carubicin and Brain-Neoplasms

Idarubicin showed the superior activity against Acute Non-Lymphocytic Leukemia (ANLL) in the prospective randomized trials comparing to daunorubicin and it is judged that the analog will become the first choice in the treatment on ANLL. Anthracyclines including SM-5887, KRN-8602, ME-2303 under studies in Japan have shown comparable or superior antitumor activities and lower cardiac toxicities compared to doxorubicin in preclinical studies and therefore the results obtained in clinical trials are expected. Phase II trials of anthrapyrazoles which is an analog of mitoxantrone are in progress. Among three compounds entered it is of note that CI-941 has demonstrated an excellent activity against advanced breast cancer.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Brain Neoplasms; Carubicin; Doxorubicin; Humans; Idarubicin; Leukemia, Experimental; Leukemia, Myeloid, Acute; Menogaril; Stomach Neoplasms

KRN8602 (MX2) is a newly developed morpholino anthracycline that crosses the blood-brain barrier where it becomes distributed in brain tissue after intravenous administration. This morpholino anthracycline has been found to be effective against human glioma cells and the intracerebrally transplanted tumors in vivo, We performed a phase II trial using KRN8602 as a single agent in malignant glioma patients who had not received prior adjuvant therapy. The 13 patients (5 glioblastomas, 7 anaplastic astrocytomas and 1 malignant oligodendroglioma) enrolled received at least 1 cycle of KRN8602 at 35 mg/m2/day in 3-4 week intervals by intravenous bolus. Ten of these patients could be evaluated for response, and 13 for toxicity. Three patients (1 glioblastoma and 2 anaplastic astrocytomas) demonstrated a complete response (3/10, 30%). Concerning side effects, myelosuppression was moderately severe, with 30.7% of patients developing grade 3 leukopenia. Severe nausea/vomiting was observed in 69% of the patients, however, cardiotoxicity was not observed. The results indicate that KRN8602 demonstrated modest activity against malignant glioma with relatively severe, but manageable toxicity. Further assessment of the efficacy and toxicity of KRN8602 against malignant glioma may be worthwhile.

Topics: Adult; Antibiotics, Antineoplastic; Astrocytoma; Brain Neoplasms; Cardiomyopathies; Carubicin; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Glioblastoma; Humans; Leukopenia; Male; Middle Aged; Nausea; Oligodendroglioma; Treatment Outcome; Vomiting

KRN8602(MX2) is a newly developed morpholino-anthracycline that has been found to cross the blood-brain barrier and be distributed in brain tissue after intravenous administration and to be effective against human glioma cells and the intracerebrally transplanted tumors in vivo. In order to confirm these promising preclinical observations clinically, we performed a phase II trial of KRN8602 in patients with recurrent malignant glioma. The 44 patients enrolled received at least 2 cycles of KRN8602 35 mg/m2/day at 3-4 week intervals by intravenous bolus. Of the 44 patients, 37 could be evaluated for response, and 39 for toxicity. One patient with anaplastic astrocytoma had a complete response (1/37, 3%), and 2 patients with anaplastic astrocytoma and 1 with brain stem glioma had a partial response (3/37, 8%). The overall response rate was 11% (4/37). All patients who responded had received prior chemotherapy that included nitrosoureas. No response was observed in the patients with glioblastoma. Myelosuppression was moderately severe, with 72% of patients developing grade 3 or 4 leukopenia. Severe nausea/vomiting was observed in 31% of the patients. No severe cardiotoxicity was observed. The results indicate that KRN8602 has modest activity against recurrent malignant glioma with relatively severe, but manageable toxicity. It seems to be worthwhile to further assess the efficacy and toxicity of KRN8602 against malignant glioma, which is generally less sensitive to chemotherapy.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Brain Neoplasms; Carubicin; Female; Glioblastoma; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local

To assess the efficacy and toxicity of KRN8602 when administered as an intravenous bolus to patients with recurrent high-grade malignant glioma.. Patients with recurrent or persistent anaplastic astrocytoma or glioblastoma multiforme who had not received recent chemotherapy or radiotherapy and were of good performance status (Eastern Cooperative Oncology Group score < or = 2) were treated with an intravenous bolus of 40 mg/m(2) KRN8602 every 28 days. Tumor responses were assessed radiologically and clinically after every second cycle of therapy. Treatment was continued until documented progression or a total of six cycles.. A median of three cycles (range, one to six cycles) of KRN8602 was administered to 55 patients, 49 of whom received at least two cycles and were, therefore, assessable for response. The overall response rate (disease stabilization or better) was 43% (95% confidence interval, 29% to 58%). There were three complete responses, one partial response, seven minor responses, and 10 patients with stable disease. The median time to progression was 2 months (range, 1.5 to 37 months) and overall survival was 11 months (range, 1.5 to 40 months). Neutropenia was the most common toxicity, although it was generally of brief duration, and there were only seven episodes of febrile neutropenia in 176 cycles delivered. Nonhematologic toxicity was mostly gastrointestinal (nausea and vomiting, diarrhea) and events were grade 2 or lower except for a single episode of grade 3 vomiting.. KRN8602 is an active new agent with minimal toxicity in the treatment of relapsed or refractory high-grade glioma. Further studies with KRN8602 in combination with other cytotoxics and in adjuvant treatment of gliomas are warranted.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Astrocytoma; Brain Neoplasms; Carubicin; Combined Modality Therapy; Female; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Survival Analysis

Idarubicin showed the superior activity against Acute Non-Lymphocytic Leukemia (ANLL) in the prospective randomized trials comparing to daunorubicin and it is judged that the analog will become the first choice in the treatment on ANLL. Anthracyclines including SM-5887, KRN-8602, ME-2303 under studies in Japan have shown comparable or superior antitumor activities and lower cardiac toxicities compared to doxorubicin in preclinical studies and therefore the results obtained in clinical trials are expected. Phase II trials of anthrapyrazoles which is an analog of mitoxantrone are in progress. Among three compounds entered it is of note that CI-941 has demonstrated an excellent activity against advanced breast cancer.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Brain Neoplasms; Carubicin; Doxorubicin; Humans; Idarubicin; Leukemia, Experimental; Leukemia, Myeloid, Acute; Menogaril; Stomach Neoplasms

MX2 is a novel morpholino anthracycline reported to have lower systemic toxicity than other anthracyclines. It has similar antitumour activity to adriamycin and is cytotoxic towards multi-drug resistant cells and anthracycline sensitive sublines of human and murine tumour cells. In this study MX2 showed a marked cytocidal effect compared to M2, the most cytotoxically active metabolite, and the nitrosourea, BCNU, when 30 ng/ml of each drug was added to separate flasks of C6 glioma cells grown in monolayer. The colony formation of C6 glioma cells was markedly inhibited by MX2 in a dose dependent manner. The LD50 values for MX2, M2 and BCNU were 10.5 ng/ml, 15.8 ng/ml and 465 ng/ml respectively. MX2 is likely to be bound to the main plasma protein, albumin, and can also interact with the plasma lipoproteins, particularly high density lipoprotein. The results in this study strongly support the further investigation of MX2 as a potential chemotherapeutic agent against brain tumours.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Brain Neoplasms; Carmustine; Carubicin; Cell Division; Glioma; Humans; Lipoproteins; Rats; Tumor Cells, Cultured; Tumor Stem Cell Assay

We examined whether the intrathecal MX2 chemotherapy for treating dissemination of malignant glioma would be a feasible therapy. In the toxicity study, physiological and histological neurotoxicity was not observed in the rats treated with less than 100 microg/kg of MX2 administered intracisternally. But physiological side effects were observed in the treatment group of more than 200 microg/kg and histological brain toxicity was in the treatment group of more than 1000 microg/kg. Dissemination models were induced in rats by intracisternal inoculation of C6 glioma cells. The median survival times of the rats treated with 100 microg/kg of intrathecal MX2 on day 1, 3, or 7 after tumor inoculation were prolonged by 52.4% (p = 0.0006), 31.5% (p = 0.0007), and 7.1% (p = 0.0180), respectively, compared to that of untreated control animals. Intrathecal MX2 treatment also cured 33.6% of rats in the treatment group. These findings suggested that there was a possibility that intrathecal MX2 would be a safe and effective method for treating dissemination of malignant glioma.

Topics: Animals; Antineoplastic Agents; Brain; Brain Neoplasms; Carubicin; Dose-Response Relationship, Drug; Feasibility Studies; Glioma; Injections, Intraventricular; Injections, Spinal; Male; Nervous System Diseases; Rats; Rats, Wistar; Survival Analysis

The potential antitumor effect of MX2, a new lipophilic morpholino anthracycline, was compared with those of ACNU or doxorubicin (DOX) using two different rodent glioma models. A mouse subcutaneous glioma model (203 glioma) was used to measure the effect of each drug on reducing the glioma size and a rat 9L intracerebral glioma model (9L glioma) was used to assess the antitumor effect on survival rate in a clinically similar fashion. Treatment with ACNU inhibited tumor growth by 94.6% (p < 0.0001) and complete regression of the tumor was observed in 3 of 25 (12.0%) of the ACNU-treated cases. Tumor growth was inhibited by 32.4% with DOX despite a tendency (p < 0.16) and by 59.4% with MX-2 (p < 0.001); neither of these drugs resulted in complete tumor regression. In the intracerebral glioma rats, only ACNU tended to ameliorate survival rate, but there was no statistical significance. These results suggest that ACNU has the most potent effect but MX2 can be an option for chemotherapy of malignant gliomas. Interestingly, all three drugs significantly elevated the brain water content on both the ipsilateral and contralateral sides of the tumor, although they did not induce brain edema in the normal rat brains. Careful management of brain edema might be required regardless of the drug used during chemotherapy to maximize the prognosis of glioma patients.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Body Weight; Brain Edema; Brain Neoplasms; Carubicin; Disease Models, Animal; Doxorubicin; Glioma; Leukocyte Count; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Nimustine; Rats; Survival Rate

The chemotherapeutic effect of MX2 (3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin), a new lipophilic morpholino anthracycline, against rat C6 and human T98G glioma cells, was examined in vitro and in vivo. The subcellular distribution of MX2 was also studied. The drug concentrations of MX2 required for the 50% inhibition of cell growth (IC50) for C6 and T98G cells were 25.5 +/- 1.3 ng/ml and 70.6 +/- 6.8 ng/ml, respectively, which were much lower than the IC50 values for nimustine (ACNU). A C6 subline resistant to ACNU, C6/ACNU, was established by continuous exposure to graded concentrations of ACNU. The IC50 of MX2 for C6/ACNU was 28.3 +/- 2.2 ng/ml, indicating no cross-resistance to MX2. In the rats bearing the intracerebral C6 tumors, the life span was increased by about 40 to 100% after intravenous administration of MX2 at doses ranging from 1 to 3 mg/kg of body weight. Confocal laser scanning microscopy demonstrated visually the good accumulation of MX2 in the implanted intracerebral C6 tumors, as well as its predominant distribution in the cytoplasm over the nucleus in both cell lines in vitro. Ultrastructural studies also demonstrated the cytotoxic effects of MX2 against glioma cells. Our results suggest that MX2 may be a useful chemotherapeutic agent in the treatment of malignant gliomas and that confocal laser scanning microscopy is useful for the study of the cellular pharmacokinetics of anthracycline derivatives, such as MX2.

Topics: Animals; Antibiotics, Antineoplastic; Brain; Brain Neoplasms; Carubicin; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Glioma; Humans; Male; Microscopy, Electron; Neoplasm Transplantation; Rats; Rats, Wistar; Subcellular Fractions; Tissue Distribution; Tumor Cells, Cultured

Topics: Animals; Antibiotics, Antineoplastic; Brain Neoplasms; Carubicin; Collagen; Drug Screening Assays, Antitumor; Gels; Glioblastoma; Humans; Medulloblastoma; Mice; Neoplasm Transplantation; Tumor Cells, Cultured

Pharmacokinetics and antitumor activity of MX2.HCl (MX2), a new morpholino anthracycline, were investigated in rats transplanted 9L gliosarcoma cells in the brain. (1) Pharmacokinetics: AUC of MX2 in the brain tumors which received intracarotid and intravenous injection of 2mg/kg of MX2 were 117.50 and 55.94 micrograms.hr/g, respectively. AUC of the brain tissue was 1.38-3.90 micrograms.hr/g. (2) Antitumor activity: The inhibition of cell growth at the concentration of 0.1 micrograms/ml was 73.1% with MTT assay. The mean survival time in tumor-bearing rats after intracarotid and intravenous injection of 2mg/kg of MX2 prolonged significantly. Therefore, it seems that MX2 will become an efficacious drug for the treatment of malignant glioma.

Topics: Animals; Antibiotics, Antineoplastic; Brain; Brain Neoplasms; Carubicin; Cell Division; Female; Glioma; Neoplasm Transplantation; Rats; Rats, Inbred F344; Tumor Cells, Cultured

MX-2, a new morpholino anthracycline derivative, showed broad anti-neoplastic activity against experimental tumors. Molecular weight of MX-2 is 622.07, and it can cross blood-brain barrier because of its high lipid solubility. In this report, we described its in vitro and in vivo effects on brain tumors. The growth of rat 9L and human KNS-42 glioma cells were markedly inhibited by the medium containing more than 1 ng/ml of MX-2. The inhibitory concentration of MX-2 for 50% cell kill was 1.8 ng/ml for 9L cell and 18 ng/ml for KNS-42, respectively. These values were the almost same as those reported with P388 leukemia. In rats with meningeal carcinomatosis induced by intracisternal inoculation of Walker 256 carcinosarcoma cells, the median survival time was significantly prolonged. The increased life span was 40, 40, 40 (p less than 0.01), and 20% (p less than 0.05) in the animals given intravenous MX-2 of 1.5, 1.0, 0.75, and 0.375 mg/kg on day 1, 5, and 9 after tumor inoculation respectively. These results indicate that MX-2 may be a promising new antineoplastic agent for the treatment of malignant brain tumor.

Topics: Animals; Antibiotics, Antineoplastic; Arachnoid; Brain Neoplasms; Carubicin; Female; Glioma; Humans; Meningeal Neoplasms; Naphthacenes; Pia Mater; Rats; Rats, Inbred Strains