carubicin and Neoplasm-Metastasis

KRN8602 (3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 x HCl) is a newly developed anthracycline that has been found to be effective against multidrug-resistant tumor cells in vitro and in vivo. In order to clinically confirm these promising preclinical observations, we performed a phase II trial of KRN8602 in patients with anthracycline-resistant metastatic breast cancer.. Of 41 patients registered with metastatic breast cancer, 37 were eligible and were given at least two cycles of KRN8602 15 mg/m2 per day at 3-4 week intervals by intravenous bolus injection on days 1, 2, and 3.. Of the 37 patients, 6 (16.2%, with a 95% confidence interval of 4.3-28.1%) had a partial response (PR). No complete responses (CRs) were observed. The difference between response rates according to prior history of anthracycline administration was not significant. Myelosuppression was moderately severe, with grade 3 or 4 leukopenia occurring in 65%. Severe nausea/vomiting was observed in 44% of the patients.. The results indicate that KRN8602 has modest activity in refractory metastatic breast cancer and is associated with relatively severe toxicity. Furthermore, the preclinical finding that KRN8602 overcomes anthracycline resistance was not reliably reproduced in this clinical phase II trial.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Breast Neoplasms; Carubicin; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Neoplasm Metastasis

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

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carubicin; Clinical Trials as Topic; Cyclophosphamide; Dacarbazine; Dactinomycin; Doxorubicin; Humans; Lymphatic Metastasis; Neoplasm Metastasis; Random Allocation; Sarcoma; Soft Tissue Neoplasms; Vincristine

Sixty-three evaluable patients with advanced breast cancer were randomly allocated to receive three-week intravenous courses of carminomycin (18 mg/m2) or 4'-epidoxorubicin (90 mg/m2). The former yielded one (3%) partial response for nine weeks among 29 patients whereas, in the other arm, nine (27%) of 34 patients achieved partial response for a median of 28 weeks (range, nine to 36 weeks; p less than 0.02). The major toxic effect of these anthracyclines was leukopenia with median white blood cell nadirs of 1,600/microL (range, 300-4,000/microL) versus 1,800/microL (range, 500-4,300/microL), respectively. Acute nonhematologic toxic effects were qualitatively similar but carminomycin produced significantly less gastrointestinal intolerance and alopecia. Patients whose disease failed to respond to first-line anthracycline received doxorubicin (60 mg/m2) every three weeks. Four partial responses were obtained among 19 patients previously treated with carminomycin. Following 4'-epidoxorubicin therapy, one of 12 evaluable patients also attained partial response. Survival curves were not affected by the initial treatment option. Carminomycin has marginal activity against breast cancer whereas 4'-epidoxorubicin deserves further evaluation of its therapeutic index relative to doxorubicin. The design used in this trial appears attractive for prompt phase II evaluation of anthracycline analogs.

Topics: Adult; Aged; Alopecia; Breast Neoplasms; Carubicin; Daunorubicin; Doxorubicin; Drug Evaluation; Epirubicin; Female; Follow-Up Studies; Heart Diseases; Humans; Leukopenia; Middle Aged; Nausea; Neoplasm Metastasis; Random Allocation; Vomiting

A more than 50% regression of tumor was observed in 19% of 64 patients treated with carminomycin for advanced primary breast cancer, its recurrences and metastases. A clinically-significant effect of treatment was recorded in 42%, while tumor process was arrested for at least 3-4 months in 37% of cases. The index of more than 50% regression of tumor rose to 28% in a group of 27 patients, following repeated courses of the drug. Only a slight toxic side--effect was observed, repeated courses included. Moderate leukopenia and a slight cardiotoxic effect were registered in 17%; phlebitis--in 12%. Carminomycin treatment should be recommended for advanced primary breast cancer, its recurrences an metastases, when other chemotherapeutic means fail to stop tumor process.

Topics: Adult; Aged; Breast Neoplasms; Carubicin; Clinical Trials as Topic; Daunorubicin; Female; Humans; Injections, Intravenous; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Time Factors

The therapeutic effect of carminomycin in various combinations with other antitumor drugs, i. e. vincristin, cyclophosphan, dactinomycin and metatrexate was studied in clinics on 18 children with wide-spread Juing sarcoma. Satisfactory direct effect was observed with the use of the above combinations in 47.0 per cent of the patients, which was evident from a decrease in the secondary tumor, disappearance of the pains and improvement of the general state of the patients.

Topics: Antibiotics, Antineoplastic; Bone Neoplasms; Carubicin; Child; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Humans; Neoplasm Metastasis; Pelvic Neoplasms; Sarcoma, Ewing; Time Factors

The therapeutic effect of carminomycin was studied in clinic at different treatment schemes with respect to 14 children and juvenile patients with osteogenic sarcoma. Pronounced local effect evident from disappearance of the pain and in some cases decrease of the metastatic tumor were noted in the patients with metastases of the osteogenic sarcoma to the bones or relapses of the primary tumor. Subjective improvement and objective effect were observed respectively in 90 and 53 per cent of the patients with metastases into the lungs and pronounced lung symptomatology.

Topics: Adolescent; Antibiotics, Antineoplastic; Arm; Bone Neoplasms; Carubicin; Child; Child, Preschool; Clinical Trials as Topic; Drug Evaluation; Humans; Leg; Neoplasm Metastasis; Osteosarcoma; Remission, Spontaneous; Time Factors

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

A total of 39 patients with sarcoma of the soft tissues were treated with carminomycin administered intravenously in doses of 10-15 mg twice a week, the total dose being 60-70 mg. The intervals between the courses were 1 month. The objective effect was observed in 17 out of 39 patients, i. e. 43.6%. The tumor decrease was registered in 6 out of 15 patients with leuomyosarcoma, in 3 out of 6 patients with synovial sarcoma, in 2 out of 4 patients with robdomyosarcoma, in 1 out of 4 patients with angiosarcoma, in 1 out of 3 patients with fibrosarcoma, in 1 patient with liposarcoma and in 3 out of 5 patients with stromal sarcoma of the uterus. A necessity for repeated treatment courses in spite of a positive effect or absence of the disease progress is underlined.

Topics: Aged; Antibiotics, Antineoplastic; Carubicin; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Moscow; Neoplasm Metastasis; Remission, Spontaneous; Sarcoma; Soft Tissue Neoplasms

A total of 203 out patients with disseminated cancer of the mammary glands subjected to chemotherapy were followed up. Of these, 44 patients were treated according to the CMFVP program, 66 were subjected to monochemotherapy with carminomycin, 42 were treated with combinations of carminomycin and dibromdulcytol, 14 patients received monochemotherapy with adriamycin and 37 polychemotherapy according to the scheme of fluorouracil + adriamycin + cyclophosphamide. In addition to the early-demonstrated efficacy of adriamycin and the Cooper scheme, the comparative estimation of the treatment programs showed that carminomycin, a new antitumor antibiotic made in the USSR, had an obvious activity when used alone or in combination with dibromdulcytol, an alkylating agent, in the treatment of primary extended forms, relapses and metastases of mammary tumors. The data indicate that wide use of carminomycin which is comparatively low toxic is advisable in the treatment of disseminated cancer of the mammary gland.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carubicin; Cyclophosphamide; Daunorubicin; Doxorubicin; Fluorouracil; Humans; Methotrexate; Neoplasm Metastasis; Prednisone; Vincristine

The results of the treatment of the prevalent form of Ewing's sarcoma in 85 children aged 3 to 16 years with various methods are presented. 21 patients were subjected to monochemotherapy with sarcolysine or cyclophosphamide. 26 patients received monochemotherapy with sarcolysine or cyclophosphamide in combination with irradiation of the metastases. Polychemotherapy in combination with radiotherapy was applied to 38 patients. The polychemotherapy in combination with radiotherapy was applied to 38 patients. The polychemotherapy included cyclophosphamide, vincristine, methotrexate, dactinomycin and carminomycin used in various combinations. The schemes of the polychemotherapy are presented. The best results were obtained with the use of the polychemotherapy in combination with radiotherapy: the index of the 3-year survival amounted to 38.5+/-14 per cent, while in the patients subjected to the monochemotherapy in combination with irradiation of the metastases it was equal to 3.8+/-3.7 per cent. After the monochemotherapy used alone all the children died by the 2nd year. It is concluded that patients with the prevalent form of Ewing's sarcoma should b subjected to systematic treatment. Polychemotherapy in combination with radiotherapy is shown to be promising.

Topics: Adolescent; Carubicin; Child; Child, Preschool; Cyclophosphamide; Daunorubicin; Drug Evaluation; Drug Therapy, Combination; Humans; Melphalan; Neoplasm Metastasis; Radiotherapy Dosage; Sarcoma, Ewing

Thirteen patients with neglected mammary cancer were treated with karminomycin in combination with hexamethylmelamine. Twelve out of the 13 patients were previously subjected many times to cytostatic and hormonal therapy. A significant therapeutic effect was registered in 5 out the 13 patients (38 per cent), the total rate of the objective effect being 54 per cent. The remission period with a significant effect was 6 to 9 months. Fifteen patients with sarcoma metastases in the soft tissue were treated with karminomycin in combnation with methotrexate and cyclophosphane. A significant therapeutic effect was observed in 45 per cent of the cases with synovial sarcoma, hemangyopericitoma and leuomyosarcoma, the remission period being 4 to 12 months. The side effects of the above combinations were determined.

Topics: Aged; Altretamine; Antibiotics, Antineoplastic; Breast Neoplasms; Carubicin; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Lymphatic Metastasis; Methotrexate; Middle Aged; Neoplasm Metastasis; Sarcoma; Soft Tissue Neoplasms

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