carubicin and Lymphoma--Non-Hodgkin

We summarize here the antitumor activity of newly developed drugs against malignant lymphoma. Irinotecan hydrochloride (CPT-11) showed a CR rate of 15% and an excellent response (CR + PR) rate of 42% in patients with non-Hodgkin's lymphoma who had prior treatment. In patients with ATL, 13% achieved CR and a response rate was 39%. MST-16, a new orally administered bis(2, 6-dioxopiperazine) analogue, showed a CR of 3% and PR of 28% (response rate 31%), among patients with ATL, 9% of 23 patients achieved CR and the response rate was 44%. Phase I studies of fludarabine demonstrated a high response rate of 64%, especially in follicular lymphoma, with a number of patients achieving CR. Subsequent phase II studies demonstrated a response rate of 89% in patients with indolent lymphoma. KRN 8602 was developed in an attempt to improve the clinical efficacy of currently used anthracyclines. KRN 8602 has been shown to produce less cardiotoxicity and alopecia, yet has comparable antitumor effects to ADM, and also has demonstrated an antitumor effect on ADM-resistant tumors. CPT-11 and MST-16 were found effective not only in refractory non-Hodgkin's lymphoma, but also in patients with ATL, which had no standard therapy. Fludarabine has been demonstrated to be a very active drug in indolent lymphoid neoplasms, particularly CLL and low grade lymphoma. These new drugs are expected to overcome malignant lymphoma refractory to treatment thus far.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Carubicin; Clinical Trials, Phase II as Topic; Female; Humans; Irinotecan; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Male; Piperazines

We performed a clinical phase II study of KRN8602, a new anthracycline derivative, for relapsed or recurrent malignant lymphoma. KRN8602 was given at doses of 12-15 mg/m2 for 3 consecutive days, repeating every 3-4 weeks. Among 44 patients entered into the study, 36 were evaluable for safety, and 35 were evaluable for efficacy. The response rate was 18.2% (6PR/33) for non-Hodgkin's lymphoma and 0% (0/2) for Hodgkin's disease. Major toxicities were bone marrow suppression and gastrointestinal toxicity. Leukopenia was observed in 77.8%, thrombocytopenia in 44.4%, hemoglobin decrease in 44.4%, nausea and vomiting in 94.4% and anorexia in 80.6%. However, all toxicities were clinically manageable.

Topics: Anorexia; Antibiotics, Antineoplastic; Carubicin; Drug Administration Schedule; Hodgkin Disease; Humans; Leukopenia; Lymphoma, Non-Hodgkin; Nausea; Thrombocytopenia; Vomiting

Thirty-nine adults with clinical stage III or IV diffuse large cell lymphoma were prospectively randomised to receive etoposide with doxorubicin (Group 1: n = 17), the same schedule of etoposide with carminomycin (Group 2: n = 8), or BACOP (Group 3: n = 14). The complete remission rates were respectively 24%, 25% and 28%, and further good partial remissions were 41%, 25% and 14%. The incidence of adverse prognostic factors was examined with the first two groups combined for comparison to patients receiving BACOP. The low complete remission rates were attributable to bone marrow invasion in 64% (16/25) of patients in groups 1 and 2, and 64% (9/14) in group 3; to extensive gastrointestinal tract involvement in 24% (6/25) of patients in groups 1 and 2, and 36% (5/14) in group 3; and to high bulk disease in 24% (6/25) of patients in groups 1 and 2, and 36% (5/14) in group 3. Actuarially predicted survival has not been reached for group 1, is 12 months for group 2, and 8 months for group 3; these different trends are not statistically significant. The trial was discontinued when it became clear that there was no difference between the two- and five-drug treatment regimens and that unacceptably low remission rates were obtained in patients having a high incidence of these poor prognostic factors, particularly when compared with results being reported in regimens that contain high or intermediate doses of methotrexate.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow; Carubicin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Gastrointestinal Neoplasms; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Invasiveness; Prednisone; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Survival Rate; Vincristine

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

Toxicity and antitumor activity of five derivatives of rubomycin and carminomycin were studied in animals. The derivatives were prepared by modification of the methyl C-14 group. These were the following: 14-chlorrubomycin, 14-chlorcarminomycin, 14-salicyloyloxyrubomycin, 14-salicyloyloxycarminomycin and 14-quinaldinoyloxyrubomycin. The chemotherapeutic study revealed that, in their activity, all the compounds were inferior to the starting antibiotics. Unlike the other derivatives, 14-chlorcarminomycin induced a significant inhibition of leukemia P-388 development (the average lifespan of the mice amounted to 165 per cent as compared to the control). However, in the magnitude of its effect, the derivative was inferior to carminomycin.

Topics: Animals; Carubicin; Daunorubicin; Drug Evaluation, Preclinical; Female; Leukemia P388; Leukemia, Experimental; Lymphoma, Non-Hodgkin; Male; Mice; Neoplasms, Experimental

The reaction of nucleophilic substitution of 14-bromine derivatives of carminomycin and rubomycin with respective nitrogen-containing heterocycles yielded six novel derivatives of carminomycin and rubomycin: 14-N-imidazolyl-carminomycin, 14-carminomycyl-N-pyridinium bromide, 14-carminomycyl-N-(3-aminocarbonyl)-pyridinium chloride, 14-rubomycyl-N-(3-amino-carbonyl)-pyridinium chloride, 14-N-succinimidocarminomycin and 14-N-succinimidorubomycin. In vitro and in vivo antitumor activity of the above derivatives and three other derivatives described earlier: 14-rubomycyl-N-pyridinium bromide, 14-N-imidazolylrubomycin and 14-N-phthalimidorubomycin was studied. It was shown that in vitro all the 9 semisynthetic derivatives had a lower (by 1.5-6 times) cytostatic action on murine lymphadenosis cells NK/LI as compared to the initial antibiotics. The in vivo experiments on mice revealed that by acute toxicity the rubomycin derivatives administered intravenously were close to rubomycin, whereas the toxicity of the analogous derivatives of carminomycin was 5-17 times lower. The in vivo experiments also showed that seven out of the nine 14-N-substituted derivatives of carminomycin and rubomycin were practically deprived of antitumor activity (strain LIO-1), while 14-carminomycyl-N-pyridinium bromide and 14-N-succinimidocarminomycin inhibited the tumor growth by 40-60 per cent.

Topics: Animals; Bacillus; Carubicin; Daunorubicin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Lethal Dose 50; Lymphoma, Non-Hodgkin; Male; Mice; Neoplasm Transplantation; Structure-Activity Relationship

Carminomycin 13-cyclohexylidenhydrazone (CCH) was prepared by interaction of carminomycin 13-hydrazone with cyclohexane. The antiblastomic properties of CCH were studied on mice with transplantable tumors. The preparation was administered intravenously or orally. The studies showed a high antitumor activity of CCH. When CCH was administered intravenously to mice with lymphosarcoma LIO-1, the antitumor effect selectivity of it was practically equal to that of carminomycin. When used in doses equivalent by their toxicity to those of carminomycin, CCH had practically the same inhibitory effect on sarcoma 180 as carminomycin. When used orally in doses equivalent by their toxicity to those of carminomycin, CCH was more effective than carminomycin in treatment of mice with lymphosarcoma LIO-1, sarcoma 180 and lymphadenosis NK/Ly.

Topics: Administration, Oral; Animals; Carubicin; Chemical Phenomena; Chemistry; Cyclohexanones; Daunorubicin; Injections, Intravenous; Lymphoma, Non-Hodgkin; Mice; Neoplasms, Experimental; Sarcoma 180

13-Tret-butoxycarbonyl hydrazone (BOC hydrazone) of carminomycin was prepared by interaction of carminomycin with tret-butoxycarbonyl hydrazine. Interaction of carminomycin with N-amino-N'-methyl piperazine resulted in 13-(4-methyl piperazinyl) imine (MP imine) of carminomycin. BOC hydrazone and MP imine of carminomycin had a significant antiblastomic activity against lymphosarcoma LIO-1. Still, they had no advantages over carminomycin.

Topics: Animals; Carubicin; Daunorubicin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Injections, Intravenous; Lethal Dose 50; Lymphoma, Non-Hodgkin; Male; Mice; Neoplasm Transplantation; Neoplasms, Experimental

The antitumor activity and effect on immunogenesis of rubomycin and carminomycin combinations with levamisole were studied comparatively. It was found that levamisole administered after carminomycin increased the intensity of delayed hypersensitivity in mice and only partially reduced immunoreactivity of the animals estimated by the number of antibody-forming cells in the spleen. No such effect was observed after injections of rubomycin. The antitumor effect of the combinations of the antibiotics wit levamisole was studied in experimental transplantable mouse lymphosarcoma L10-1. The use of rubomycin or carminomycin in combination with levamisole increased the survival of the animals and sometimes resulted in complete resolution of the tumors. No such effect was observed in treatment of the animals with the drugs alone. The data are indicative of a possible use of levamisole in combination with antitumor antibiotics in immunochemotherapy of tumors.

Topics: Animals; Antibody Formation; Carubicin; Daunorubicin; Dose-Response Relationship, Immunologic; Drug Combinations; Drug Evaluation, Preclinical; Drug Hypersensitivity; Hypersensitivity, Delayed; Immunity, Cellular; Levamisole; Lymphoma, Non-Hodgkin; Male; Mice; Mice, Inbred Strains; Neoplasms, Experimental

Bovine serum albumin (BSA) and carminomycin, an anthracycline antibiotic, were subjected to conjugation with glutaraldehyde and their complexes with various contents of the antibiotic were prepared. The molar ratios of carminomycin and BSA were 8:1, 4:1, and 2:1. The antitumor effect of the preparations was studied on the models of mouse transplantable lymphosarcoma LIO equal 1 and ascitic forms of mouse lymphadenosis NK/Ly in vivo and in vitro. Their immunodepressant effect was evaluated from the decrease in the hemagglutinin titers in the mice immunized with sheep red blood cells. It was shown that when the toxicity of the complexes was the same, their antitumor and immunodepressant activities were different. The therapeutic activity of carminomycin in the four- and eight-substituted complexes was much higher than that of carminomycin alone. It is suggested that the differences in the activity of the complexes were connected with differences in their pharmacokinetics. It was found that the chemotherapeutic properties of the complexes may have changed by variation of the number of the cytostatic residues in the albumin molecule. The findings indicate that the whole complex molecule interacts with the malignant cell and not carminomycin preliminarily detached from it.

Topics: Animals; Antibiotics, Antineoplastic; Antibody Formation; Carubicin; Daunorubicin; Drug Combinations; Drug Evaluation, Preclinical; In Vitro Techniques; Lethal Dose 50; Lymphoma; Lymphoma, Non-Hodgkin; Male; Mice; Neoplasms, Experimental; Serum Albumin, Bovine; Time Factors

Carminomycin azine designated as carminazine was prepared by condensation of carminomycin with hydrazine hydrate. It was shown in the experiments on mice that the toxicity of carminazine was 2 and 7 times lower than that of carminomycin on its intravenous and oral administration respectively. The effect of both drugs on hemopoiesis of the mice was similar. As regards the selectivity of the antitumor effect on lymphosarcoma, strain L10-1, carminazine was inferior to carminomycin.

Topics: Animals; Antibiotics, Antineoplastic; Carubicin; Daunorubicin; Drug Evaluation, Preclinical; Hematopoiesis; Lethal Dose 50; Lymphoma, Non-Hodgkin; Male; Mice; Neoplasm Transplantation; Neoplasms, Experimental

Karminazon (13-benzoylhydrazon) was prepared by condensation of karminomycin with benzoylhydrazine. In its intravenous use in the treatment of mice with lymphosarcoma L10-1 karminazon was less toxic and had lower antitumor activity than karminomycin. Karminazon had a lower selective antitumor activity with respect to lymphosarcoma than karminomycin.

Topics: Animals; Antibiotics, Antineoplastic; Carubicin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Lymphoma, Non-Hodgkin; Male; Mice; Neoplasms, Experimental

The properties of carminomycin complexes with protein, a bovine serum albumin prepared with two different methods using glutaraldehyde or carbodiimine were studied. The complex prepared with the use of carbodiimine was biologically inactive. The complex prepared with the use of glutaraldehyde had a molecular mass of about 15 000 000 dalton, was more toxic than carminomycin and possessed proportionally higher antitumor activity and a wider antitumor spectrum. The studies on the use of the method of carminomycin complex formation with antitumor immunoglobulins are promising.

Topics: Animals; Antibiotics, Antineoplastic; Carubicin; Cattle; Drug Combinations; Drug Evaluation, Preclinical; Lethal Dose 50; Lymphoma, Non-Hodgkin; Macromolecular Substances; Male; Mice; Neoplasms, Experimental; Serum Albumin, Bovine; Structure-Activity Relationship

The antiblastomic activity of the carminomycin complex components was studied with respect to 8 strains of transplantable tumors of mice: lymphosarcoma L10-1, prestomach cancer OZh-5, sarcoma 180, lymphoid leucosis L 1210, lung bronchogenic cancer RL, lymphodenosis NK/LI, Ehrlich carcinoma and Garding-Passy melanoma. It was shown that components I, II and III possessed almost the same high antiblastomic activity and the same optimal administration schemes should be used for them. The scheme consisted of two-fold administration of the drug at intervals of 96-120 hours. Component I had broader therapeutic ranges and was more active against the lung bronchogenic cancer as compared to component II. All 3 components had no selective antiblastomic effect on the ascitic form of Ehrlich carcinoma. A comparative study of the component toxicity and pharmacology is required for final conclusion as to the recommendation of one of the components for clinical trials.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Bronchogenic; Carcinoma, Ehrlich Tumor; Carubicin; Drug Evaluation, Preclinical; Lethal Dose 50; Leukemia L1210; Lung Neoplasms; Lymphoma; Lymphoma, Non-Hodgkin; Melanoma; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasms, Experimental; Sarcoma 180; Time Factors

The authors obtained 14-oxykarminomycin by alkaline hydrolysis of 14-bromokarminomycin. On two-fold intravenous administration to mice with lymphosarcoma, strain L10-1, 14-oxycarminomycin showed the same toxicity as karminomycin. The preparation had the same selective antitumor activity as karminomycin.

Topics: Animals; Antibiotics, Antineoplastic; Carubicin; Drug Evaluation; Hydrolysis; Lethal Dose 50; Lymphoma, Non-Hodgkin; Mice; Neoplasms, Experimental

Antitumor activity of karminomycin used perorally was studied with respect to 3 strains of mouse transplantable tumors, i. e. one ascitic strain of lymphadenosis NK/LI and two solid strains of lymphosarcoma L10-1 and sarcoma 180. Karminomycin was shown to have a high antitumor activity against the above tumors on its oral administration. In the experiments with lymphadenosis NK/LI the efficiency of karminomycin was higher when it was used perorally as compared to its intravenous administration. It was found that karminomycin had practically the same inhibitory effect on growth of lymphosarcoma L10-1 and sarcoma 180 on its peroral and intravenous administration in doses equivalent by their toxicity.

Topics: Administration, Oral; Animals; Antibiotics, Antineoplastic; Carubicin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Injections, Intravenous; Lymphoma; Lymphoma, Non-Hodgkin; Male; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Sarcoma 180; Time Factors

A dihydro derivative of karminomycin was prepared using chemical reduction with potassium boron hydride. When dihydrokarminomycin was administered intravenously to healthy albino mice in a single dose it practically showed the same toxicity as karminomycin. However, unlike the latter dihydrokarminomycin induced the death of the animals at later periods of time. Studies on mice with transplantable tumours showed high antitumor activity of dihydrokarminomycin against lymphosarcoma L10-1, sarcoma 180, Garding-Passy melanoma, lymphoid leukosis L-1210 and lymphocytal leukosis P-388. In treatment of the mice with leukosis L-1210 and Garding-Passy melanoma dihydrokapminomycin was much inferior by its efficiency than karminomycin.

Topics: Animals; Antibiotics, Antineoplastic; Carubicin; Lethal Dose 50; Leukemia, Experimental; Lymphoma, Non-Hodgkin; Male; Melanoma; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Sarcoma 180