aclarubicin and Lymphoma

Aclacinomycin A (aclarubicin; ACM) is a new class II anthracycline antibiotic. Preclinical studies suggested that ACM had approximately equivalent antitumour activity but produced substantially less cardiotoxicity compared to other anthracyclines. Because of the recognized importance of these compounds in the treatment of haematological tumours, clinical trials of ACM were initiated in the late 1970s. ACM has been extensively evaluated in patients with relapsed leukaemia and advanced malignant lymphoma. Analysis of results compiled from Europe, Japan, and the United States shows that ACM is probably equivalent to doxorubicin for remission induction of patients with relapsed acute non-lymphoblastic leukaemia. Initial studies using ACM alone and in combination with standard cytotoxic drugs in previously untreated patients compare favourably with the best standard treatment for this disease. The antitumour activity of ACM in patients with acute lymphoblastic leukaemia or malignant lymphoma who have previously received doxorubicin or daunorubicin is low, and the issue of whether ACM lacks clinical cross-resistance to other anthracyclines is unresolved. Acute cardiac arrhythmias have been observed following administration of ACM, but congestive cardiomyopathy has been uncommon. Results to date all indicate that ACM has fulfilled its early expectations of antileukaemic activity and reduced toxicity. These hypotheses should now be evaluated in prospective, randomized trials with conventional anthracyclines.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Arrhythmias, Cardiac; Clinical Trials as Topic; Drug Evaluation; Drug Evaluation, Preclinical; Drug Resistance; Heart; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Naphthacenes

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Carubicin; Daunorubicin; Doxorubicin; Female; Glycosides; Hodgkin Disease; Humans; Leukemia; Lung Neoplasms; Lymphoma; Naphthacenes; Ovarian Neoplasms; Sarcoma

Topics: Aclarubicin; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Female; Hematuria; Humans; Infant; Leukemia; Lymphoma; Male; Multicenter Studies as Topic; Retrospective Studies

Aclacinomycin A (aclarubicin; ACM) is a new class II anthracycline antibiotic. Preclinical studies suggested that ACM had approximately equivalent antitumour activity but produced substantially less cardiotoxicity compared to other anthracyclines. Because of the recognized importance of these compounds in the treatment of haematological tumours, clinical trials of ACM were initiated in the late 1970s. ACM has been extensively evaluated in patients with relapsed leukaemia and advanced malignant lymphoma. Analysis of results compiled from Europe, Japan, and the United States shows that ACM is probably equivalent to doxorubicin for remission induction of patients with relapsed acute non-lymphoblastic leukaemia. Initial studies using ACM alone and in combination with standard cytotoxic drugs in previously untreated patients compare favourably with the best standard treatment for this disease. The antitumour activity of ACM in patients with acute lymphoblastic leukaemia or malignant lymphoma who have previously received doxorubicin or daunorubicin is low, and the issue of whether ACM lacks clinical cross-resistance to other anthracyclines is unresolved. Acute cardiac arrhythmias have been observed following administration of ACM, but congestive cardiomyopathy has been uncommon. Results to date all indicate that ACM has fulfilled its early expectations of antileukaemic activity and reduced toxicity. These hypotheses should now be evaluated in prospective, randomized trials with conventional anthracyclines.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Arrhythmias, Cardiac; Clinical Trials as Topic; Drug Evaluation; Drug Evaluation, Preclinical; Drug Resistance; Heart; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Naphthacenes

Topics: Aclarubicin; Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Clinical Trials as Topic; Cytarabine; Doxorubicin; Drug Evaluation; Humans; Infusions, Parenteral; Leukemia, Myeloid, Acute; Lymphoma; Middle Aged; Naphthacenes

Current evidence has suggested the possible involvement of ROS as signaling messengers in IL-1beta- or LPS-induced gene expression. We previously reported that both IL-1beta and LPS induce uPA in RC-K8 human lymphoma cells. Here, we provide evidence that ROS-generating anthracycline antibiotics, including doxorubicin and aclarubicin, upregulate uPA expression in 2 human malignant cell lines, RC-K8 and H69 small-cell lung-carcinoma cells. Both doxorubicin and aclarubicin markedly increased uPA accumulation in RC-K8- and H69-conditioned medium in a dose-dependent manner. In each case, maximal induction was observed at a sublethal concentration, i.e., at a concentration where cell growth was slightly inhibited. Both doxorubicin and aclarubicin increased uPA mRNA levels, and induction in each case reached the maximal level 9 hr after stimulation. Doxorubicin barely changed the half-life of uPA mRNA and activated uPA gene transcription. Antioxidants such as NAC and PDTC inhibited doxorubicin-induced uPA mRNA accumulation. Microarray analysis, using Human Cancer CHIP version 2 (Takara Shuzo, Kyoto, Japan), in which 425 human cancer-related genes were spotted on glass plates, revealed that uPA is 1 of 3 genes that were clearly upregulated in H69 cells by doxorubicin stimulation. These findings suggest that the anthracycline induces uPA in human malignant cells by activating gene transcription in which ROS may be involved. Therefore, by upregulating uPA expression, the anthracycline may influence many biologic cell functions mediated by the uPA/plasmin system.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Antioxidants; Blotting, Northern; Cell Nucleus; Cycloheximide; Dactinomycin; Dose-Response Relationship, Drug; Doxorubicin; Humans; Lung Neoplasms; Lymphoma; Oligonucleotide Array Sequence Analysis; Protein Synthesis Inhibitors; RNA, Messenger; Time Factors; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator

The following presents 6 cases of therapy related leukemia (TRL) along with discussion of their clinical features in comparison with those previously reported in Japan. Common primary malignancies were mammalian cancer, lung cancer and malignant lymphoma in both groups. It was observed that, 1) average age was higher (68 years), 2) average latent period from primary malignancy to leukemia was longer (10 years), particularly in patients treated solely with radiation, 3) in 4 out of 6 patients (67%) karyotype analysis of leukemia cells showed normal results, but in one case previously administered etoposide, translocation involving 15q+, 17q- was noted, and 4) the CR ratio in our cases was 83%; half the cases are still alive at 10 months of follow-up, while in previously reported cases the CR ratio was 41%, and the median survival time was 12 months according to Kaplan-Meier analysis. Although poor response to conventional chemotherapy has been reported in TRL patients, the present data indicated TRL in some cases to achieve complete response and long-term survival. Aggressive chemotherapy should be considered for such patients.

Topics: Aclarubicin; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Daunorubicin; Female; Humans; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Lung Neoplasms; Lymphoma; Male; Middle Aged; Neoplasms, Second Primary; Survival Rate

Topics: Aclarubicin; B-Lymphocytes; Cell Division; Doxorubicin; Humans; Hybridomas; Liposomes; Lymphoma; Octoxynol; Phosphatidylcholines; Polyethylene Glycols; Spectrometry, Fluorescence

We developed an effective method for harvesting large numbers of peripheral blood stem cells (PBSC) for use in autotransplantation. Twenty patients with hematological malignancies were treated with high doses of Ara-C (12 g/m2) and VP-16/aclarubicin followed by administration of rhG-CSF (50 micrograms/m2). The optimal time for starting PBSC collection was determined by monitoring the CD34-positive stem cells in blood using immunomagnetic beads. PBSC were collected with a CS-3000 blood cell separator. A total blood volume between 7000 and 9000 ml was processed in each apheresis. Under these conditions, a total of 64 apheresis procedures was performed in the 20 patients. The mean numbers of mononuclear cells and of CFU-GM harvested per apheresis were 4.1 x 10(8)/kg and 110 x 10(4)/kg, respectively. A number of CFU-GM sufficient for engraftment (> 30 x 10(4)/kg) could be harvested by a single apheresis in 15 of the 20 patients. So far, 11 patients have been transplanted with PBSC and obtained rapid hematopoietic recovery. The median time to recover neutrophils more than 0.5 x 10(9)/l was 10 days, and that for platelets 50 x 10(9)/l was 11 days. This method for harvesting large numbers of PBSC allows safer autotransplantation in patients with chemoradiosensitive tumors, and is applicable to older patients.

Topics: Aclarubicin; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Cells; Blood Component Removal; Blood Transfusion, Autologous; Cytarabine; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukemia; Lymphoma; Male; Middle Aged; Recombinant Proteins

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

Nineteen patients with refractory non-Hodgkin's lymphoma were treated with a combination of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (150-200 mg/m2), aclacinomycin (15 mg/m2), etoposide (70 mg/m2 i.v. or 100 mg/m2 p.o) and prednisolone (20 mg/m2) (ABEP regimen). Patients who achieved complete remission (CR) received 10 courses of consolidation therapy with ACOP-E chemotherapy (adriamycin, cyclophosphamide, vincristine, prednisolone and etoposide). Seven patients achieved CR and three partial remission. Twelve patients with fresh non-Hodgkin's lymphoma stage IV were treated with ABEP regimen. CR was obtained in eight patients (66.7%). The median duration of CR was 11+ alpha months. Hematological toxicity was a dose-limiting factor but this was manageable.

Topics: Aclarubicin; Adult; Aged; Alopecia; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Leukopenia; Lymphoma; Male; Middle Aged; Naphthacenes; Prednisolone; Thrombocytopenia; Vincristine

Aclarubicin, a new anthracycline antibiotic with less cardiotoxicity relative to doxorubicin, was utilized in 33 patients with advanced lymphoma at a dose of 100 mg/m2 iv every 3 weeks. Five patients developed partial response (2, 2, 2, 4, and 8+ months). None of the patients who had received prior anthracycline responded to aclarubicin. The dose-limiting toxic effect was hematologic. One of ten patients having serial measurements of cardiac function had a significant reduction in left ventricular function, but cardiac symptoms did not occur.

Topics: Aclarubicin; Adult; Aged; Drug Evaluation; Heart; Humans; Leukocyte Count; Lymphoma; Middle Aged; Naphthacenes; Platelet Count; Stroke Volume

Characteristics of Drug-Resistant Cell Sublines L5178Y: We isolated aclarubicin (ACR)-, adriamycin (ADM)-, bleomycin (BLM-, and macromomycin (MCR)-resistant (r) cell sublines. The BLMr cell line did not show cross-resistance to other drugs. The ACRr and ADMr cell lines displayed cross-resistance to other anthracyclines. The drug-resistance of these cell lines was due to changes in membrane transport. All four resistant cell lines showed higher activity of membrane alkaline phosphodiesterase (APD) than the parental cells. The APD of the BLMr scell line differed from that of the parental line in molecular size. 2-Crotonyloxymethyl-4, 5, 6-trihydroxycyclohex-2-enone: We isolated an inhibitor of APD from a Streptomyces species. This substance inhibited the drug-resistant cell lines of L5178Y more markedly than the parental line in culture and showed synergistic effects with ACR against the ACRr cell line. It was an SH-inhibitor, and prevented DNA polymerase alpha and some mitotic processes. Transplantability of Drug-Resistant L5178Y Cells: DBA/2 mice, the syngeneic host, exhibited more resistance to ip transplantation of drug-resistant cell lines than parental cells. The animals showed the strongest resistance to the ACRr cell line. Treatment with cyclophosphamide markedly reversed the host resistance, suggesting that the immune mechanism was involved in the resistance. The ACRr cells were sensitive to NK cells, but the parental cells were not. Injection with anti-asialo GM1 markedly decreased host resistance. The results suggested that NK cells were involved in the transplantation resistance of mice to the ACRr cells. 230-Kilodalton Membrane Protein of ACRr Cells Identified by Monoclonal Antibody: We prepared monoclonal antibodies to the ACRr cells, and found that a monoclonal antibody, designated SC438, specifically agglutinated the ACRr cells. A specific 230K membrane protein was found in the ACRr cells by immunoprecipitation. Natural BLM Resistance of Chinese Hamster V79 Cells: V79 cells were more resistant to BLM than CHO cells. This natural drug-resistance was is due to higher BLM hydrolase activity. We isolated BLM cell lines, and found that BLM supersensitivity was not due to BLM hydrolase, but to decreased repairing activity of DNA damage.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Bleomycin; Cell Cycle; Cell Line; Cells, Cultured; Cricetinae; Cricetulus; Daunorubicin; Doxorubicin; Drug Resistance; Lymphoma; Mice; Naphthacenes; Neoplasms, Experimental

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Drug Evaluation; Humans; Lymphoma; Middle Aged; Naphthacenes

Topics: Aclarubicin; Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Drug Administration Schedule; Female; Humans; Lymphoma; Male; Middle Aged; Naphthacenes

A number of hybridomas producing antibodies to plasma membrane of an aclarubicin-resistant subline of L5178Y cells were obtained. Among the hybridoma antibodies, one was found by agglutination tests to react with the aclarubicin-resistant cell line, but not significantly with the parental and adriamycin-, bleomycin- and macromomycin-resistant cell lines. The monoclonal antibody was designated SC438, and showed complement-dependent cytolytic activity more markedly against the aclarubicin-resistant cells than against the parental cells. Fluorographs of [14C] leucine-labeled aclarubicin-resistant cells demonstrated two protein bands of 230k and 20k daltons, which were precipitated by the SC438 antibody. The former seemed to be specific for the aclarubicin-resistant cells.

Topics: Aclarubicin; Animals; Antibodies, Monoclonal; Antibody Specificity; Antigens, Neoplasm; Antigens, Surface; Cell Line; Cell Membrane; Drug Resistance; Lymphoma; Membrane Proteins; Mice; Molecular Weight; Naphthacenes; Neoplasms, Experimental

Aclacinomycine-A (ACM), a new anthracycline derivative, was administered intravenously to 50 patients in doses of 10-30 mg/m2/day for periods of 6 to 30 days. Among the 45 patients who could be assessed, 17 were suffering from acute myeloid leukaemia, 19 from acute lymphoid leukaemia and 9 from non-hodgkin lymphoma. The results confirmed those first published by the authors in 1978 and led them to propose new measures aimed at reducing the toxicity of ACM. Depending on the dosage, complete or partial (more than 50%) remissions were obtained in patients with acute myeloid leukaemia. In the 19 patients with acute lymphoid leukaemia, complete remission was observed in 2 and partial remission in 2. Among the 9 patients with non-hodgkin lymphoma, there was 3 complete and 1 partial remissions. ACM did not produce alopecia and, as predicted by the authors' experimental study on hamsters, did not have major cardiac toxicity. The gastrointestinal toxicity, which had forced a reduction of the total dose in the first trial, proved moderate, even with normal dosage.

Topics: Aclarubicin; Acute Disease; Adolescent; Adult; Antibiotics, Antineoplastic; Child; Child, Preschool; Drug Evaluation; Female; Humans; Leukemia; Lymphoma; Male; Middle Aged; Naphthacenes