aclarubicin and Breast-Neoplasms

The nuclear enzyme DNA topoisomerase II is a major target for antineoplastic agents. All topoisomerase II-directed agents are able to interfere with at least one step of the catalytic cycle. Agents able to stabilize the covalent DNA topoisomerase II complex (also known as the cleavable complex) are traditionally called topoisomerase II poisons, while agents acting on any of the other steps in the catalytic cycle are called catalytic inhibitors. Thus, catalytic topoisomerase II inhibitors are a heterogeneous group of compounds that might interfere with the binding between DNA and topoisomerase II (aclarubicin and suramin), stabilize noncovalent DNA topoisomerase II complexes (merbarone, ICRF-187, and structurally related bisdioxopiperazine derivatives), or inhibit ATP binding (novobiocin). Some, such as fostriecin, may also have alternative biological targets. Whereas topoisomerase II poisons are used solely for their antitumor activities, catalytic inhibitors are utilized for a variety of reasons, including their activity as antineoplastic agents (aclarubicin and MST-16), cardioprotectors (ICRF-187), or modulators in order to increase the efficacy of other agents (suramin and novobiocin). In this review, the mechanism and biological activity of different catalytic inhibitors is described, with emphasis on therapeutically used compounds. We will then discuss future development and applications of this interesting class of compounds.

Topics: Aclarubicin; Antineoplastic Agents; Breast Neoplasms; DNA Topoisomerases, Type II; Enzyme Inhibitors; Female; Hematologic Neoplasms; Humans; Lung Neoplasms; Male; Piperazines; Prostatic Neoplasms; Sarcoma; Topoisomerase II Inhibitors

Topics: Aclarubicin; Anthraquinones; Antibiotics, Antineoplastic; Breast Neoplasms; Carubicin; Cell Survival; Daunorubicin; Doxorubicin; Drug Evaluation; Epirubicin; Heart; Humans; Idarubicin; Leukemia; Menogaril; Mitoxantrone; Naphthacenes; Nogalamycin; Sarcoma; Structure-Activity Relationship

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

To determine the efficacy of aclarubicin hydrochloride in local control of malignant pericardial effusion, the authors carried out a trial of pericardial drainage with local administration of this agent in five patients, whose effusions had produced cardiac tamponade. All patients were women, and their primary cancers, all initially treated surgically, had arisen in the breast (two patients), or lung (three patients). Mean patient age was 54.2 years (range, 43-62). In four patients, improvement permitted removal of the drainage catheter. Two patients (40%) had a complete remission of the malignant pericardial effusion. The other three patients were difficult to evaluate because nonpericardial metastases limited their survival. All patients, however, showed disappearance of malignant cells from the pericardial sac with no cytopathologically demonstrable recurrence. In our few patients, intrapericardial aclarubicin appeared to be highly effective against malignant pericardial effusion.

Topics: Aclarubicin; Adult; Antineoplastic Agents; Breast Neoplasms; Cardiac Tamponade; Catheterization; Drainage; Female; Humans; Injections, Intralesional; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Pericardial Effusion; Treatment Outcome

ACR-CH, which consists of aclarubicin (ACR) adsorbed onto activated carbon particles, was developed for locoregional chemotherapy for breast cancer. Thirty patients with breast cancer received an ACR (10 mg) injection intra- and peri-tumorally, either as ACR-CH or as ACR aqueous solution (ACR-AQ) 5 min before the operation for breast cancer. The ACR concentrations were significantly higher in the peritumoral regions and regional lymph nodes, and were also significantly lower in the blood plasma in patients given ACR-CH versus patients given ACR-AQ.

Topics: Aclarubicin; Adsorption; Antibiotics, Antineoplastic; Breast Neoplasms; Charcoal; Drug Carriers; Female; Humans; Lymph Nodes; Lymphatic Metastasis; Middle Aged

A new dosage formulation (ACR-CH), composed of aclarubicin (ACR) bound to fine activated carbon particles, was developed for the treatment of lymph node metastases in patients with breast cancer. In a mice experimental model, ACR-CH had superior therapeutic effects on lymph node metastases compared to the same dose of ACR aqueous solution. In clinical trials, patients with breast cancer received a local injection of 10 mg/person of ACR in the form of ACR-CH or ACR aqueous solution just before mastectomy. In the regional lymph nodes removed by the operation, the ACR concentration of 40.7 micrograms/g in patients given ACR-CH was higher than the 25.1 micrograms/g in patients given ACR aqueous solution, whereas in blood plasma the concentration was higher in patients given ACR aqueous solution than in those given ACR-CH.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Carbon; Combined Modality Therapy; Delayed-Action Preparations; Female; Humans; Leukemia P388; Lymphatic Metastasis; Mastectomy; Mice

We treated breast cancer patients with Ps node involvement using an extended surgery (Ps+Sc, n = 17, group A) combined with targeting chemotherapy and compared the survival rate by this method with that by the dissection of the Ps node alone (n = 23, group B) to assess the prognosis of advanced breast cancer by extended surgery. 1) Overall patients: The disease-free survival rate was significantly higher in group A, while the overall survival rate was not significant. 2) Survival rate in relation to the number of metastatic Ps nodes or axillary (Ax) nodes: In patients with Ps = 1 or Ax < or = 3, the difference in the overall and disease-free rates were not significant. In patients with Ps > or = 2 or Ax > or = 4, both overall and disease-free rates were significantly higher in group A. It was therefore suggested that extended surgery should be performed if metastasis is found in 2 or more Ps nodes in the frozen section intraoperatively. The result of this study, although it is not a randomized trial, suggested a possibility that extended surgery may improve the prognosis of advanced breast cancer.

Topics: Aclarubicin; Adult; Breast Neoplasms; Carbon; Clavicle; Combined Modality Therapy; Disease-Free Survival; Humans; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Mastectomy, Extended Radical; Middle Aged; Prognosis; Sternum

Aclarubicin is an anthracycline antibiotic that differs from doxorubicin in its structure, mechanism of action, and preclinical toxicity profile, especially its reduced cardiotoxicity. We therefore conducted a side-by-side in vivo and in vitro trial of this agent in metastatic breast-cancer patients and their biopsied tumor specimens, respectively. Aclarubicin (100 mg/m2) was given by intravenous infusion every 3 weeks to 22 patients with objectively measurable metastatic breast cancer, 15 of whom had not previously received doxorubicin. The dose-limiting toxicity consisted primarily of leukopenia and severe nausea and vomiting. No objective response was observed in the 19 evaluable patients. After disease progression, 10 of the 15 doxorubicin-naive patients were treated with doxorubicin; 6 patients achieved a partial response, including 4 who responded to doxorubicin alone and 2 who responded to doxorubicin in combination with thiotepa and vinblastine. Tumor specimens were obtained from 14 of the 22 patients prior to the start of therapy and were tested for in vitro sensitivity to aclarubicin and doxorubicin using a soft agar colony-forming assay. Adequate colony growth occurred in 9 of 14 cultured tumor specimens. All 9 specimens, including 3 obtained from doxorubicin-naive patients, demonstrated in vitro resistance to aclarubicin. In all, 1 of 3 specimens taken from doxorubicin-naive patients demonstrated in vitro sensitivity to doxorubicin, whereas 6 tumor specimens obtained from patients who had undergone prior doxorubicin therapy demonstrated in vitro resistance. The patient whose tumor demonstrated in vitro doxorubicin sensitivity responded to a doxorubicin regimen after failing aclarubicin treatment; in vitro doxorubicin resistance correlated with clinical resistance in all cases. We conclude that aclarubicin is inactive in metastatic breast cancer at the dose and schedule used. Side-by-side in vivo and in vitro trials are feasible and could be useful in the development of investigational agents with activity greater than that of aclarubicin and, particularly, in the evaluation of analogs of clinically active drugs.

Topics: Aclarubicin; Adult; Aged; Breast Neoplasms; Doxorubicin; Drug Resistance; Female; Humans; In Vitro Techniques; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Tumor Stem Cell Assay

Topics: Aclarubicin; Adenocarcinoma; Adult; Aged; Alopecia; Antibiotics, Antineoplastic; Breast Neoplasms; Drug Evaluation; Female; Humans; Middle Aged; Naphthacenes; Nausea; Neoplasm Metastasis; Neutropenia

A 46-year-old woman had undergone a mastectomy in 1994, and metastases to the lung, bones and liver were detected in 1998. Brain metastases were detected later. Chemotherapy consisting of docetaxel, aclarubicin and UFT was administered, and image diagnosis revealed that CR was achieved. The chemotherapy was continued on a long-term basis, both as an inpatient and outpatient. The total administered doses have reached 2,000 mg of docetaxel and 1,000 mg of aclarubicin. The CR is being maintained as of this writing, 2 years and 4 months after the detection of the metastases. The patient's course continues to be monitored.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Docetaxel; Drug Administration Schedule; Drug Combinations; Female; Humans; Liver Neoplasms; Lung Neoplasms; Middle Aged; Paclitaxel; Taxoids; Tegafur; Uracil

Echocardiographic reports on 144 adults receiving anthracycline therapy and 18 controls were reviewed for the possible relationship between dosage and ejection fractions. The cardiotoxicity of each anthracycline drug was evaluated as follows: Pirarubicin = 0.8, Mitoxantrone = 3.4, Daunorubicin = 0.5, Aclarubicin = 0, and Epirubicin = 0.6 with Doxorubicin = 1 as a control. As a whole, the ejection fractions, which decreased subsequently compared with increasing amount of dosage, showed a remarkable decrease at the dosage level of 600 mg/m2. However, the ejection fractions differed among individual patients. It was predicted that heart failure would not develop when the ejection fractions exceeded 55%. It is desirable to stop anthracycline therapy when the ejection fractions drop to 55%.

Topics: Aclarubicin; Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Breast Neoplasms; Daunorubicin; Doxorubicin; Echocardiography; Epirubicin; Female; Heart; Hematologic Diseases; Humans; Male; Middle Aged; Mitoxantrone; Radionuclide Imaging; Stroke Volume

A new dosage formulation (ACR-CH), composed of aclarubicin (ACR) bound to fine activated carbon particles, has been developed for the treatment of lymph node metastases in breast cancer. ACR-CH is designed to (a) adsorb a great amount of aclarubicin and desorb in a free state; (b) distribute a greater amount of ACR for a longer period of time selectively to the regional lymph nodes; (c) be decreased in the systemic toxicity; and (d) enhance its therapeutic effect on lymph node metastases. In this clinical trial in 20 patients with breast cancer, ACR-CH was injected intra- and peritumorally just before operation for breast cancer, and we examined the extent of blackened nodes produced by ACR-CH. ACR-CH blackened about 70% of the axillary lymph nodes with cancer metastasis as well as the nodes without metastasis. In conclusion, ACR-CH will be useful for dissection of lymph nodes by visualizing the nodes during operation for breast cancer.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Carbon; Dosage Forms; Female; Humans; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Rats

We have previously detected by immunofluorescent assay that the cellular localization of nucleophosmin/B23 (NPM) shifts from the nucleolus to the nucleoplasm (NPM-translocation) after exposure of cells to multiple agents. In order to improve the quantification of the NPM-translocation, we have developed a digital imaging technique. Human Lo leukemia cells, MCF-7 breast carcinoma cells, and fresh human leukemia cells were exposed to anthracyclines or actinomycin D for 4 h. The degree of NPM-translocation was determined and presented as the localization index (LI). Control cells had a LI of about 10, which indicates that the majority of NPM was localized in nucleoli. The LI for drug-treated cells decreased in a dosage- and time-dependent manner. The effect of two classes of anthracycline (daunomycin and aclacinomycin A) and different types of intercalators (daunomycin and actinomycin D) had additive effects on induction of NPM-translocation. The imaging procedure was easily applied to fresh leukemia cells, thus providing useful information regarding drug effects on cancer cells.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Nucleolus; Dactinomycin; Daunorubicin; Dose-Response Relationship, Drug; Fluorescent Antibody Technique; Humans; Image Processing, Computer-Assisted; Leukemia, Monocytic, Acute; Nuclear Proteins; Nucleophosmin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured

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

Breast and colon tumor response to emoxyl, a nitroxyl derivative of daunomycin, was detected using human tumor heterotransplantation under the renal capsule of immunocompetent mice. The substitution of adriamycin by emoxyl in the combined therapy led to enhanced therapeutic efficacy. The evidence of enhanced response of breast tumors to emoxyl obtained during the histologic examination of xenografts is in good agreement with measurements of tumor fragment weight. It is suggested to use a quantitative kinetic index kappa calculated by the method of equivalent exponents for objective evaluation of tumor response to the drugs.

Topics: Aclarubicin; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Colonic Neoplasms; Cyclophosphamide; Daunorubicin; Dose-Response Relationship, Drug; Doxorubicin; Evaluation Studies as Topic; Fluorouracil; Humans; Mice; Neoplasm Transplantation; Subrenal Capsule Assay

ACR-CH was injected prior to surgery of breast cancer. Incidence of black staining of regional lymph nodes and concentration of ACR in the nodes were examined in order to evaluate the usefulness of preoperative local injection of ACR-CH. 1) In 13 cases of extended radical mastectomy, black staining was seen in nodes of all the regions. Especially, in parasternal, retromanubrial, anterior mediastinal and supraclavicular nodes, 46% or more of the nodes were stained and ACR concentration of 6-7 micrograms/g was obtained. 2) When incidence of black staining of the metastasis-free nodes was compared with that of the nodes with metastasis, it was 79% in the metastasis free nodes and 42% in the nodes with metastasis. The average ACR concentration was 54.16 +/- 123.16 in the stained nodes and 2.58 +/- 3.59 in unstained nodes, the former being significantly higher than the latter. 3) Majority of the stained nodes with metastasis had only very small metastatic foci and nodes with significant metastasis were only very rarely stained. 4) In conclusion, we believe that anticancer effect of ACR-CH can be expected to small metastatic foci in the parasternal lymph nodes and more distal nodes, dissection of which tends to be incomplete at extended radical mastectomy, as well as to free cancer cells in the lymph vessels.

Topics: Aclarubicin; Breast Neoplasms; Carbon; Female; Humans; Injections, Intralesional; Lymphatic Metastasis; Mastectomy, Extended Radical; Preoperative Care

Variants of Friend leukemia cells (FLC) selected for resistance to either adriamycin (ADM), daunorubicin (DNR) or aclacinomycin A (ACM) by step-wise exposure to each drug, were found to be cross-resistant to ADM and DNR but not to ACM. In addition, an epithelial cell line isolated from normal monkey kidney (CV-1) was found to be intrinsically resistant to ADM and DNR but not to ACM. In contrast, a human breast carcinoma cell line (MCF-7) was found to be sensitive to all three compounds. In these latter cell lines as well as in the FLC variants, lowered intracellular amounts of ADM and DNR correlated with resistance, but ACM levels were the same in sensitive and resistant cells. When cells with either acquired or intrinsic resistance were treated with ACM in combination with ADM or DNR, significant increases in the intracellular amounts of these latter compounds were found. Increased drug accumulation in resistant cells treated this way was accompanied by increased cytotoxicity. When resistant cells were exposed to ACM in combination with other anthracyclines, similar results were obtained. In comparison, these phenomena were not observed when either one of the sensitive cell types (parental FLC and MCF-7) were treated similarly. Since ADM and DNR resistant cells are sensitive to ACM and their resistance circumvented by ACM, this drug may have important clinical applications when used in combination with other anthracyclines.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Daunorubicin; Doxorubicin; Drug Resistance; Drug Synergism; Epithelial Cells; Humans; Kidney; Leukemia, Experimental; Naphthacenes; Tumor Cells, Cultured

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Breast Neoplasms; Doxorubicin; Female; Humans; Middle Aged; Naphthacenes

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Middle Aged; Naphthacenes; Neoplasm Metastasis

Aclacinomycin A (ACM) in a daily dose of 30 mg/m2 was infused over 1 h on 4 consecutive days to 50 patients. Myelotoxicity was acceptable, nausea and vomiting was frequent, hair loss was mild. Grade 1-2 cardiac rhythm abnormalities were observed in 12% of the patients. Between days 1 and 4 the heart rate and the corrected Q-T interval increased while the amplitude of the T wave decreased significantly, cardiac contractility remained unchanged. In 24 evaluable breast cancer patients 1 complete remission (4%) and 2 partial remissions (8%) lasting for only 2-3 months were seen. None of the 8 patients suffering from ovarial cancer benefitted from ACM therapy.

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Bone Marrow; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Electrocardiography; Female; Heart; Humans; Male; Middle Aged; Naphthacenes; Neoplasms; Ovarian Neoplasms

A multidisciplinary treatment including intra-arterial infusion chemotherapy as an induction therapy was administered to 55 patients with locally advanced breast cancer. Intra-arterial chemotherapy conducted preoperatively produced marked responses in primary and lymph node lesions with 78% complete + partial response (CR + PR), subsequently permitting extended radical mastectomy. Histologic examination of resected specimens also revealed that 33% of the patients had no viable cancer cells remaining in their lesions. Five-year and 10-year survival rates were 57% and 41%, respectively, compared with 24% and 18%, respectively for the 17 patients of historic control. Patients showing better local responses to intra-arterial chemotherapy had longer survival time with less frequent local recurrences. Intra-arterial chemotherapy is an effective modality for the treatment of locally advanced breast cancer.

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intra-Arterial; Middle Aged; Mitomycin; Mitomycins; Naphthacenes; Time Factors

A series of experiments with ACM was performed to evaluate the effect for local treatment of malignant pleurisy from the view points of (1) clinical response, (2) pharmacokinetics following intrapleural administration, and (3) pleural reaction. The results were as follows: (1) In 6 patients with malignant pleural effusion, ACM was intrapleurally administered at a dose of 40 mg. In 4 out of the 5 evaluable cases, an extreme decrease in the pleural fluid volume and suppression of reswelling were observed, including 2 cases found to be negative for tumor cells upon cytodiagnosis. (2) In 5 patients, the pharmacokinetics was studied by using compartment model. The clearance curves of ACM in pleural fluid were described by a two-compartment model. The mean half lives of initial phase and terminal phase were 0.78 hr, and 15.28 hr, respectively. The time to reach the maximal whole blood level was 1 to 2 hrs after pleural administration, followed by a slow decline. (3) The pleural reaction to ACM was studied in rabbits by scanning and transmission electron microscope. At a dose of 4 mg per kg of body weight, the shortened microvilli, the degenerated mesothelial cells and the disappearance of basement membrane were observed. On the basis of these findings, we suggest that ACM might be an agent of choice in the treatment of malignant pleurisy.

Topics: Aclarubicin; Adenocarcinoma; Aged; Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Carcinoma, Small Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Naphthacenes; Pleural Effusion; Rabbits

Topics: Aclarubicin; Adult; Aged; Breast Neoplasms; Drug Evaluation; Female; Gastrointestinal Diseases; Humans; Leukopenia; Middle Aged; Naphthacenes; Thrombocytopenia

Aclacinomycin (ACM), a new anthracycline antibiotic compound, was given intravenously q x 3 to 6 weeks in a dosage of 4 x 60 mg/4 days to 10 patients with metastasizing breast cancer and 5 patients with gastric carcinoma. Breast cancer patients, prior to ACM had extensive cytotoxic and hormonal treatments, gastric cancer patients received ACM as a first chemotherapeutic tumor treatment. No life-threatening hematologic toxicities could be noticed. All patients experienced moderate to severe gastrointestinal toxicities. No patient had considerable hair loss. 4 patients showed clinical signs of cardiac dysfunction: 1 ECG changes, 4 developed edema of lower extremities, 2 developed pericardial effusion. Moreover, 1 patient developed significant elevation of the pulmonary capillary wedge pressure (PCW) and prolongation of the systolic time intervals indicating pulmonary congestion grade I to II (Braunwald). No significant increase in heart volume was registered. Clear signs of cardiotoxicity could be demonstrated in patients pretreated with adriamycin exclusively. In animal experience, ACM had been reported as less cardiotoxic as compared to adriamycin. Present studies seem to indicate ACM being considerably cardiotoxic at relatively low cumulative dosages. Among the 15 patients there was one with metastatic breast cancer pretreated with adriamycin and resistant to that drug in whom partial remission was achieved. The other patients did not objectively respond to ACM therapy. 3 out of 5 patients with gastric cancer had stabilisation of the disease but no objective response.

Topics: Aclarubicin; Adult; Antibiotics, Antineoplastic; Breast Neoplasms; Doxorubicin; Female; Gastrointestinal Neoplasms; Heart Failure; Humans; Male; Middle Aged; Naphthacenes