aclarubicin and pirarubicin

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

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; Acute Disease; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Cytarabine; Doxorubicin; Humans; Interferon Type I; Leukemia; Middle Aged; Naphthacenes

Topics: Aclarubicin; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Bacteria; Benzodiazepinones; Bleomycin; Chemistry; Doxorubicin; Fungi; History, 20th Century; Japan; Maytansine; Naphthacenes; Peplomycin; Peptide Biosynthesis; Peptides; Structure-Activity Relationship

This study analyzed data on 35 infants with acute myeloid leukemia (AML) who were treated with intensive chemotherapy between 1995 and 1998 in Japan. The incidence of boys, younger age (< 6 months old), and hyperleukocytosis at onset was high in patients with the M4/M5 subtype (n = 23) in the French-American-British classification, compared with the non-M4/M5 subtype (n = 12). Thirteen (56%) and 16 (70%) patients with the M4/M5 subtype also showed 11q23 translocations and MLL gene rearrangements, respectively, whereas only one patient with the non-M4/M5 subtype had this rearrangement. All 35 patients were treated with the ANLL91 protocol consisting of etoposide, high-dose cytarabine, and anthracyclines. Overall survival and the event-free survival (EFS) rates at 3 years of all patients were 76% (95% confidence interval [CI], 61.3%-90.7%) and 72% (95% CI, 56.4%-87.9%), respectively. EFS showed no significant difference between 2 subgroups divided by age, gender, presence of the MLL gene rearrangements, and white blood cell count at onset; EFS in patients with the M4/M5 subtype tended to be better than those with the non-M4/M5 subtype. Although all 6 patients who underwent allogeneic stem cell transplantation (SCT) have been in complete remission, no benefit of SCT was confirmed. These findings suggest that the intensive chemotherapy with the ANLL91 protocol might have been responsible for the observed good outcome of infant AML, even without SCT. The presence of the MLL gene rearrangements or the age at onset had no impact on the outcome of infant AML.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 11; Cytarabine; Disease-Free Survival; DNA-Binding Proteins; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Histone-Lysine N-Methyltransferase; Humans; Immunophenotyping; Infant; Leukemia, Myeloid, Acute; Male; Mitoxantrone; Myeloid-Lymphoid Leukemia Protein; Prognosis; Proto-Oncogenes; Remission Induction; Survival Rate; Transcription Factors; Translocation, Genetic; Treatment Outcome; Vincristine

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

Topics: Aclarubicin; Acute Disease; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Cytarabine; Doxorubicin; Humans; Interferon Type I; Leukemia; Middle Aged; 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

Carbonyl reduction biotransformation pathway of anthracyclines (doxorubicin, daunorubicin) is a significant process, associated with drug metabolism and elimination. However, it also plays a pivotal role in anthracyclines-induced cardiotoxicity and cancer resistance. Herein, carbonyl reduction of eight anthracyclines, at in vivo relevant concentrations (20 μM), was studied in human liver cytosol, to describe the relationship between their structure and metabolism. Significant differences of intrinsic clearance between anthracyclines, ranging from 0,62-74,9 μL/min/mg were found and associated with data from in silico analyses, considering their binding in active sites of the main anthracyclines-reducing enzymes: carbonyl reductase 1 (CBR1) and aldo-keto reductase 1C3 (AKR1C3). Partial atomic charges of carbonyl oxygen atom were also determined and considered as a factor associated with reaction rate. Structural features, including presence or absence of side-chain hydroxy group, a configuration of sugar chain hydroxy group, and tetracyclic rings substitution, affecting anthracyclines susceptibility for carbonyl reduction were identified.

Topics: Aclarubicin; Alcohol Oxidoreductases; Aldo-Keto Reductase Family 1 Member C3; Antineoplastic Agents; Binding Sites; Biotransformation; Cytosol; Doxorubicin; Gene Expression Regulation, Enzymologic; Hepatocytes; Humans; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Oxidoreductases; Protein Conformation

To explore the clinical efficacy and adverse effects of GHA(G-CSF+homoharringtonin+cytarabine C) and new combined priming chemotherapeutic regimens(GHAA/GHTA) with high efficacy and low toxicity for treatment of relapsed and refractory acute myeloid leukemia(AML) and myelodysplastic syndrome(MDS), and to analyze the relation of above-mentioned regimens with the expression of co-stimuolating molecule B7.1.. Standard GHA regimen consisting of G-CSF: 100 µg/(m2·d) subcutaneous injection, d 0-14; homoharringtonine: 1.0 mg/(m2·d) intravenous drip, d 1-14; Ara-C: 7.5-10 mg/(m2·d) subcutaneous injection, q12h, d 1-14. Other regimens as GHAA/GHTA were combined respectively with aclarubicin 20 mg d 1-7, or pirarubicin 20 mg d 1-7. 74 patients with refractory AML and 46 patients with MDS received these priming chemotherapy. The clinical efficacy and toxicity of above-mentioned priming chemotherapy were compared with 56 patients received routine chemotherapy (MA/TAE) respectively. And the expression of costimulatory molecule B7.1 on leukemia cells in patients of different subtypes was also detected by immunofluoressence and its relationship with clinical efficiency was explored.. (1) for AML patients treated with priming chemotherapy, the total remission was 67.56% (CR 54.05%, PR 13.51%), which was much higher than that of patients received routine chemotherapy (P<0.05). The CR rate of AML-M2 and AML-M5 group (65.51%, 61.90% respectively) was much higher than that of AML other subtypes (P<0.05), and the longest remission period lasted for 4 years; (2) for MDS patients treated with priming chemotherapy, the total remission was 60.87% (CR 45.65%, PR 15.22%), which was also significantly higher than that of patients received routine chemotherapy (P<0.05); (3) in comparison with patients received standard GHA priming regimen, the remission rate of combined priming chemotherapy GHAA/GHTA was significantly higher both in patients with AML (85.18%) and MDS (81.25%); (4) side effects after chemotheropy, including granulocyte deficiency, thrombocytopenia and anemia etc, lasted for 7-14 days; the severe infection rate was 1%, there were no severe bleeding, digest effect and damage of function in heart, liver and kidney. The therapy-related mortality was zero. Compared with routine chemotherapy, priming chemotherapy proved significantly safe and effective (P<0.05); (5) the expression rate of costimulatory molecule B7.1 showed large variance between AML and MDS, it was higher in AML-M2/AML-M5 and lower in AML of other subtypes (P<0.05). In the same case, B7.1 expression was positive correlated with efficiency of priming chemotherapy.. GHA priming chemotherapy, as well as other combination regimens GHAA/GHTA, are well-tolerated, effective regimens for refractory AML and advanced MDS, without severe side effects and therapy-related mortality. Especially the new regimens GHAA/GHTA has better efficacy, which are proved more efficient than conventional GHA. Efficiency of priming chemotherapy is positive correlated with B7.1 expression, its mechanism will be further explored.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; B7-1 Antigen; Cohort Studies; Cytarabine; Doxorubicin; Granulocyte Colony-Stimulating Factor; Granulocytes; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Recurrence; Thrombocytopenia

To clarify the mechanism of the cardiotoxic action of adriamycin (ADM), the participation of free radicals from ADM in cardiotoxicity was investigated through the protective action of glutathione (GSH) or by using electron spin resonance (ESR). Oxidation of ADM by horseradish peroxidase and H2O2 (HRP-H2O2) was blocked by GSH concentration dependently. Inactivation of creatine kinase (CK) induced during interaction of ADM with HRP-H2O2 was also protected by GSH. Other anthracycline antitumor drugs that have a p-hydroquinone structure in the B ring also inactivated CK, and GSH inhibited the inactivation of CK. These results suggest that ADM was activated through oxidation of the p-hydroquinone in the B ring by HRP-H2O2. Although ESR signals of the oxidative ADM B ring semiquinone were not detected, glutathionyl radicals were formed during the interaction of ADM with HRP-H2O2 in the presence of GSH. ADM may be oxidized to the ADM B ring semiquinone and then reacts with the SH group. However, ESR signals of ADM C ring semiquinone, which was reductively formed by xanthine oxidase (XO) and hypoxanthine (HX) under anaerobic conditions, were not diminished by GSH, but they completely disappeared with ferric ion. These results indicate that oxidative ADM B ring semiquinones oxidized the SH group in CK, but reductive ADM C ring semiquinone radicals may participate in the oxidation of lipids or DNA and not of the SH group.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Benzoquinones; Creatine Kinase; Daunorubicin; Doxorubicin; Electron Spin Resonance Spectroscopy; Epirubicin; Free Radicals; Glutathione; Horseradish Peroxidase; Hydrogen Peroxide; Hypoxanthine; Idarubicin; Oxidation-Reduction; Sulfhydryl Compounds; Xanthine Oxidase

Previously we have detected a stimulatory effect on immunoglobulin (IgG) synthesis when hybridoma cells were treated with doxorubicin. In order to determine whether this is a general property of anthracycline, we have selected three analogs--doxorubicin (DOX), pirarubicin (THP-DOX) and aclarubicin (ACR)--which differ mainly in the methylation state of their amino sugars. Cell cycle analysis by flow cytometry and drug localization by scanning confocal microscopy were also performed. The results show that when cells (UN2 hybridoma B cells), were exposed to subtoxic doses of DOX or THP (with unmethylated amino sugars), a strong increases in IgG secretion, heavy (H) and light (L) chain synthesis and the corresponding mRNA levels were induced. Furthermore these two drugs arrested the cells in the G2/M phase of the cell cycle. In contrast, exposure to ACR (with its methylated amino sugar) at similar subtoxic doses induced a blockade of cells in the G1 phase with no increase of IgG synthesis, at the subtoxic doses used, all three drugs could still be detected in the nucleus as well as in the cytoplasm, as determined by confocal laser microscopy. Thus, the relationship between cell cycle blockade, IgG stimulation and anthracycline structure is suggested by these results.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; B-Lymphocytes; Cell Cycle; Cell Differentiation; Cell Division; Doxorubicin; Hybridomas; Immunoglobulin G; Kinetics; Mice; Neoplasms, Experimental; Time Factors

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

It is vital to develop effective therapy for children with acute lymphoblastic leukemia (ALL), in whom no remission occurs or who suffer relapse with current protocols. Cellular drug resistance is thought to be an important cause of induction failure and relapse. We performed in vitro tests of bone marrow samples in 196 children with newly diagnosed ALL with a 4-day culture and a methyl-thiazol-tetrazolium assay. We tested 16 drugs and calculated the 70% lethal dose (LD70) for 14 drugs and the leukemic cell survival (LCS) rate for dexamethasone and prednisolone. For each single drug, patients were classified into two groups, sensitive or resistant, by median concentration of LD70 or LCS. When patients were classified into three groups by sensitivity to four drugs of DPAV (dexamethasone, prednisolone, L-asparaginase, and vincristine), 3-year event-free survival (EFS; 95% confidence intervals) of the super sensitive group (SS; sensitive to all 4 drugs) was 0.833 (0.690 to 0.976), that of the intermediate sensitive group (IS; sensitive to 2 or 3 drugs) was 0.735 (0.609 to 0.863), and that of the relatively resistant group (RR; sensitive to no drugs or to 1 drug) was 0.541 (0.411 to 0.670; P = .0008). We then investigated the relationship between the above four-drug sensitivity and the time of relapse. The SS and IS patients tended to maintain continuous complete remission, and RR patients tended to undergo induction failure and early and late relapse (P = .004). Initial white blood cell count, immunologic classification, and age were also predictive factors, but the patient numbers showed no statistical correlation between these factors and the four-drug sensitivity groups (SS, IS, and RR). When we took three groups SS/IS/RR and investigated the EFS for various clinical groups, DPAV sensitivity strongly influenced EFS in the standard-risk ALL (P = .016). In vitro drug sensitivity testing provides additional prognostic information about childhood ALL, and early detection of drug resistance at the time chemotherapy commences may provide a successful strategy for individualizing treatment, as the results indicate de novo resistance to front-line drugs and suggest alternative, second-line drugs.

Topics: Aclarubicin; Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bleomycin; Bone Marrow; Cell Survival; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Etoposide; Follow-Up Studies; Humans; Infant; Infant, Newborn; Life Tables; Melphalan; Methotrexate; Mitomycin; Mitoxantrone; Neoplastic Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Recurrence; Remission Induction; Tumor Cells, Cultured; Vincristine

The cardiac actions of doxorubicin were compared with those of pirarubicin and aclarubicin to understand the mechanisms responsible for differences in cardiotoxic effects of anthracycline agents. In left atrial muscle preparations obtained from guinea-pig heart and stimulated at 2 Hz, anthracyclines produced positive inotropic effects. The magnitude of the effect was pirarubicin > doxorubicin > aclarubicin. The order for depression of potentiated postrest contraction and prolongation of the time to peak twitch tension was doxorubicin > pirarubicin > aclarubicin. Drug washout following a 2-h incubation with 100 microM doxorubicin prevented a further increase in the time to peak twitch tension, caused a marked recovery of depressed potentiated postrest contractions, and augmented the positive inotropic effect. Pirarubicin and doxorubicin, but not aclarubicin, caused a parallel rightward shift of the dose-response curve for the negative inotropic effect of acetylcholine. The potency of inhibition of [3H]quinuclidinyl benzilate binding was pirarubicin > doxorubicin > aclarubicin. These results indicate that three anthracycline anticancer agents share similar effects on cardiac muscle contractility and on muscarinic acetylcholine receptors. The actions of aclarubicin were weak compared to those of doxorubicin or pirarubicin. Increases in the time to peak twitch tension and the depression of potentiated postrest contraction are apparently mediated by mechanisms different from those responsible for the positive inotropic effects or antagonism at muscarinic acetylcholine receptors.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Calcium; Doxorubicin; Electric Stimulation; Female; Guinea Pigs; Heart; In Vitro Techniques; Male; Myocardial Contraction; Parasympatholytics; Quinuclidinyl Benzilate

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

For the purpose of establishing a method for reasonable clinical use of anthracyclines in leukemia chemotherapy, we examined the pharmacokinetics and the mode of action with five anthracyclines such as daunorubicin (DNR), doxorubicin (DOX), aclarubicin (ACR), THP adriamycin (THP), idarubicin (IDA). In the patients with AML, blood ACR or IDA level increased and then disappeared very rapidly after iv bolus injection. In contrast, their metabolites (M1 or IDAol) increased for up to 2 or 4 hrs and remained much longer than ACR or IDA. The concentration of ACR, IDA or their metabolites were found to be much higher in the leukocyte fraction than in erythrocyte fraction or plasma. In HL60 cell suspension, anthracyclines were rapidly accumulated into the cells, and the uptake of IDA or THP were higher than the other agents. In HL60 cells, anthracyclines accumulated in the nuclear fraction but ACR was accumulated markedly in the cytosol fraction. From the result of DNA binding assay, binding at excess to calf thymus DNA of ACR was suggested to be approximately 2 times higher than that of other agents. DNA strand brakes in HL60 cells treated with anthracyclines were shown by pulse field gel electrophoresis, and IDA was found to have stronger activity to cause the DNA strand breaks. In conclusion, it seemed that anthracyclines showed similar action mechanisms, but in some respects quantitative differences were existed among them. Anthracyclines should be given to patients based on their pharmacological characteristics to obtain higher remission rate and suppress resistant cells.

Topics: Aclarubicin; Acute Disease; Antibiotics, Antineoplastic; Daunorubicin; DNA; DNA Damage; DNA Replication; Doxorubicin; Humans; Leukemia, Myeloid

Effects of anthracycline type antitumor agents (aclarubicin, ACL; daunorubicin, DAU; doxorubicin, DOX; epirubicin, EPI; pirarubicin, PIR) on the acute toxicity to mouse, rat liver microsomal lipid peroxidation and mitochondrial functions in vitro were studied. ACL showed the least production of liver microsomal lipid peroxidation in all tested anthracyclines in the increasing order of PIR, DOX, DAU and EPI. The increase of production of lipid peroxidation induced by these drugs correlated well with the decrease in body weight of mice administered i.p. at 20 mg/kg and 50% lethal dose of these drugs. On the effect of mitochondrial function, all drugs tested decreased the oxygen uptake of state 3 and the level of respiratory control index. ACL showed the most severe inhibition of these functions in all drugs. These observations suggest that the degree of microsomal lipid peroxidation induced with the anthracycline drugs was related to the development of the drug acute toxicity.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Body Weight; Daunorubicin; Doxorubicin; Epirubicin; Lipid Peroxidation; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; Mitochondria, Liver; Rats; Rats, Inbred Strains

The effect of a combination of lithotripter shock waves and cytotoxic drugs was examined in vitro. L1210 cells in suspension were exposed to shock waves during incubation with cislatin, doxorubicin, daunorubicin, THP-doxorubicin, or aclacinomycin. Proliferation was determined using the 3-4,5 dimethylthiazol-2,5 diphenyl tetrazolium bromide assay. Dose enhancement ratios were calculated for each drug in order to determine the effect of the additional exposure to shock waves. In addition, partition coefficients and IC50s of the drugs were determined. It was found, that the dose enhancement ratios increased for the drugs with decreasing cytotoxicity. The effect of all five drugs was enhanced by shock waves to a higher degree at 7 min incubation as compared to 50 min incubation. The effect of cisplatin was most significantly enhanced, with a dose enhancement ratio of 6.7 at 7 min incubation. The enhancement increased with the operating voltage used for generating the shock waves, and was only present when cells were exposed to shock waves during the incubation with the drug. An increase in cellular membrane permeability is proposed as the mechanism of interaction between shock waves and drugs.

Topics: Aclarubicin; Animals; Antineoplastic Agents; Cell Survival; Cisplatin; Daunorubicin; Dose-Response Relationship, Drug; Doxorubicin; Leukemia L1210; Lithotripsy; Mice; Tumor Cells, Cultured

Two new experimental models of transplantable mouse sarcoma 180 were developed in ICR mice in order to examine the optimum transplantation sites and methods. The cervicodorsal hypoderm was evaluated as the best transplantation site for mouse sarcoma 180 among seemingly usable transplantation sites such as groin, armpit, cervicodorsal, abdominal and lumbodorsal hypoderms by hypodermic transplantation. In addition, the lung transplantation model was established by monitoring the survival period as a reliable parameter for evaluation of anti-tumor effects.

Topics: Aclarubicin; Animals; Antineoplastic Agents; Daunorubicin; Disease Models, Animal; Doxorubicin; Lung Neoplasms; Male; Mice; Mice, Inbred ICR; Neoplasm Transplantation; Sarcoma 180; Skin Neoplasms; Specific Pathogen-Free Organisms

The survival rate of human melanoma cells after X-ray irradiation, treatment with adriamycin derivatives and combined treatment with X-rays and adriamycin derivatives was measured by means of the colony formation test. After X-ray irradiation the melanoma cells showed a high resistance for cell survival. In all tests the Be11-cells were more resistant than MeWo-cells. On combined exposure especially with higher doses of adriamycin derivatives, both cell lines showed the interesting effect, that with increasing concentration the survival rate decreased whereas the D(o) increased. Aclacinomycin-A (ACM-A) and Pirarubicin reduced recovery processes after X-ray irradiation. Therefore Be11-cells showed a four times higher DMF (dosis modifying factor) after ACM-A-treatment than MeWo-cells. Low ACM-A-concentrations combined with low X-ray doses showed on both cell lines supraadditive effects. The effect of pirarubicin was in most of the tests only additive. Compared with ACM-A, pirarubicin was less cytotoxic, showed a larger therapeutic range, caused a smaller D(o) and Dq and had a supraadditive effect in low concentrations on both cell lines. For clinical combined therapy with patients ACM-A is probably better suited than pirarubicin.

Topics: Aclarubicin; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Doxorubicin; Humans; Melanoma

Fluorescence method was used to study the interactions of anthracyclines with purified DNA and with cell nuclei at 37 degrees C, at pH ranging from 6.8 to 8. Four anthracyclines were used; adriamycin (ADR), 4'-o-tetrahydropyranyladriamycin (THP-ADR), daunorubicin (DNR) and aclacinomycin (ACM). The values of pKa of deprotonation of these four drugs in the pH range 6.5-8.5 are 8.4, 7.7, 8.4 and 7.0 for ADR, THP-ADR, DNR and ACM, respectively. The overall binding constants K* of these four drugs to purified DNA was determined at various pH values. The binding constants K0 and K+ of the respectively neutral form and once protonated form of the drugs to DNA were calculated. Using cell nuclei from K562 cells, the amount of drug intercalated (CN) within the nuclei of K562 cells and the amount of free drug (CE) in the solution were determined at various pH values: measuring at the same pH values, a linear correlation occurred between K* and CN/CE.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Antineoplastic Agents; Cell Nucleus; Daunorubicin; DNA; Doxorubicin; Kinetics; Molecular Structure; Structure-Activity Relationship

Male Wistar rats received adriamycin, aclacinomycin or thepirubicin at a dose of 4 mg/kg b.w. by slow infusion. Cardiac tissue sections were examined by fluorescence microscopy to evaluate the distribution of the three anthracyclines. The nuclei regularly exhibited a stronger coloring with respect to the cytoplasm for all three drugs. Adriamycin cytoplasm fluoresced intensely, unlike aclacinomycin and thepirubicin. Our results indicate a lower uptake of these last two molecules into cardiac tissue, thus suggesting a different pharmacokinetic profile which might account for their lower cardiotoxicity.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Doxorubicin; Male; Microscopy, Fluorescence; Myocardium; Rats; Rats, Inbred Strains; Tissue Distribution

Aclacinomycin is a member of naturally occurring anthracyclines having three sugar moieties in the molecule. It showed antitumour activity on various mouse and rat tumours. Combination therapy with AraC etc. gave remarkable clinical results on acute myeloid leukaemia. Aclacinomycin strongly inhibits RNA synthesis of the tumour cells. It has lower cardiac toxicity than adriamycin and no mutagenicity. THP-Adriamycin is a derivative of adriamycin designed from the structure of baumycins. It showed stronger effects than adriamycin in inhibiting many mouse tumours such as L1210 and P388 leukaemia, B16 melanoma and colon 38 adenocarcinoma. THP-Adriamycin is rapidly taken up by both adriamycin-sensitive and resistant leukaemic cells. Its level of cardiac toxicity is as low as that of aclacinomycin. Ditrisarubicins are new naturally occurring anthracyclines isolated from Streptomyces having six sugar moieties in the molecule. Ditrisarubicin has a potent cytostatic and antitumour activities on adriamycin resistant mouse leukaemia. Its binding constant to DNA is extremely high compared with other anthracyclines.

Topics: Aclarubicin; Animals; Anthracyclines; Antibiotics, Antineoplastic; Cricetinae; Doxorubicin; Heart; Leukemia L1210; Leukemia L5178; Mice; Myocardium; Naphthacenes; Rats; RNA

The following paragraphs summarize the properties of ADR, THP and ACR in terms of their pharmacokinetics. The blood level of anthracyclines shows a three-phase function of decline: alpha, beta and gamma phases. Compared with other classes of anticancer agents, the anthracyclines are characterized by an extremely short T1/2(alpha) and an extremely long T1/2(gamma). These characteristics reflect the facts that anthracyclines are rapidly transferred to the tissues and that they are retained for a long time in the body. In comparison with ADR, the T1/2(alpha) of THP is relatively short and T1/2(alpha, beta and gamma) of ACR are also short. Anthracyclines show large values for K12 and K13, transfer rate constants of the drug from the blood to the tissues, and small values for K21 and K31 transfer rate constants of the drug from the tissues to the blood. This means that these drugs are rapidly transferred to the tissues, from which they are then slowly released. The order of magnitude of K12 and K13 was THP greater than ACR greater than ADR. The order for K21 and K31 was ACR greater than THP greater than ADR. Anthracyclines are also characterized by small distribution volumes (V1) in the blood circulation, and very large distribution volumes (V2 and V3) in the tissue compartments. The order of magnitude for V2 and V3 was THP greater than ADR greater than ACR. Anthracyclines achieved high concentrations in such thoracic and abdominal organs such as lung, heart, thymus, liver, kidney, spleen and digestive tract. ADR showed the highest levels in liver and kidney, while THP and ACR showed their highest concentrations in lung and spleen. A decrease in the drug concentration in various organs is slow in the case of ADR, while rapid in the cases of THP and ACR. Most of the distributed drug is the unchanged form with ADR, whereas metabolites are common with ACR. THP is partially converted to ADR in liver. Anthracyclines were usually excreted over a long period of time at a high rate in the bile and at a low rate in the urine. Orally-administered ACR showed considerably good absorption from the digestive tract. The metabolism of anthracyclines was carried out in vivo and resulted in the formation of bioactive glycoside metabolites and inactive aglycone metabolites.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Aclarubicin; Administration, Oral; Animals; Chromatography, High Pressure Liquid; Doxorubicin; Humans; Injections, Intravenous; Kinetics; Mice; Mice, Inbred ICR; Naphthacenes; Rabbits; Sarcoma, Experimental; Tissue Distribution

Topics: Aclarubicin; Acute Disease; Adult; Antineoplastic Agents; Cytarabine; Doxorubicin; Drug Evaluation; Humans; Interferon Type I; Leukemia; Naphthacenes

Aclacinomycin, 4'-epi-doxorubicin and 4'-epi-tetrahydropyranyl-adriamycin, three novel anthraquinone derivatives under investigation for their antitumour activity, showed an inhibitory effect on the in vitro respiration of mitochondria from rat hearts. The inhibition proved to be concentration-dependent in the range 0.05 to 1.40 mM and both the NADH-oxidase and the succinate oxidase systems were affected to different extents. Among the compounds tested, 4'-epi-tetrahydropyranyl-adriamycin appeared to be the least powerful effector, requiring a significantly higher concentration for 50% inhibition of oxidation than doxorubicin and the other analogues examined.

Topics: Aclarubicin; Animals; Doxorubicin; Epirubicin; In Vitro Techniques; Male; Mitochondria, Heart; Naphthacenes; Oxidative Phosphorylation; Oxygen Consumption; Rats; Rats, Inbred Strains

A set of three novel anthracyclines, active as antitumour agents, has been examined for their possible effects on rat heart mitochondrial respiration. The in vitro inhibiting effects of the compounds have been compared with that of the older doxorubicin. Aclacinomycin was generally more inhibitory than doxorubicin, 4'-epi-doxorubicin and 4'-epi-tetrahydropyranyl-adriamycin, with both succinate and NAD+-linked substrates. Attempts to prevent anthracycline from inhibiting the succinate oxidase activity by means of adding exogenous coenzyme Q10 gave encouraging results, the inhibiting effect being in fact reduced.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Coenzymes; Doxorubicin; Epirubicin; In Vitro Techniques; Male; Mitochondria, Heart; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Naphthacenes; Oxidoreductases; Oxygen Consumption; Rats; Ubiquinone

Recently marked progress in many fields around the treatment of acute leukemia has resulted a marked improvement in the therapeutic results. Establishment of fundamental principles of therapy, i.e., understanding of remission induction, consolidation and maintenance has supported a systemic analysis of treatment. New antileukemia drugs such as Aclacinomycin, THP-adriamycin, Epirubicin, Mitoxantrone, Vindesine, Etoposide, PL-AC together with the immunotherapeutic agent i.e., Bestatin, kurestin and Nocardia-CWS were studied and found to show their merits in the treatment. Monitoring the patients by 5000 leukocyte differential or the development of new antibiotics or improvement of laminar air flow rooms etc, has supported the antileukemic therapy. Bone marrow transplantation, allogeneic, syngeneic or autologous, has shown a very rapid progress and is proved to be a reliable treatment with very high rate of complete cure.

Topics: Aclarubicin; Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Doxorubicin; Humans; Leukemia; Naphthacenes; Vincristine; Vindesine

The in vitro sensitivity of peripheral blood myeloblast clonogenic cells (CFU-MLs) to doxorubicin (DOX), aclacinomycin (ACL), and 4'-O-tetrapyranyl-doxorubicin (THP-DOX) was studied to evaluate the individual chemosensitivity of CFU-MLs. CFU-MLs from untreated patients were sensitive to the three tested anthracyclines (in 60% to 69% of the patients). Conversely, CFU-MLs from relapsed patients previously treated with DOX-containing regimens were sensitive to ACL and THP-DOX (in 71% and 75% of the patients, respectively) but resistant to DOX. Six of ten patients who entered complete remission with a combination of DOX, vincristine, and cytosine arabinoside had CFU-MLs in vitro which were sensitive to DOX. Conversely, none of the 13 patients resistant to this chemotherapy regimen displayed CFU-MLs which were sensitive in vitro to DOX. Nine of ten patients who responded to ACL as well as one of three resistant patients had CFU-MLs sensitive to ACL in vitro. No clinical responses were observed with THP-DOX in five of seven patients with CFU-MLs sensitive to this drug. The results indicate that myeloblast clonogenic assays can be used to predict the in vitro sensitivity of CFU-MLs to compounds with established antileukemic activity (ie, DOX, ACL). However, the discrepancy between in vitro and in vivo sensitivity to THP-DOX underlines the importance of knowledge of drug pharmacokinetics and the difficulty of using the CFU-ML test for screening new drugs.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Doxorubicin; Humans; In Vitro Techniques; Leukemia; Naphthacenes; Neoplastic Stem Cells; Stem Cells; Tumor Stem Cell Assay

Studies of anthracycline antibiotics which have been carried out for the purpose of finding compounds useful in the treatment of cancer are described. Synthetic development of derivatives and analogs which have stronger activities and lower characteristic toxicities than parent antitumor antibiotics such as daunomycin, adriamycin, etc., have been illustrated namely: (1) syntheses of 4'-O-derivatives such as 4'-O-tetrahydropyranyl-adriamycin; (2) syntheses of N-alkyl derivatives such as 3'-deamino-3'-morpholino-adriamycin; and (3) syntheses of 11-deoxy-adriamycin. Notably, 4'-O-tetrahydropyranyl-adriamycin having a (2" R)-configuration has been confirmed to have stronger activity and lower toxicity than adriamycin by Phase II study. New, naturally occurring anthracycline antibiotics (decilorubicin, arugomycin, ditrisarubicin, etc.) have also been reviewed.

Topics: Aclarubicin; Animals; Anthracyclines; Antibiotics, Antineoplastic; Daunorubicin; Doxorubicin; Leukemia L1210; Mice; Naphthacenes; Structure-Activity Relationship

Aclacinomycin, isolated from the culture of a Streptomyces, and 4'-O-tetrahydropyranyladriamycin, prepared by chemical derivation, exhibit significantly low cardiac toxicity and more effectiveness than does adriamycin. Pepleomycin, a new derivative of bleomycin, has 4-5 times lower pulmonary toxicity and more potent activity than the parent antibiotic. The future prospects of studies on antibiotics with potential usefulness in treatment of lung cancer are discussed.

Topics: Aclarubicin; Adjuvants, Immunologic; Animals; Antibiotics, Antineoplastic; Bleomycin; Daunorubicin; Doxorubicin; Humans; Leukemia L1210; Lung; Lung Neoplasms; Mice; Molecular Weight; Naphthacenes; Peplomycin; Structure-Activity Relationship