythroblastic, Acute; Leukemia, Experimental; Mice; Mutation; Naphthacenes

Thirteen previously untreated patients aged 70 and above with acute nonlymphocytic leukemia were treated with aclarubicin (ACR) alone. Among 10 cases (3, acute myelocytic leukemia; 4, acute myelomonocytic leukemia; 2, acute monocytic leukemia; and one, acute erythroleukemia) in which an evaluation was possible, 5 cases (3, acute myelomonocytic leukemia; and 2, acute monocytic leukemia) obtained complete remission (CR). The CR rate was 83% in 6 patients with acute myelomonocytic leukemia or acute monocytic leukemia. The median CR duration and survival was 7.5 and 10 + months, respectively. Although side effects of the drug on digestive system such as nausea, vomiting and anorexia were observed in all patients, they were controllable by conventional treatments. The results suggest that ACR is effective for the clinical management of elderly patients with acute nonlymphocytic leukemia, especially those with acute myelomonocytic leukemia or acute monocytic leukemia.

Topics: Aclarubicin; Aged; Antibiotics, Antineoplastic; Female; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Naphthacenes

The oligosaccharide anthracycline aclacinomycin A is of considerable clinical interest since, in comparison to adriamycin and daunomycin, the compound exhibits reduced cardiac toxicity and is devoid of mutagenicity/carcinogenicity. In addition, induction of differentiation in the human promyelocytic leukemia cell line HL 60 and possibly in one case of human acute myeloblastic leukemia by aclacinomycin A has been observed. Our data indicate that aclacinomycin A and related compounds, such as musettamycin and marcellomycin, are extremely potent inducers of differentiation in mouse (Friend leukemia cells, clone F4-6), rat (rat erythroleukemia, clone D5A1), and human erythroid cell lines (K 562 cell line) and that the relative inductive potency of marcellomycin and musettamycin, in general, is higher than that of aclacinomycin A. This potency difference may be due to the presence of a Cl-hydroxyl group in the aglycone of the marcellomycin and musettamycin molecule. Thus, oligosaccharide anthracyclines are a new class of inducers of erythroid differentiation. The high potency of these compounds, the possibility to study structure-activity relationships relative to their inductive potency and the fact that they induce erythroid differentiation in cells of different species as well as granulocytic differentiation in human cells should facilitate the study of basic mechanisms of hemopoietic differentiation. In addition, the therapeutical significance of these anthracycline effects should be investigated by studying, comparatively, the differentiation-inducing and antitumor effects of these compounds in primary leukemic cell cultures from patients.

Topics: Aclarubicin; Animals; Anthracyclines; Antibiotics, Antineoplastic; Cell Differentiation; Cell Line; Friend murine leukemia virus; Humans; Leukemia, Erythroblastic, Acute; Mice; Naphthacenes; Rats; Structure-Activity Relationship

A marked prolongation of QTc (corrected QT interval for heart rate) in ECG developed in two patients with acute leukemia during induction chemotherapy with aclarubicin, one of the anthracycline antibiotics. This ECG change was followed by ventricular fibrillation. No signs or symptoms of congestive heart failure were noted. The outcome in one case was fatal; in the other case, the ECG change was reversible. These observations suggest that QTc prolongation, which has been considered to be a sign of acute cardiotoxicity of anthracycline derivatives, may signal a clinical risk of ventricular fibrillation.

Topics: Aclarubicin; Adolescent; Adult; Antibiotics, Antineoplastic; Electrocardiography; Female; Heart Rate; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Male; Naphthacenes; Ventricular Fibrillation