aclarubicin and Neoplasms

Anthracyclines including doxorubicin, epirubicin, daunorubicin, aclarubicin are extensively used as chemotherapeutic agents for treatment of hematological and other malignancies. In cancer therapy anthracyclines are often used in combinations with other chemotherapeutic drugs and agents for molecularly targeted therapy. Anthracyclines are effective and powerful antineoplastic drugs with wide spectrum of application but active use of preparations of this group is limited because of such side effects as cardiotoxicity, myelotoxicity, thromboembolism, alopecia, etc. Cardiotoxicity is the most severe side effect of anthracycline administration. Clinical studies have shown that it is progressive and irreversible. Therefore, early detection and prevention of anthracycline cardiotoxicity has become an important trend in cardiology.

Topics: Aclarubicin; Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Doxorubicin; Epirubicin; Humans; Neoplasms

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Topics: Aclarubicin; Amino Acid Sequence; Animals; Anthracyclines; Antineoplastic Agents; Carubicin; Daunorubicin; Doxorubicin; Drug Resistance, Neoplasm; Humans; Neoplasms

Doxorubicin is an essential component of the treatment of aggressive lymphoma, childhood solid tumors, bone and soft tissue sarcomas, and breast cancer and additional indications are emerging. On the other hand, daunorubicin has occupied the central position of interest in the treatment of acute leukemia. Epirubicin has a spectrum very similar to doxorubicin but lesser toxicity. The ability to protect against cardiotoxicity with ICRF-187 further enhances clinical interest in exploiting modifications in doze intensity to therapeutic advantage. Idarubicin has at least equivalent activity to daunorubicin and doxorubicin in leukemia. New areas of research in relation to anthracycline antibiotics include introduction of new the analogs, insight into mechanisms of resistance, the reversal of multidrug resistance in vitro, the protection of cardiac toxicity, and the study of other important biochemical reactions relevant to cytotoxicity. Orally active anthracyclines such as idarubicin and compounds which lack cross-resistance with the parent drugs or have other mechanisms for cytotoxicity are being developed. It is likely that these modifications will lead to an expanding therapeutic spectrum for these already widely useful drugs.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Cardiomyopathies; Carubicin; Doxorubicin; Drug Resistance; Epirubicin; Humans; Idarubicin; Menogaril; Molecular Structure; Neoplasms; Nogalamycin

Optimal dose schedule of administration of antitumor antibiotics-bleomycin, adriamycin and aclacinomycin A-was reviewed from a point of view of pharmacokinetics. In case of bleomycin, according to its fast disappearance from blood, fast and significant excretion into urine, cell-cycle-dependent antitumor action, fast repair of potentially lethal damage, and pulmonary toxicity due to damage in endothelium of pulmonary capillary caused by high blood concentration of bleomycin, continuous intravenous administration seems to be a useful method to prevent pulmonary toxicity and to enhance antitumor effect. In case of adriamycin, according to its cardiotoxicity due to damage in cardiac muscle cell caused by high blood concentration on adriamycin, drip infusion or weekly low dose schedule is a safe, effective therapy to prevent cardiomyopathy. In case of aclacinomycin A, based on the mechanism of action of its marked inhibition in RNA synthesis compared to adriamycin, daily administration for certain days is an effective method.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Bleomycin; Doxorubicin; Drug Administration Schedule; Humans; Infusions, Parenteral; Kinetics; Naphthacenes; Neoplasms; Peplomycin

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Chemical Phenomena; Chemistry, Physical; Clinical Trials as Topic; Cricetinae; Culture Media; Doxorubicin; Drug Evaluation, Preclinical; Drug Resistance; Heart; Humans; Mice; Naphthacenes; Neoplasms; Neoplasms, Experimental; Rats; Streptomyces; Structure-Activity Relationship

To test the feasibility of myocardial 123I-MIBG and 123I-BMIPP imaging for the early detection of anthracycline cardiotoxicity, 13 patients who had received anthracycline anticancer chemotherapeutic agents were studied. Two-dimensional echocardiography and myocardial imaging with both 123I-MIBG and 123I-BMIPP were performed in 13 patients treated with anthracycline (group A) and 10 normal control subjects (group C). Anterior myocardial images were obtained 15 minutes and 3 hours after the injection of isotopes. The heart-to-mediastinum ratio (H/M ratio) was used to quantify cardiac 123I-MIBG and 123I-BMIPP uptake. The left ventricular shortening fraction (%SF) and the ratio of peak mitral flow velocity in early diastole to that at the time of atrial systole (E/A ratio) were measured by echocardiography. The H/M ratio of 123I-MIBG was lower in group A than in group C (1.5 +/- 0.2 vs. 1.9 +/- 0.2, p < 0.01). The patients in group A had faster clearance of 123I-MIBG from the myocardium than those in group C (27 +/- 10% vs. 22 +/- 4%, p < 0.05). However, the H/M ratio and clearance of 123I-BMIPP were similar between the two groups (H/M ratio: 2.1 +/- 0.2 vs. 2.0 +/- 0.2, clearance: 24 +/- 6% vs. 26 +/- 6%). The %SF (37 +/- 8% vs. 36 +/- 7%) and E/A ratio (1.4 +/- 0.4 vs. 1.6 +/- 0.3) were comparable in groups A and C. The present findings indicated that myocardial imaging with 123I-MIBG could detect myocardial damage in patients treated with anthracycline in the early stage when cardiac systolic and diastolic function was still preserved. Early detection of anthracycline cardiotoxicity by 123I-MIBG would reduce the incidence and severity of heart failure.

Topics: 3-Iodobenzylguanidine; Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Daunorubicin; Doxorubicin; Echocardiography; Fatty Acids; Female; Heart; Humans; Iodine Radioisotopes; Iodobenzenes; Male; Middle Aged; Neoplasms; Radionuclide Imaging

Doxorubicin is an essential component of the treatment of aggressive lymphoma, childhood solid tumors, bone and soft tissue sarcomas, and breast cancer and additional indications are emerging. On the other hand, daunorubicin has occupied the central position of interest in the treatment of acute leukemia. Epirubicin has a spectrum very similar to doxorubicin but lesser toxicity. The ability to protect against cardiotoxicity with ICRF-187 further enhances clinical interest in exploiting modifications in doze intensity to therapeutic advantage. Idarubicin has at least equivalent activity to daunorubicin and doxorubicin in leukemia. New areas of research in relation to anthracycline antibiotics include introduction of new the analogs, insight into mechanisms of resistance, the reversal of multidrug resistance in vitro, the protection of cardiac toxicity, and the study of other important biochemical reactions relevant to cytotoxicity. Orally active anthracyclines such as idarubicin and compounds which lack cross-resistance with the parent drugs or have other mechanisms for cytotoxicity are being developed. It is likely that these modifications will lead to an expanding therapeutic spectrum for these already widely useful drugs.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Cardiomyopathies; Carubicin; Doxorubicin; Drug Resistance; Epirubicin; Humans; Idarubicin; Menogaril; Molecular Structure; Neoplasms; Nogalamycin

Sixty six patients with an advanced or a relapsed cancer have been treated with a combination of radiation and aclarubicin (ACR). The average irradiation dose was 45 +/- 15 Gy, and the combined total dose of ACR ranged from 130 to 260 mg, depending upon the following differing schedules: 10 mg x 3 or 5/w, 20 mg x 2 or 3/w and 20 mg x 2/d x 2/w. The tumor response attained was 70%, including 30% who achieved a complete response. A high response rate also was observed in rather radioresistant cancerous tumor, such as those of the lung, stomach and esophagus. The adverse effects, such as anorexia, nausea, and so on, were found increase with an increase in the dose of ACR. It thus was concluded that for clinical usefulness, 10 mg of ACR should administered every other day in combination with a definite program of radiotherapy.

Topics: Aclarubicin; Aged; Anorexia; Combined Modality Therapy; Drug Administration Schedule; Evaluation Studies as Topic; Female; Humans; Japan; Male; Middle Aged; Multicenter Studies as Topic; Nausea; Neoplasms; Radiation-Sensitizing Agents; Radiotherapy Dosage; Remission Induction

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Chemical Phenomena; Chemistry, Physical; Clinical Trials as Topic; Cricetinae; Culture Media; Doxorubicin; Drug Evaluation, Preclinical; Drug Resistance; Heart; Humans; Mice; Naphthacenes; Neoplasms; Neoplasms, Experimental; Rats; Streptomyces; Structure-Activity Relationship

This study aimed to investigate aclarubicin (ACR)-induced oxidative DNA damage and apoptosis.. ACR-induced apoptosis was analyzed using HL-60 leukemia cells and HP100 cells, hydrogen peroxide (H. HL-60 cells were more sensitive to ACR than HP100 cells. In HP100 cells, DNA ladder formation and caspase-3/7 activity induced by ACR were suppressed or delayed in comparison to those in HL-60 cells. ACR-induced DNA damage occurred in the presence of Cu(II), and scavenger experiments showed that the reactive species causing DNA damage appeared to be generated from H. ACR-induced DNA damage and apoptosis can be accounted for by the involvement of H

Topics: Aclarubicin; Antibiotics, Antineoplastic; Apoptosis; Cell Line, Tumor; Copper; DNA Damage; Humans; Hydrogen Peroxide; Neoplasms

Many anticancer drugs induce DNA breaks to eliminate tumor cells. The anthracycline topoisomerase II inhibitors additionally cause histone eviction. Here, we performed genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II (TopoI and II) inhibitors and integrated this mapping with established maps of genomic or epigenomic features to show their activities in different genomic regions. The TopoI inhibitor topotecan and the TopoII inhibitor etoposide are similar in inducing DNA damage at transcriptionally active genomic regions. The anthracycline daunorubicin induces DNA breaks and evicts histones from active chromatin, thus quenching local DNA damage responses. Another anthracycline, aclarubicin, has a different genomic specificity and evicts histones from H3K27me3-marked heterochromatin, with consequences for diffuse large B-cell lymphoma cells with elevated levels of H3K27me3. Modifying anthracycline structures may yield compounds with selectivity for different genomic regions and activity for different tumor types.

Topics: Aclarubicin; Antineoplastic Agents; Cell Line, Tumor; Chromatin; Daunorubicin; DNA Damage; DNA, Neoplasm; Etoposide; Gene Expression Regulation, Neoplastic; Genome, Human; Histones; Humans; Molecular Targeted Therapy; Neoplasms; Organ Specificity; Protein Transport; Structure-Activity Relationship; Topoisomerase Inhibitors; Topotecan

To investigate the use of folate-targeted nanoemulsion-loaded aclacinomycin A (ACM) to folate receptor (FR)-positive cells, we attempted to optimize the targeting ability of nanoemulsions by modifying the chain length and amount of the folate-PEG linker. Folate-linked, nanoemulsion-loaded ACM were formulated with 0.24 mol% of folate-poly (ethylene glycol)(3400)- (folate-PEG(3400)-) and folate-PEG(5000)-distearoylphosphatidylethanolamine (DSPE), and 0.03 mol% of folate-PEG(5000)-DSPE in nanoemulsions. Selective FR-mediated uptake was achieved in a human nasopharyngeal tumor cell line, KB, which overexpresses FR, but not in a human hepatoblastoma cell line, (FR(-)) HepG2. At the same amount of folate modification, the association with KB cells was increased with increasing the PEG-chain length. The association of 0.03 and 0.24 mol% folate-PEG(5000)-linked nanoemulsions with cells was 5- and 3.3-fold higher than that of non-folate nanoemulsion, respectively, while their cytotoxicity was similar. Both 0.03 and 0.24 mol% folate-PEG(5000)-linked nanoemulsions and non-folate nanoemulsion following intravenous injection inhibited tumor growth more significantly than ACM solution on day 24 following tumor inoculation (p < 0.01). This study demonstrates that a folate-linked nanoemulsion is feasible for tumor-targeted ACM delivery, and that folate modification with a sufficiently long PEG-chain and a small amount of nanoemulsion is an effective way of targeting nanoemulsion to tumor cells.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Delivery Systems; Female; Folic Acid; Humans; Mice; Mice, Nude; Nanostructures; Nasopharynx; Neoplasms; Polyethylene Glycols; Specific Pathogen-Free Organisms; Transplantation, Heterologous

Due to the essential role played by DNA topoisomerases (topos) in cell survival, the use of topoisomerase inhibitors as chemotherapeutic drugs in combination with radiation has become a common strategy for the treatment of cancer. Catalytic inhibitors of these enzymes would be promising to improve the effectiveness of radiation and therefore, it appears reasonable to incorporate them in combined modality trials. In this work, we have investigated the capacity of both ICRF-193 and Aclarubicin (ACLA), two catalytic inhibitors of topoisomerase II (Topo II), to modulate radiation response in Chinese hamster V79 cell line and its radiosensitive mutant irs2. We also have explored potential mechanisms underlying these interactions. Experiments were performed in the presence and absence of either ICRF-193 or ACLA, and topo II activity was measured using an assay based upon decatenation of kinetoplast DNA (kDNA). For the combined experiments cells were incubated for 3 h in the presence of various inhibitor concentrations and irradiated 30 min prior to the end of treatments and cell survival was determined by clonogenic assay. DNA-damaging activity was measured by single-cell gel electrophoresis. Our results demonstrate that combinations of catalytic inhibitors of topo II and radiation produce an increase in cell killing induced by ionising radiation. The mechanism of radiation enhancement may involve a direct or indirect participation of topo II in the repair of radiation-induced DNA damage.

Topics: Aclarubicin; Animals; Cell Line; Cell Survival; Cricetinae; Diketopiperazines; DNA Damage; DNA, Kinetoplast; Enzyme Inhibitors; Humans; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Mutation; Neoplasms; Phosphoproteins; Piperazines; Radiation Tolerance; Topoisomerase II Inhibitors

The photodynamic response of the anthraquinone anticancer drug aclarubicin (ACL) was investigated in vitro and compared with that of mitoxantrone (MTX). Cultured immortalized rodent B14 and NIH 3T3 cells were used in the experiments as a model for cells with neoplastic phenotype. Long-term cytotoxicity and inhibition of cell proliferation assayed by the clonal growth and MTT-tetrazolium methods were estimated to compare the efficacy of aclarubicin and mitoxantrone in photosensitizing cells and their death after non-thermal exposure to monochromatic laser light. Green He-Ne (543.5 nm) or red semiconductor (670 nm) low-power laser (LPL) irradiations were applied. Different dose-responses of both cell lines to aclarubicin and mitoxantrone were found so that the cytotoxicity of MTX was considerably greater than the cytotoxicity of ACL. Phototherapy response (P < 0.0001) was observed only for B14 cells after sensitisation with aclarubicin. Under the same conditions no significant effect of red light irradiation (semiconductor 670 nm laser) on survival of both cell lines treated with mitoxantrone was found.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Cell Line; Cell Survival; Lasers; Mice; Mitoxantrone; Molecular Structure; Neoplasms; Photochemotherapy; Photosensitizing Agents

The aklavinone 11-hydroxylase gene and two doxorubicin resistance genes cloned from Streptomyces peucetius subsp. caesius ATCC 27952 were introduced into doxorubicin-sensitive Streptomyces galilaeus ATCC 31133, an aclacinomycin producer. The doxorubicin resistance genes drrA and drrB endowed S. galilaeus with high-level resistance to doxorubicin, indicating that the resistance mechanism for doxorubicin might be different from that for aclacinomycin A. Transformation of S. galilaeus ATCC 31133 with plasmid pMC213 containing the aklavinone 11-hydroxylase gene (dnrF) resulted in the production of many red pigments. A new metabolite was purified, and the position of the newly introduced hydroxyl group was determined. This result indicated that the aklavinone 11-hydroxylase gene was stably expressed in S. galilaeus ATCC 31133 and that it gave rise to a hybrid aclacinomycin A which showed highly specific in vitro cytotoxicity against leukemia and melanoma cell lines.

Topics: Aclarubicin; Aryl Hydrocarbon Hydroxylases; Carbohydrate Sequence; Doxorubicin; Drug Resistance, Microbial; Gene Expression; Genes, Bacterial; Humans; Molecular Sequence Data; Neoplasms; Streptomyces; Tumor Cells, Cultured

The cytotoxic activities of several natural and semisynthetic anthracyclines against L1210 leukemia and two human colon tumor cells (Colon 4, HT 29) in vitro were examined after short (1 h) and long (7 days) incubation times and correlated with the water/octanol partition coefficients and the DNA-binding affinity of the compounds. Analysis of equation in which cytotoxicity against L1210 (1-h incubation) was parabolically related to the partition coefficient revealed an almost exclusive correlation (r = 0.80) between the cytotoxicity and the parameters, and this correlation was only slightly improved by addition of DNA-binding affinity (r = 0.85). On the other hand, cytotoxic activities displayed after continuous incubation were partially related to both partition coefficients (parabolic dependence) and DNA-binding affinities (linear dependence). In this case the correlation between the activity and partition coefficient (r = 0.67) was significantly improved by addition of DNA-binding affinity (r = 0.90). Similar results were also obtained for human colon tumor cells although the corresponding correlation coefficients were generally of lower value, indicating that cytotoxic activity of anthracyclines against these primary resistant cells may be influenced by additional factors not yet determined.

Topics: Animals; Antibiotics, Antineoplastic; Chemical Phenomena; Chemistry, Physical; Colonic Neoplasms; DNA; Humans; Leukemia L1210; Molecular Structure; Neoplasms; Regression Analysis; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Humans; Naphthacenes; Neoplasms

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

Single agent activity of aclacinomycin A or aclarubicin (ACR) for acute leukaemia in adults was as follows: complete remission was achieved in 8 of 21 (38%) with untreated patients and 7 of 41 (17%) with prior chemotherapy; thus the overall complete remission rate was 24%. The optimal dose schedule was 14 mg/m2/d daily i.v. administration, and a median total dose of 200 mg/m2 and 16 days were necessary for induction of complete remission. In combination, with behenoyl ara-C, ACR, 6-mercaptopurine and prednisolone, complete remission was achieved in 40 of 60 (67%) previously untreated patients, and 41 of 65 (63%) with prior chemotherapy; thus the overall rate was 65%. In a phase II study of ACR for solid tumours, response was achieved in carcinoma of oesophagus (1/3), stomach (12/84, 14%), gall bladder (1/4), pancreas (1/8), lung (4/30, 13%), breast (6/33, 18%), uterus (1/4), ovary (3/9, 33%), head and neck (1/5) and sarcoma (1/5). Side-effects of ACR most frequently observed were nausea and vomiting (around 30%) and a moderate grade marrow suppression was noted. An ECG change was observed in 7%, but there were no cases of chronic heart failure.

Topics: Aclarubicin; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Humans; Leukemia, Myeloid, Acute; Naphthacenes; Nausea; Neoplasms; Vomiting

Selective deposition of lipiodol in primary and metastatic liver cancer, lung cancer, gallbladder cancer, pancreatic cancer and renal cancer was elucidated by plain X-ray film and CT. Selective delivery of anticancer agent, SMANCS was also proved by measurement of its biological activities of removed specimen. Because of these selective delivery of anticancer agent and embolization of neovasculature in the tumor, highly effective chemotherapy of unresectable cancer was established. Drug was given via celiac, the hepatic, bronchial or renal artery mostly 1-5 mg in 1-5 ml of lipiodol once every 3-8 weeks. Antitumor effects of this therapy for hepatocellular carcinoma was confirmed based on decrease in AFP levels (92% of the cases), reduction in tumor size (90% of the cases) and histology. In 76 percent of the patients with the other malignant solid tumors reduction in tumor size was recognized. Decrease in CEA level occurred in 88 percent of the cases with metastatic liver cancer and lung cancer. Major side effect was transient fever in about 50% of cases. Mitomycin C and aclarubicin dissolved in lipiodol showed remarkable antitumor effects for experimental liver cancer.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Furans; Humans; Infusions, Intra-Arterial; Iodized Oil; Maleic Anhydrides; Mitomycin; Mitomycins; Naphthacenes; Neoplasms; Polystyrenes; Rabbits; Zinostatin

Experimental and clinical studies were performed on aclarubicin in the treatment of solid tumors. In experimental cancer chemotherapy using human tumor xenografts transplanted to nude mice, aclarubicin showed a moderate antitumor effect (retardation of tumor growth) and nearly the same spectrum of activity in vivo as Adriamycin (doxorubicin). In in vitro sensitivity tests using 3H-thymidine uptake inhibition of a single cell suspension prepared from xenografts, aclarubicin showed a stronger inhibition than that of Adriamycin, mitomycin C and cyclophosphamide. In phase II clinical studies in patients with solid tumors, 3 intravenous dose schedules [schedule A: 20 mg (equal to 14 mg/m2) daily every other week, schedule B: 40 to 60 mg (28 to 42 mg/m2) twice a week, and schedule C: 60 to 100 mg (42 to 70 mg/m2) once a week] were investigated. Aclarubicin produced a 15 to 20% response rate for carcinomas of the stomach, lung, breast and ovary by schedules A and B. Dose-schedule limiting factors were digestive and hematologic toxicity.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Drug Evaluation; Humans; Mice; Mice, Inbred BALB C; Naphthacenes; Neoplasms

Topics: Aclarubicin; Acute Disease; Animals; Antibiotics, Antineoplastic; Cricetinae; Drug Evaluation; Humans; Leukemia; Naphthacenes; Neoplasms

Since 1970, we have carried out cancer chemotherapy and immunotherapy in cooperation with Japanese scientists, particularly Prof. H. Umezawa, who has generously supplied bleomycin, peplomycin, acalcinomycin A (ACM), THP-adriamycin (THP), neothramycin and bestatin. Malignant tumors curable by pharmacotherapy are polycythemia vera (CR 100%), acute lymphoid leukemia (ALL) (CR 80%), Burkitt tumor (CR 80 or 50%), Hodgkin disease (CR 80%), chorioepithelioma (CR 80%), testicular cancer (CR 80%), ovary cancer of children (CR 80%), Wilms renal cancer (CR 60%), rhabdomyosarcoma (CR 75%), osteosarcoma (CR 60%), Ewing tumor (CR 60%), brain tumor of children (CR greater than 50%), testicular embryonal cancer of children (CR greater than 50%), acute myeloid leukemia (AML) (CR 50%), non-Hodgkin lymphoma (NHL) (CR 50%), ovary cancer of adults (CR 40%), small cell lung cancer (CR 20%) and breast cancer. Our experimental and/or clinical experience with ACM, THP, methoxy-9-ellipticine lactate, navelbine, 4-demethyl-epipodophyllotoxin-beta-d-ethyledene glucoside, bestatin and interferon is presented. ACM is effective against AML, ALL, NHL, Burkitt tumor, breast cancer. We have comparatively investigated cardiac and dermal toxicity of 12 kinds of anthracycline antibiotics and mitoxantrone, using golden hamsters. Of the drugs examined, ACM, THP, AD-32 and AD-143 cause much less cardiomyopathy and alopecia than the other agents. The results have been confirmed by electron microscopic studies. Bestatin is an immunorestorator, which recovers immunological functions decreased in aged animals. We hope that cancer chemotherapy and immunotherapy will progress in future and contribute to cure of neoplasms. Japanese scientists have been making a great contribution in the field of cancer pharmacotherapy, and we are eager to cooperate with Japanese scientists in cancer treatment studies.

Topics: Aclarubicin; Animals; Anthraquinones; Antibiotics, Antineoplastic; Antineoplastic Agents; Cricetinae; Doxorubicin; Ellipticines; France; Heart; Humans; Interferons; International Cooperation; Japan; Mesocricetus; Mitoxantrone; Myocardium; Naphthacenes; Neoplasms

Aclarubicin was given iv every 3 weeks to 21 patients with a variety of solid tumors. Four dose levels were tested: 80, 100, 120, and 140 mg/m2. The median cumulative dose was 270 mg/m2 (range, 80-900). No objective responses were observed. Hematologic toxicity was dose-limiting. All patients experienced moderate to severe gastrointestinal toxicity. Five of 13 patients evaluable for cardiac function showed clinical signs and ECG changes suggestive of cardiac dysfunction. The suggested maximum dose for phase II trials is 120-140 mg/m2 iv given in an intermittent 3-week schedule.

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Drug Evaluation; Female; Heart; Humans; Male; Middle Aged; Naphthacenes; Neoplasms

Aclacinomycin-A is a new anthracycline antibiotic with a broad spectrum of antitumor activity in animals. Compared to doxorubicin, it was found to produce less cardiotoxicity and alopecia. A Phase I trial of aclacinomycin-A given as a weekly 15 min IV infusion was conducted in 20 previously treated patients with advanced solid tumors. Four dose levels ranging from 40 to 100 mg/m2 were studied; myelotoxicity was dose-limiting at 85 and 100 mg/m2. Other toxicities were moderate to severe nausea and vomiting in 9 patients, mild phlebitis in 2 patients, and mild abnormality of liver function tests in 3 patients. No cardiac or renal toxicities were seen, but two partial responses were observed. The pharmacokinetic profile of aclacinomycin-A in plasma and urine was studied in 3 patients given 65 mg/m2 using a high performance liquid chromatography assay. The data obtained were consistent with a two compartment model of drug disposition with initial and terminal half-life values of 6.6 min and 13.3 h, respectively. The major fluorescent metabolite was eliminated with a terminal half-life of 25 h. Two metabolites as well as the parent drug were excreted in the urine as less than 10% of the doses given. This pharmacokinetic profile is similar to that of other anthracyclines, although aclacinomycin-A appears to have lower blood levels than doxorubicin given at equivalent doses. On this weekly schedule, the recommended dose is 65 mg/m2 for Phase II trials.

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Bone Marrow; Digestive System; Drug Evaluation; Female; Half-Life; Humans; Kinetics; Male; Middle Aged; Naphthacenes; Neoplasms

Aclacinomycin A (ACM-A), an anthracycline analog, was given to 17 patients with solid tumors and to one patient with multiple myeloma, in a phase I clinical trial. A single dose of 60-120 mg/m2 was given every 3 weeks. Dose-limiting toxicity was myelosuppression, especially thrombocytopenia. Granulocytopenia was variable and did not always recover by Day 21 in time for the next ACM-A treatment. Other toxic effects were nausea, vomiting, urticaria, and elevation of hepatic enzymes. Alopecia was not a side effect, even in patients receiving multiple courses of ACM-A. Nine patients were monitored with 24-hour continuous ECG recordings (Holter) on 19 ACM-A treatment days. The incidence of premature atrial and ventricular beats was significantly increased following ACM-A administration. In addition, one patient developed episodes of high-degree atrioventricular block and complete heart block after each of four ACM-A doses, necessitating the insertion of a pacemaker. No antitumor responses were seen in the ten patients who had measurable disease and who had received two or more courses of ACM-A. The recommended doses for solid tumor phase II studies are 100 mg/m2 as a single dose every 4 weeks for patients with high performance status and minimal prior chemotherapy and 60 mg/m2 every 4 weeks for all other patients. Until the acute cardiac effects of ACM-A are further understood, we recommend that all patients receiving ACM-A be monitored by ECG recordings.

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Arrhythmias, Cardiac; Blood Cells; Drug Evaluation; Female; Humans; Male; Middle Aged; Naphthacenes; Neoplasms

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Cricetinae; Daunorubicin; Dogs; Doxorubicin; Drug Evaluation; Drug Evaluation, Preclinical; Female; Humans; In Vitro Techniques; Male; Mice; Naphthacenes; Neoplasms; Neoplasms, Experimental; Rabbits; Rats

A phase I study of a new anthracycline antibiotic, aclacinomycin A, was performed in a total of 15 patients with advanced malignancy to determine the maximum-tolerated dose. The gastrointestinal toxicity which occurred was not dose-related and was not severe. Epilation and stomatitis were extremely minimal. Both hepatic dysfunction and hematologic toxicity were dose-limiting. A recommended dose for phase II study was determined to be 2.5--3.0 mg/kg (approximately 100--120 mg/m2) given in 3-week intervals. Objective response was observed in two patients with malignant lymphomas.

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Drug Evaluation; Female; Glycosides; Humans; Male; Middle Aged; Naphthacenes; Neoplasms

An effective treatment schedule with bleomycin in combination with mitomycin and a new effective area in treatment with neocarzinostatin was introduced. Studies on more useful derivatives or analogues of bleomycin and anthracycline antitumor antibiotics were described. Bleomycin PEP thus selected may become a useful agent. Aclacinomycin and various other anthracycline glycosides were isolated from beer fermentation and tested. Future progress in microbiol secondary metabolites useful in cancer treatment was discussed.

Topics: Aclarubicin; Animals; Anthraquinones; Antibiotics, Antineoplastic; Bleomycin; Daunorubicin; DNA; Glycosides; Humans; Neoplasms; Structure-Activity Relationship; Zinostatin