carubicin and Glioma

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

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

MX2, a new lipophilic morpholino anthracycline, has been reported to have chemotherapeutic effects superior to those of adriamycin against murine and human glioma cells in vitro and in vivo. To assess the combination effect of MX2 and hyperthermia in vitro, the thermo-chemosensitivities of cultured human (U251MG and KC) and rat (C6 and 9L) glioma cell lines were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The number of viable cells in each cell line was markedly and dose-dependently decreased by MX2 treatment, but the sensitivity of U251MG to MX2 was less than that of the other cell lines. The survival of each cell line was decreased with the hyperthermic treatment at 43 degrees C for 60 minutes. Combined treatment with MX2 and hyperthermia had an additive effect on cultured glioma cells when MX2 was added to the medium at a dose below 50 ng/ml. However, combined treatment indicated neither an additive nor a synergistic effect when the dose of MX2 was above 50 ng/ml. We conclude that MX2 may be clinically useful against malignant gliomas when administered alone or in combination with hyperthermia.

Topics: Animals; Antibiotics, Antineoplastic; Carubicin; Cell Survival; Coloring Agents; Combined Modality Therapy; Culture Media; Glioma; Humans; Hyperthermia, Induced; Rats; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured

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

MX2, a new lipophilic morpholino anthracycline, has been reported to have superior chemotherapeutic effects to adriamycin against murine and human tumor cells. In this study the chemotherapeutic effect of MX2 against C6 glioma cells was examined as well as the photocytotoxicity of MX2 and the combination effect of MX2 and photodynamic therapy (PDT) in vitro. Colony formation is inhibited even with only 2 hour treatment with MX2 in a dose-dependent manner. In this colony forming efficiency assay the drug concentration required for 50% inhibition of colony formation for C6 glioma cells was 24.0 +/- 4.5 ng/ml. Mild photocytotoxicity of MX2 against C6 glioma cells was observed at a high concentration (100 ng/ml) of MX2 following exposure to white light but not red light. In combination, MX2 and the photosensitizer haematoporphyrin derivative (HpD) exhibited an additive cytotoxic effect against C6 glioma cells when the cells were treated with MX2 either immediately after red light illumination following incubation with HpD or at an interval of 24 hours before incubation with HpD. We conclude that MX2 may be clinically useful against malignant glioma alone, and in combination with other therapies such as PDT.

Topics: Animals; Antibiotics, Antineoplastic; Carubicin; Glioma; Photochemotherapy; Rats; Tumor Cells, Cultured; Tumor Stem Cell Assay

The cellular uptake, subcellular distribution and retention of MX2, a new morpholino anthracycline, were compared with those of adriamycin (ADM) using confocal laser scanning microscopy (CLSM) in rat C6 and human T98G glioma cell lines. The tumor cells were exposed to 1-30 micrograms ml-1 of MX2 and ADM for 120 min and further incubated without drugs for 120 min after washing twice with medium. During incubation, real-time subcellular distribution of MX2 and ADM in living tumour cells were observed at various intervals using CLSM. For analysis of the in vivo uptake. Wistar rats bearing the C6 glioma were intravenously administered MX2 at a dose of 5 mg per kg body weight 60 min before sacrifice. The fluorescence of MX2 was predominantly seen in the cytoplasm in both C6 cells and T98G cells, although it was also present in the nucleus. In contrast, that of ADM was mainly confined to the nucleus in both cell lines. The fluorescent intensity of ADM in the nucleus after 120 min of exposure was approximately 1.5-fold higher than that of MX2 at the same dose exposure, probably indicating a greater amount of ADM accumulated in the nucleus than MX2. The influx and efflux of MX2 were much more rapid and greater than those of ADM in both cell lines. There was almost no difference in subcellular distribution among the doses tested in this study. The subcellular distribution of MX2 in vivo was almost similar to that of MX2 in vitro. These results suggest other mechanisms by which MX2 exerts its cytotoxic effects on tumour cells together with the inhibition of DNA topoisomerase II, which has been reported previously. It is considered that the CLSM technique is useful for the study of the cellular pharmacokinetics of antitumour agents such as anthracycline derivatives.

Topics: Animals; Antibiotics, Antineoplastic; Biological Transport; Carubicin; Cell Line; Doxorubicin; Glioma; Humans; Male; Microscopy, Confocal; Microscopy, Electron; Rats; Rats, Wistar; Subcellular Fractions; Time Factors

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

A new morpholino anthracycline derivative, MX2, has a potent antitumor activity similar to adriamycin. Because of high lipid solubility of MX2 (log P = 2.84, pH 7.4), the compound can cross the blood-brain barrier easier than adriamycin. In this study we tested the anti-tumor activity of MX2 against human glioma in vitro and in vivo. MX2 showed a marked cytocidal effect against U105MG, U251MG, U373MG and KMG4 cells when more than 30 ng/ml was added in the medium. Although the sensitivity against MX2 differed depending on the cell lines, the cytocidal effect of MX2 was similar to adriamycin. The colony formation of KMG4 cells was markedly inhibited by MX2 dose-dependently. The growth of KMG4 cells inoculated subcutaneously into nude mice was inhibited by the intraperitoneal administration of MX2 4 or 1.3 mg/kg. These results suggest that MX2 seemed to be useful in the treatment of malignant glioma.

Topics: Animals; Antibiotics, Antineoplastic; Carubicin; Cell Line; Doxorubicin; Glioma; Humans; In Vitro Techniques; Mice; Mice, Nude; Neoplasm Transplantation; Transplantation, Heterologous; 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