zinostatin and Brain-Neoplasms

Topics: Animals; Brain Neoplasms; Dogs; Glioma; Humans; Meningeal Neoplasms; Meningioma; Neoplasm Metastasis; Neoplasm Seeding; Rabbits; Rats; Subarachnoid Space; Zinostatin

An early phase II multicentered study of YM 881 (zinostatin stimalamer) was conducted in 36 patients to investigate response and the safety of the drug in malignant tumors. The response could be evaluated in 18 patients, one with brain tumor, 2 with lung cancer, one with breast cancer, one with liver cancer, one with pancreatic cancer, 6 with gastric cancer, and 6 with colon cancer. PR was found in the patient with brain tumor. Major subjective unwanted effects were gastrointestinal symptoms. Objective evidence of hematological changes (thrombocytopenia, decreased hematocrit, and lymphocytopenia) was also obtained.

Topics: Adult; Aged; Anorexia; Brain Neoplasms; Drug Evaluation; Female; Humans; Injections, Intravenous; Lung Neoplasms; Male; Maleic Anhydrides; Middle Aged; Neoplasms; Polystyrenes; Stomach Neoplasms; Thrombocytopenia; Vomiting; Zinostatin

Neocarzinostatin (NCS) is a member of enediyne antibiotics with high anticancer potential. Our study was performed to explore the synergistic anti-glioma effects of NCS and paclitaxel (PTX) in vitro and in vivo. By 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the cytotoxicities of the drugs to human glioma cells U87MG and rat glioma cells C6 were evaluated. The results showed that the combinations of NCS and PTX can synergistically inhibit glioma cells survival. Cell apoptosis was detected by flow cytometry, and the results showed that the combinations of NCS and PTX synergistically enhanced apoptosis ratio of glioma cells. Western blot revealed that the cell signaling pathways of proliferation and apoptosis were synergistically regulated, in which Akt was synergistically inactivated, p53 was up-regulated with down-regulation of bcl-2. Meanwhile, with the subcutaneous model of U87MG cells and intracerebral implantation model of C6 cells, the combination strategy could synergistically delay the glioma growth and significantly prolong the survival of rats bearing orthotopic glioma. This study demonstrates that the combination of NCS and PTX can potentiate the effect on survival and apoptosis of glioma cells via suppression of Akt, bcl-2, and activations of p53; Meanwhile, the in vivo studies also confirmed that the combination of NCS and PTX synergistically inhibit the gliom growth. Our data about the combinational effects of NCS with PTX may provide an alternative strategy for glioma therapy.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Glioma; Humans; Male; Mice, Nude; Paclitaxel; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats, Wistar; Tumor Burden; Tumor Suppressor Protein p53; Zinostatin

Gliomas are resistant to radiation therapy, as well as to TNFα induced killing. Radiation-induced TNFα triggers Nuclear factor κB (NFκB)-mediated radioresistance. As inhibition of NFκB activation sensitizes glioma cells to TNFα-induced apoptosis, we investigated whether TNFα modulates the responsiveness of glioma cells to ionizing radiation-mimetic Neocarzinostatin (NCS). TNFα enhanced the ability of NCS to induce glioma cell apoptosis. NCS-mediated death involved caspase-9 activation, reduction of mitochondrial copy number and lactate production. Death was concurrent with NFκB, Akt and Erk activation. Abrogation of Akt and NFκB activation further potentiated the death inducing ability of NCS in TNFα cotreated cells. NCS-induced p53 expression was accompanied by increase in TP53-induced glycolysis and apoptosis regulator (TIGAR) levels and ATM phosphorylation. siRNA-mediated knockdown of TIGAR abrogated NCS-induced apoptosis. While DN-IκB abrogated NCS-induced TIGAR both in the presence and absence of TNFα, TIGAR had no effect on NFκB activation. Transfection with TIGAR mutant (i) decreased apoptosis and γH2AX foci formation (ii) decreased p53 (iii) elevated ROS and (iv) increased Akt/Erk activation in cells cotreated with NCS and TNFα. Heightened TIGAR expression was observed in GBM tumors. While NCS induced ATM phosphorylation in a NFκB independent manner, ATM inhibition abrogated TIGAR and NFκB activation. Metabolic gene profiling indicated that TNFα affects NCS-mediated regulation of several genes associated with glycolysis. The existence of ATM-NFκB axis that regulate metabolic modeler TIGAR to overcome prosurvival response in NCS and TNFα cotreated cells, suggests mechanisms through which inflammation could affect resistance and adaptation to radiomimetics despite concurrent induction of death.

Topics: Adenosine Triphosphate; Antibiotics, Antineoplastic; Apoptosis; Apoptosis Regulatory Proteins; Ataxia Telangiectasia Mutated Proteins; Brain Neoplasms; Caspase 9; Cell Cycle Proteins; Cell Line, Tumor; DNA-Binding Proteins; Glioma; Glycolysis; Humans; Intracellular Signaling Peptides and Proteins; Lactic Acid; Microtubule-Associated Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Zinostatin

Studies of the response of neural crest tumor cells to the DNA cleaving antimitotic agent, neocarzinostatin, have left unanswered the question of whether the DNA cleavage per se or the antimitotic effect is responsible for this response. Furthermore, they do not define the timeframe within which a cell commits to its fate. Using the reversible microtubule-active agent, vinblastine, we now demonstrate that mitotic arrest, even without DNA cleavage, results in the same cellular changes as those seen with neocarzinostatin treatment. The commitment of the cell to its fate occurs within a 15 min treatment with vinblastine, and requires new protein synthesis. The immediate early gene products, c-Fos and c-Jun, appear not to be determinants of this process.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Brain Neoplasms; Cell Count; Cell Differentiation; Cells, Cultured; Chromatin; Cycloheximide; Humans; Microtubules; Mitosis; Neuroblastoma; Oncogene Proteins v-fos; Protein Synthesis Inhibitors; Proto-Oncogene Proteins c-jun; Vinblastine; Zinostatin

Topics: Animals; Brain Neoplasms; Glioma; Infusions, Intravenous; Maleic Anhydrides; Neoplasm Transplantation; Polystyrenes; Rats; Rats, Inbred Strains; Survival Rate; Zinostatin

We present six patients with intracranial nongerminomatous germ cell tumors that produced alpha-fetoprotein (AFP). Their ages ranged from 8 to 20 years (average, 11.5 years old); two were male and four were female. Four of the tumors originated in the pineal region and two in the suprachiasmatic region. One patient treated with only radiation therapy died within 3 months of admission as a result of intraperitoneal metastasis via a ventriculoperitoneal shunt. Another patient, treated with radiation therapy and intrathecal administration of neocarzinostatin, died after 12 months because of tumor progression and subarachnoid dissemination. Two patients who received radiation and combination therapy with cisplatin, vinblastine, and bleomycin died after 13 and 25 months. The remaining two patients treated with radiation therapy and adjuvant chemotherapy (cisplatin and etoposide) are now alive without recurrence after 16 and 19 months from admission. Adjuvant chemotherapy with cisplatin and etoposide appears to be efficacious in the treatment of intracranial nongerminomatous germ cell tumor.

Topics: Adolescent; Adult; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bleomycin; Brain Neoplasms; Cerebrospinal Fluid Shunts; Child; Chorionic Gonadotropin; Cisplatin; Cranial Irradiation; Etoposide; Female; Humans; Hydrocephalus; Male; Neoplasm Proteins; Neoplasms, Germ Cell and Embryonal; Pineal Gland; Remission Induction; Vinblastine; Zinostatin

Because of technical difficulties, the pharmacokinetics of neocarzinostatin (NCS) have not been thoroughly evaluated in patients with malignant glioma. The authors produced anti-NCS antibody by immunizing rabbits with NCS and established a means of quantifying tissue levels of NCS with enzyme-linked immunosorbent assay. In one patient given a bolus injection of 1 mg of NCS intra-arterially, the concentration of drug in neoplastic tissue at 25 minutes (0.1136 micrograms/g) was higher than that in blood at 20 minutes and was retained for a longer period. Rapid entry of NCS into the tumor cavity was observed at 5 minutes. In two postoperative cases, NCS applied topically to the tumor site (50 and 100 micrograms) was retained at high levels (0.2941 and 3.33 micrograms/ml) even after 48 hours, although no NCS was detected in blood after 60 minutes. NCS concentrations as low as 1 microgram/ml demonstrated cytocidal effects, and a delay in tumor growth was observed even at an NCS level of 0.1 microgram/ml, despite the fact that the half-life of NCS is extremely short (3 seconds in serum). Because its cytotoxic effect seems to be very rapid, it appears more important to obtain a high initial NCS concentration than to maintain a constant blood level.

Topics: Animals; Antibiotics, Antineoplastic; Brain Neoplasms; Drug Screening Assays, Antitumor; Enzyme-Linked Immunosorbent Assay; Glioma; Humans; Rats; Tissue Distribution; Tumor Cells, Cultured; Zinostatin

Topics: Adult; Aged; Antibiotics, Antineoplastic; Astrocytoma; Brain Neoplasms; Carotid Arteries; Combined Modality Therapy; Female; Glioma; Humans; Injections, Intra-Arterial; Male; Middle Aged; Zinostatin

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Astrocytoma; Brain Neoplasms; Carotid Artery, Internal; Chemotherapy, Cancer, Regional Perfusion; Eye Diseases; Female; Glioma; Humans; Male; Middle Aged; Zinostatin

Topics: Adult; Aged; Antibiotics, Antineoplastic; Astrocytoma; Brain Neoplasms; Child; Female; Glioma; Humans; Male; Zinostatin

A pharmacokinetic one-compartment model for the cerebrospinal infusion for the brain tumor chemotherapy is described together with various parameters used for computer simulation. An antitumor protein, neocarzinostatin (NCS) as a prototype drug, has been utilized since it was found effective against glioblastoma cells at extremely low concentration (less than 5 ng/ml) and it is readily inactivated by serum. A very slow infusion velocity was found necessary for an appropriate dose regimen; for example, 0.25mg of the drug should be infused into CSF for about 40 min to attain a drug level of 8 ng/ml.

Topics: Antibiotics, Antineoplastic; Brain Neoplasms; Cell Line; Computers; Glioma; Humans; Kinetics; Models, Biological; Zinostatin

Neocarzinostatin as previously reported, appeared to exhibit an intense cytotoxicity to the glioblastoma cells and some other malignant brain tumor cells, such as pineal germinoma or medulloblastoma, which are notoriously known to disseminate into the cerebrospinal fluid space. In vitro study, the minimum susceptibility of glioblastoma cells to neocarzinostatin was found to be below 0.005 microgram/ml, whereas normal glia cells were not affected at 0.3 microgram/ml. This study indicated that neocarzinostatin was extremely effective in the treatment of malignant brain tumor without affecting normal neural tissue. Pharmacokinetic study was performed in order to establish intermittent intrathecal perfusion therapy and to prevent subarachnoid dissemination of the brain tumor cells. Experimental results were applied to the treatment of 12 patients with brain tumor, who had shown positive cytology of the cerebrospinal fluid. Follow-up investigation showed quite a favorable result and it was considered that prophylactic irradiation to the entire spinal column could be replaced with intrathecal administration of neocarzinostatin. During clinical application no noticeable side effect was encountered and active stimulation of macrophages, which were mobilized into the CSF space, was another unexpected advantage of this treatment.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Astrocytoma; Brain Neoplasms; Cerebrospinal Fluid Shunts; Child; Child, Preschool; Female; Glioma; Humans; Injections, Intraventricular; Injections, Spinal; Kinetics; Male; Medulloblastoma; Middle Aged; Pinealoma; Zinostatin

A pharmacokinetic two-compartment model for the treatment of brain tumors in man was simulated with the aid of a computer. The parameters necessary for the simulations such as inactivation rate constant, elimination rate constant, distribution volume, blood volume, cerebral blood flow, and cytotoxic drug concentration were either determined in this study or obtained from the literature. A proteinaceous antitumor antibiotic, neocarzinostatin (NCS), was utilized as a prototype drug because it has features making it advantageous in the treatment of brain tumor. In particular, NCS has an extremely short half-life in serum (t 1/2 less than or equal to 3 s), while it is relatively stable in the cerebrospinal fluid (CSF) (t 1/2 approximately 50 s). Therefore, the drug level in the cerebral compartment can be made adequately high with an appropriate infusion velocity into the cerebral compartment; however, it was possible to keep the plasma level of the drug much lower than the toxic level. Thus, few side-effects should result. In an in vitro study, NCS was found to exhibit its cytotoxicity to glioblastoma cells at a concentration as low as 0.005 microgram/ml. In contrast, the cytotoxicity was not apparent for the normal glia cells at 0.1 microgram/ml. The model being considered in this investigation is a two-compartment model, which consists of the cerebral compartment and the rest of the circulatory system of the body. In this case the drug is infused via an internal carotid artery. The results of pharmacokinetic simulation and dose regimens for NCs are presented, based on the effective concentration of the drug to glioblastoma cells in culture and the available pharmacological parameters.

Topics: Antibiotics, Antineoplastic; Brain Neoplasms; Carotid Arteries; Cells, Cultured; Humans; Infusions, Intra-Arterial; Kinetics; Models, Biological; Zinostatin