carubicin and Neoplasms

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

This review describes the current clinical results of phase I and II trials of new antitumor drugs such as the new anthracyclines: epirubicin, idarubicin, esorubicin, carminomycin and marcellomycin; the second generation cisplatin: carboplantin, CHIP, TNO-6, DACCP and JM-40; mitoxantrone, AMSA, AZQ, Tiazofurin, DFMO and others.

Topics: Aminoacridines; Amsacrine; Anthracyclines; Anthraquinones; Antibiotics, Antineoplastic; Antineoplastic Agents; Aziridines; Benzoquinones; Carboplatin; Carubicin; Cisplatin; Daunorubicin; Doxorubicin; Eflornithine; Epirubicin; Humans; Idarubicin; Mitoxantrone; Naphthacenes; Neoplasms; Organoplatinum Compounds; Ornithine; Ribavirin

Topics: Animals; Biological Transport; Carubicin; Chemical Phenomena; Chemistry; Daunorubicin; DNA; Humans; Mice; Neoplasms; Neoplasms, Experimental; Nocardia; Protein Biosynthesis; RNA

To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2.. A total of 25 patients with advanced malignant disease participated in a dose-escalation study in the first cycle of treatment given i.v. at doses of 50-80 mg/m2 (74-152 mg) with concomitant filgrastim (G-CSF, 5 microg/kg) given daily beginning at 24 h after the dose of MX2.. The mean fast distribution half-life (1.5 +/- 1.0 min) and the mean plasma clearance (2.18 +/- 0.95 l/min) were significantly lower than the respective mean values found in a previous study in which 27 patients had received MX2 (16.8-107.5 mg) alone (3.3 +/- 2.2 min and 2.98 +/- 1.68 l/min, respectively; P < 0.05). There was no correlation between plasma clearance and the delivered dose for the combined MX2-alone and MX2-filgrastim groups, indicating that the lower clearance observed in the G-CSF group was probably not due to the higher dose. Elimination half-lives of the metabolites M1 and M4 were significantly greater in the filgrastim group (19.8 +/- 14.7 and 11.8 +/- 5.0 h for M1 and 14.8 +/- 4.1 and 12.3 +/- 6.3 h for M2, respectively). Unlike the MX2-alone group, there was no relationship in the MX2-filgrastim group between the relative nadir neutrophil count and the dose or between the duration of grade IV neutropenia and the dose of MX2.. This study shows that filgrastim decreased the plasma clearance of MX2 by approximately 25%, possibly by inhibition of metabolism.

Topics: Antibiotics, Antineoplastic; Area Under Curve; Carubicin; Dose-Response Relationship, Drug; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Metabolic Clearance Rate; Neoplasms; Neutrophils; Recombinant Proteins

To determine the recommended dose, toxicity profile, and pharmacokinetics of KRN8602 (MX2-hydrochloride), a novel morpholino anthracycline with potent cytotoxicity against anthracycline-sensitive and resistant experimental tumors in vitro and in vivo.. KRN8602 was administered alone in increasing doses to patients with advanced cancer or high-grade gliomas until dose-limiting toxicity (DLT) was observed in three or more of five patients treated in a dose level. Because neutropenia was dose limiting, further escalation was investigated with filgrastim support.. Fifty-six assessable patients completed at least one cycle of chemotherapy. The recommended dose of KRN8602 alone was 40 mg/m2. Dose escalation was limited by neutropenia. The recommended dose of KRN8602 with filgrastim was 70 mg/m2, and limiting toxicities were neutropenia, diarrhea, and vomiting. The most commonly experienced nonhematologic toxicity was nausea and vomiting. Alopecia and mucositis were infrequent and mild. Pharmacokinetic parameters showed substantial variation, although the area under the plasma concentration-time curve (AUC) and maximum concentration both increased with dose. There was no relationship between pharmacokinetic parameters and toxicity.. KRN8602 at doses of 40 mg/m2 when administered alone and 70 mg/m2 when administered with filgrastim appeared to be manageable. The major DLTs were neutropenia and, at higher doses, diarrhea and vomiting. The efficacy of this drug is currently being tested in phase II studies.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Carubicin; Dose-Response Relationship, Drug; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Neoplasms; Neutropenia; Recombinant Proteins; Treatment Outcome

The purpose of the present study was to investigate the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. A total of 27 patients with advanced cancer participated in a dose-escalation study in the first cycle of treatment with drug given i.v. at doses of 10-50 mg/m2 (total dose 16.8-107.5 mg). The mean total systemic plasma clearance (CL) of MX2 was 2.98 +/- 1.68 l/min, the mean volume of distribution at steady state was 1460 +/- 749 l and mean elimination half-life was 10.8 +/- 5.1 h. The area under the plasma concentration-time curve (AUC) of MX2 was linearly related to the dose per kilogram and the dose per body surface area (r2 = 0.43, P < 0.01 and r2 = 0.44, P < 0.01, respectively). CL did not correlate with total body weight, lean body mass or body surface area. The mean elimination half-lives of the metabolites M1, M2, M3 and M4 were 11.8 +/- 5.0, 21.9 +/- 11.8, 19.0 +/- 11.3 and 12.3 +/- 6.3 h, respectively. The fractional Emax model produced a much better fit to the relative nadir neutrophil count versus dose data (r2 = 0.42) than to the relative nadir neutrophil count versus AUC or peak concentration (Cmax) data (r2 = 0.15 and 0.09, respectively). There seemed to be a threshold dose of about 65 mg of MX2 at or above which a large proportion of patients had a nadir neutrophil count of less than 0.5 x 10(9)/l. This study shows that the pharmacokinetics of MX2 are similar to those of other anthracyclines. With other anthracyclines the degree of myelosuppression seems to depend more on the AUC and Cmax than on the delivered dose; however, with MX2 the degree of myelosuppression depends more on the dose given than on drug exposure expressed as the AUC or Cmax.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Area Under Curve; Carubicin; Doxorubicin; Female; Half-Life; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Neutropenia; Neutrophils; Safety

Carminomycin is an original antitumor antibiotic from the anthracycline group isolated at the Institute of New Antibiotics (USSR) in 1973. Pharmacological investigation of carminomycin revealed its satisfactory absorption from the gastrointestinal tract which proved to be a distinguishing property of the antibiotic as compared to other anthracyclines such as adriamycin and rubomycin. The clinical trials of carminomycin showed that it was mainly active against soft tissue sarcoma and breast cancer, lymphosarcoma, neuroblastoma, Wilms' tumor and Ewing's sarcoma in children, as well as acute leukemia. Various regimens for the antibiotic administration were applied: short-term, single and long-term. Suppression of hemopoiesis was considered as a limiting toxic effect. By the data available carminomycin had lower cardiotoxicity as compared with rubomycin and adriamycin. Development of oral carminomycin is believed promising.

Topics: Adult; Breast Neoplasms; Carubicin; Child; Female; Humans; Kidney Neoplasms; Leukemia, Myeloid, Acute; Liver Neoplasms; Neoplasms; Sarcoma; Soft Tissue Neoplasms; Uterine Neoplasms; Wilms Tumor

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

Karminomycin effect on the activity of some serum enzymes, such as hexokinase (HK), lactate dehydrogenase (LDG), its isoenzymes and glucose-6-phosphatase (G-6-P-ase) was studied. Biochemical assays were applied to 52 patients with neglected malignant tumors. The course dose of the drug was on the average 72mg. The objective antitumor effect was registered in 15 patients. A reliable increase in the values of LDG-5 and G-6-P-ase was observed after the treatment course in the combined group consisting of all the patients subjected to the biochemical assay. Normalization of the serum enzyme spectrum was observed in 15 patients effectively treated with karminomycin: activity of HK and the cathode fractions of LDG decreased. When treatment with karminomycin was ineffective (37 cases), the changes in the enzymatic activity recorded before the treatment further aggraviated. It was found that the level of G-6-P-ase in the patients' treated with karminomycin increased independent of the treatment effect which was probably associated with its toxic effect on the liver. The increase was reversible.

Topics: Antibiotics, Antineoplastic; Blood; Carubicin; Clinical Trials as Topic; Enzyme Activation; Female; Glucose-6-Phosphatase; Hexokinase; Humans; Isoenzymes; L-Lactate Dehydrogenase; Neoplasms

Carminomycin chemotherapy of the patients with malignant tumors is often complicated with cardiopathy which is sometimes assymptomic and registered only electrocardiographycally. Chemotherapy on the background of reparative regeneration stimulators from the series of synthetic pyrrimidine derivatives, such as methyluracyl for oral use and a soluble salt of methyluracyl for parenteral administration significantly decreased the rate of the cardiotoxic complications and promoted a decrease in their level. The use of methyluracyl and its soluble salt did not decrease the therapeutic effect of carminomycin. Methyluracyl and its soluble salt may be recommended for prophylaxis of cardiotoxic complications in chemotherapy of malignant tumors with carminomycin.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Carubicin; Clinical Trials as Topic; Drug Evaluation; Drug Interactions; Drug Therapy, Combination; Heart; Humans; Methylthiouracil; Middle Aged; Neoplasm Metastasis; Neoplasms

Side reactions and therapeutic effect of carminomycin were studied in 21 children with various malignant tumors. Carminomycin was administered intravenously in doses of 0.15-0.2 mg/kg twice a week for 2-3 weeks. The treatment courses were repeated in a month. The drug was better tolerated by children than by adults. After the treatment course leucopenia may develop. When used alone or in combination with vincristin or cyclophosphan carminomycin proved to be effective in treatment of sarcoma of the soft tissues (liposarcoma, synovial sarcoma), chondrosarcoma and reticulosarcoma.

Topics: Adolescent; Antibiotics, Antineoplastic; Carubicin; Child; Child, Preschool; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Lymphatic Metastasis; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Moscow; Neoplasms; Remission, Spontaneous; Sarcoma

The clinical trials of karminomycin, a new Soviet antitumor antibiotic in treatment of different malignant tumors showed that the drug had a pronounced antitumor activity against the soft tissue sarcomas of various histogenesis, lympho- and reticulosarcoma, acute leukemia and some other neoplasms.

Topics: Adolescent; Antibiotics, Antineoplastic; Carubicin; Clinical Trials as Topic; Drug Evaluation; Humans; Leukemia; Male; Middle Aged; Neoplasms; Remission, Spontaneous; USSR

In several preclinical systems, the morpholino anthracycline MX2 has greater antitumor activity than doxorubicin, is less cardiotoxic, and is effective against multidrug resistant cancer cells. We used a human tumor soft-agar cloning assay to test the cytotoxicity of MX2 against single cell suspensions from freshly obtained human tumors. Tumor cells were exposed to MX2 at 0.05 and 0.5 micrograms/ml either for 1 hour (2-1 specimens; 77 [38%] assessable) or continuously (231 specimens; 91 [39%] assessable). Superior antitumor activity was observed with continuous exposure (19% in vitro response at 0.05 micrograms/ml and 69% at 0.5 micrograms/ml) than with 1-hour exposure (1.3% at 0.05 micrograms/ml and 12% at 0.5 micrograms/ml). Activity was seen against all types of cancer tested including renal (91%), melanoma (88%), ovarian (73%), breast (71%) and non-small-cell lung (67%) cancer at a MX2 concentration of 0.5 micrograms/ml after continuous exposure. If appropriate plasma levels can be achieved in patients, MX2 could have significant clinical activity with those tumors.

Topics: Antibiotics, Antineoplastic; Carubicin; Cell Division; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drugs, Investigational; Humans; Neoplasms; Neoplastic Stem Cells; Tumor Cells, Cultured; Tumor Stem Cell Assay

Carminomycin (CMN) was administered i.v. to 44 patients with a variety of nonhematological cancers every 4 weeks at doses of 15, 20, 22.5, and 25 mg/sq m. Granulocytopenia was the dose-limiting toxicity. The median granulocyte count for previously untreated patients receiving 22.5 mg/sq m was 0.962 cells/microliters, and for previously treated patients receiving 20 mg/sq m it was 0.420 cell/microliters. Moderate to severe phlebitis was associated with drug administration in 50% of cases. Nausea, vomiting, and alopecia were mild. Three of nine patients who received a total CMN dose of greater than or equal to 100 mg/sq m (mean, 132 mg/sq m) developed unexplained decreases in radionuclide cardiac ejection fraction, with one patient developing decreased QRS amplitude and congestive heart failure at a total dose of 160 mg/sq m. CMN is rapidly metabolized to carminomycinol. The elimination half-lives of CMN and carminomycinol are 6 to 10 and 50 hr, respectively. CMN was found to be a more potent inhibitor of human granulocyte-macrophage colony-forming units than was carminomycinol. Objective partial responses were seen in two of seven previously untreated patients with non-small cell lung cancer and one of three patients with squamous cell carcinoma of the head and neck previously untreated with chemotherapy.

Topics: Adult; Aged; Agranulocytosis; Carubicin; Colony-Forming Units Assay; Daunorubicin; Drug Evaluation; Female; Heart Diseases; Humans; Infusions, Parenteral; Male; Middle Aged; Neoplasms

Topics: Adolescent; Adult; Aged; Carubicin; Daunorubicin; Drug Administration Schedule; Drug Evaluation; Humans; Injections, Intravenous; Leukopenia; Middle Aged; Neoplasms; United States

A method is given for the determination of carminomycin (CMM) and a major metabolite carminomycinol (CMMOH) in serum from cancer patients after intravenous administration of carminomycin as the free drug. CMM and CMMOH are extracted from serum with chloroform, the extract evaporated and the residue dissolved in methanol. High performance liquid chromatography analysis utilized a C18 microBondapak reversed-phase column eluted with 0.1 mol/l acetate buffer (pH 4)-acetonitrile (60:40, v/v) with fluorescence detection. The assay is linear, reproducible, and precise with a limit of detection of 2 ng/ml. Representative serum levels of CMM and CMMOH in a cancer patients are presented.

Topics: Analysis of Variance; Carubicin; Chromatography, High Pressure Liquid; Daunorubicin; Humans; Injections, Intravenous; Neoplasms; Reference Standards; Time Factors

The paper reports on a trial in which nitrosomethylurea (NMU) was compared with CCNU both in combination with vincristine and dactinomycin or the same combination with DTIC in the treatment of disseminated skin melanoma. The long-term results were statistically better in the groups with NMU than in that with CCNU while there was no statistical difference regarding the complete regression. A second trial compared NMU with CCNU in the treatment of small cell carcinoma in a regimen of combined chemo-radiotherapy. No statistical difference was to be noticed in regard to objective response and median live duration. In comparison with regimens including adriamycin the study showed an equal effectiveness of the two drugs. A third part deals with carminomycin therapy in metastatic soft tissue sarcomas and with the preventive role of postoperative 5-fluorouracil in gastric carcinoma and colo-rectal cancer.

Topics: Antineoplastic Agents; Carcinoma, Small Cell; Carubicin; Dacarbazine; Dactinomycin; Drug Therapy, Combination; Female; Humans; Lomustine; Lung Neoplasms; Male; Melanoma; Methylnitrosourea; Neoplasms; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Vincristine

Topics: Adult; Aged; Carubicin; Daunorubicin; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Leukopenia; Male; Middle Aged; Neoplasms; Thrombocytopenia

Topics: Animals; Antibiotics, Antineoplastic; Carubicin; Dogs; Haplorhini; Humans; Neoplasms; Rats

Topics: Bleomycin; Carubicin; Humans; Neoplasms; Tegafur

This paper reviews methods which have evolved at the Research Triangle Institute during the last 15 years for the isolation and characterization of antitumor agents from plants. The isolation procedures stress mild, nonchemical methods. Solvent partition and the Craig Counter Current Distribution are used during the early stages of fractionation. Subsequent purification involves many types of chromatography: adsorption, partition, thin-layer, preparative thin layer, gel-exclusion, and medium- and high-pressure liquid chromatography. The pure compound is crystallized from a suitable solvent. The fractionation is monitored with in vitro and in vivo bioassays. Physical methods used for structure determination are: ultraviolet, infrared, and nuclear magnetic resonance spectrometry, and X-ray crystallography.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Carubicin; Chemical Fractionation; Chemical Phenomena; Chemistry; Chromatography; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Countercurrent Distribution; Humans; Leukemia L1210; Leukemia, Experimental; Longevity; Mice; Neoplasms; Plant Extracts; Spectrum Analysis

Systems of blood coagulation in patients treated with antibiotics of the anthracycline group were studied. Rubomycin was used in the treatment of patients with acute leukemia Adriamycin and carminomycin were used in the treatment of patients with solid tumors. The antibiotics affected the process of blood coagulation mainly through their cytostatic effect on thrombocytopoesis. Thrombocytopenia induced deficit of thrombocytal factors participating in the process of blood coagulation which resulted in hypocoagulation and hemorrhagic complications. The plasmic factors did not significantly change during the antibiotic therapy. A tendency to decrease in the levels of prothrombine, fibrinase and fibrinogen was noted which was possible due to an inhibitory effect of the antibiotics on the function of the reticuloendothelial tissue cells or indirectly to suppression of the tumor process. More pronounced changes in the system of blood coagulation of patients treated with rubomycin were probably associated with inferiority of the thrombocytal apparatus of the patients with acute leukemia treated with the antibiotic.

Topics: Antibiotics, Antineoplastic; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Carubicin; Doxorubicin; Drug Therapy, Combination; Hematopoiesis; Humans; Neoplasm Metastasis; Neoplasms; Prednisolone; Thrombelastography; Time Factors