zinostatin and Medulloblastoma

To identify and mathematically model molecular predictors of response to the enediyne chemotherapeutic agent, neocarzinostatin, in nervous system cancer cell lines.. Human neuroblastoma, breast cancer, glioma, and medulloblastoma cell lines were maintained in culture. Content of caspase-3 and Bcl-2, respectively, was determined relative to actin content for each cell line by Western blotting and optical densitometry. For each cell line, sensitivity to neocarzinostatin was determined. Brain tumor cell lines were stably transfected with human Bcl-2 cDNA cloned into the pcDNA3 plasmid vector.. In human tumor cell lines of different tissue origins, sensitivity to neocarzinostatin is proportional to the product of the relative contents of Bcl-2 and caspase-3 (r (2) = 0.9; P < 0.01). Neuroblastoma and brain tumor cell lines are particularly sensitive to neocarzinostatin; the sensitivity of brain tumor lines to neocarzinostatin is enhanced by transfection with an expression construct for Bcl-2 and is proportional in transfected cells to the product of the relative contents of Bcl-2 and caspase-3 (r (2) = 0.7).. These studies underscore the potential of molecular profiling in identifying effective chemotherapeutic paradigms for cancer in general and tumors of the nervous system in particular.

Topics: Antibiotics, Antineoplastic; Biomarkers, Tumor; Caspase 3; Cell Line, Tumor; Cell Survival; Drug Resistance; Drug Screening Assays, Antitumor; Gene Expression Profiling; Glioma; Humans; Medulloblastoma; Nervous System Neoplasms; Neuroblastoma; Predictive Value of Tests; Proto-Oncogene Proteins c-bcl-2; Zinostatin

Topics: Adjuvants, Immunologic; Animals; Antibiotics, Antineoplastic; Brain; Cerebellar Neoplasms; Child, Preschool; Combined Modality Therapy; Guinea Pigs; Humans; Injections, Spinal; Macrophages; Male; Medulloblastoma; 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