aclarubicin and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Ph1-positive chronic myelocytic leukemia (CML) developing in a treated case of acute promyelocytic leukemia (APL) is reported. The patient was a 62-year-old male who was diagnosed as having APL in December 1978. He was treated with daunorubicin, Ara-C and 6MP and a complete remission was obtained 4 months later. But APL recurred in February 1981. He was treated with BHAC, aclarubicin, 6MP and prednisolone. He remained in continuous complete remission for 5 years, when all therapy was discontinued. After then, the leukocytes count continued to rise and a diagnosis of Ph1-positive CML was made in September 1986. His leukocytes count has been well controlled with the use of busulfan. The event in this case suggests a possibility of the Ph1-positive CML being a secondary disease related to prior long term chemotherapy.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisolone; Remission Induction

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

Expression of oncogenic Bcr-Abl inhibits cell differentiation of hematopoietic stem/progenitor cells in chronic myeloid leukemia (CML). Differentiation therapy is considered to be a new strategy for treating this type of leukemia. Aclacinomycin A (ACM) is an antitumor antibiotic. Previous studies have shown that ACM induced erythroid differentiation of CML cells. In this study, we investigate the effect of ACM on the sensitivity of human CML cell line K562 to Bcr-Abl specific inhibitor imatinib (STI571, Gleevec). We first determined the optimal concentration of ACM for erythroid differentiation but not growth inhibition and apoptosis in K562 cells. Then, pretreatment with this optimal concentration of ACM followed by a minimally toxic concentration of imatinib strongly induced growth inhibition and apoptosis compared to that with simultaneous co-treatment, indicating that ACM-induced erythroid differentiation sensitizes K562 cells to imatinib. Sequential treatment with ACM and imatinib induced Bcr-Abl down-regulation, cytochrome c release into the cytosol, and caspase-3 activation, as well as decreased Mcl-1 and Bcl-xL expressions, but did not affect Fas ligand/Fas death receptor and procaspase-8 expressions. ACM/imatinib sequential treatment-induced apoptosis was suppressed by a caspase-9 inhibitor and a caspase-3 inhibitor, indicating that the caspase cascade is involved in this apoptosis. Furthermore, we demonstrated that ACM induced erythroid differentiation through the p38 mitogen-activated protein kinase (MAPK) pathway. The inhibition of erythroid differentiation by p38MAPK inhibitor SB202190, p38MAPK dominant negative mutant or p38MAPK shRNA knockdown, reduced the ACM/imatinib sequential treatment-mediated growth inhibition and apoptosis. These results suggest that differentiated K562 cells induced by ACM-mediated p38MAPK pathway become more sensitive to imatinib and result in down-regulations of Bcr-Abl and anti-apoptotic proteins, growth inhibition and apoptosis. These results provided a potential management by which ACM might have a crucial impact on increasing sensitivity of CML cells to imatinib in the differentiation therapeutic approaches.

Topics: Aclarubicin; Apoptosis; bcl-X Protein; Benzamides; Caspase 3; Cell Differentiation; Cell Proliferation; Down-Regulation; Drug Screening Assays, Antitumor; Enzyme Activation; Erythroid Cells; fas Receptor; Fusion Proteins, bcr-abl; Gene Knockdown Techniques; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; MAP Kinase Signaling System; Myeloid Cell Leukemia Sequence 1 Protein; p38 Mitogen-Activated Protein Kinases; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrimidines

Topics: Aclarubicin; Daunorubicin; Doxorubicin; Flow Cytometry; Humans; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Tumor Cells, Cultured

Acquired resistance to anthracyclines is characterised by a lower sensitivity to these agents, associated with impaired accumulation of drug. We have examined the ability of aclacinomycin A (ACM) associated with doxorubicin (DOX), to increase intranuclear DOX concentrations and, consequently, to enhance cytotoxic effects against drug resistant cells in vitro. A recently developed microspectrofluorometric technique is used to measure intranuclear DOX concentrations in sensitive and DOX-resistant K562 cells treated with DOX and ACM. Fluorescence emission spectra are collected from a microvolume of single living cell nuclei. From both DOX and ACM model fluorescence spectra (free, DNA-bound and metabolites), the intranuclear spectral profile is analysed according to the amount of each component. This quantitative analysis determines intranuclear DOX concentrations with an error of 10%. Non-cytotoxic doses of ACM, in combination with DOX, increase cytotoxic activity of DOX against K562 resistant cells. When DOX-resistant cells are exposed simultaneously to ACM and DOX, significant increases in intranuclear DOX concentrations are found compared with the case of exposure to DOX alone. The measure of the intranuclear retention of DOX shows that ACM partly blocks the DOX efflux in resistant cell nuclei, resulting in enhanced accumulation of DOX. These data lead us to conclude that ACM-DOX association partly reverses the DOX resistance at clinically achievable concentrations.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Resistance; Drug Synergism; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Tumor Cells, Cultured

Sixteen children with refractory hematological malignancies were treated with a combination of BH.AC, aclacinomycin-A, 6-MP and predonisolone (BH-AC.AMP protocol). They were ALL(6), ANLL(8), CML(1) and NHL(1). The CR ratio was 17% in ALL, 50% in ANLL, and blast crisis of CML was treated successfully but NHL failed in the induction remission. Major complications were vomiting, nausea, gastrointestinal bleeding, hematuria and hemorrhagic cystitis. More than 10 days or 120 mg/m2 administration of aclacinomycin-A was thought to induce more severe side effects.

Topics: Aclarubicin; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Drug Administration Schedule; Female; Humans; Infant; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Lymphoma; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction