tiazofurin and Glioblastoma

The National Cancer Institute of Canada conducted a Phase II study of tiazofurin 1100 to 1375 mg/m2 IV daily x 5 days in adults with grade 2, 3, and 4 gliomas. No responses were seen. Five of sixteen evaluable patients had stable disease for 38 to 147 days (median, 75 days). Treatment was generally well tolerated, and hence the dose was escalated from 1100 mg/m2/day to 1375 mg/m2/day after the first twelve patients were entered. Treatment-induced hypertension requiring pharmacological intervention was seen in four patients. Gastrointestinal toxicity was generally mild. Treatment-related headache was seen in thirteen patients, and drowsiness or weakness was seen in seven patients. In summary, tiazofurin on this dose schedule does not have major activity against grade 2, 3, and 4 gliomas.

Topics: Adult; Antineoplastic Agents; Brain Neoplasms; Female; Glioblastoma; Humans; Male; Ribavirin

Compounds that could block tumor angiogenesis and induce tumor cell differentiation in malignant gliomas represent a very valuable tool in anticancer treatments. In this paper, we demonstrate that more selective drugs, which interfere with specific cellular targets, could treat glioma more effectively. 8-Cl-cAMP and tiazofurin (TR) are site-specific analogs that selectively inhibit PKAI and IMP dehydrogenase, are directly involved in cell proliferation and apoptosis, and mediate the mitogenic effects of different oncogenes and growth factors. In this study, we have examined influence of 8-Cl-cAMP and TR on the production of an angiogenic factor [vascular endothelial growth factor (VEGF)] by human glioblastoma U251 MG cells, as well as their influence on the expression of a differentiating marker [glial fibrillary acidic protein (GFAP)]. Using a cell proliferation assay, VEGF enzyme-linked immunoassay and GFAP immunocytochemistry we demonstrated the effects of these compounds. Our results demonstrate that 8-Cl-cAMP and TR decrease VEGF production by U251 MG cells, and that under the influence of both agents these cells increase GFAP expression and change their morphology, becoming more differentiated. These findings also suggest that 8-Cl-cAMP and TR may have potential for further investigation of their antiangiogenic and differentiational role in malignant disease such as human gliomas.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Antineoplastic Agents; Cell Differentiation; Cell Division; Endothelial Growth Factors; Glial Fibrillary Acidic Protein; Glioblastoma; Humans; Lymphokines; Ribavirin; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The aim of this study was to identify targets for rational chemotherapy of glioblastoma. In order to elucidate differences in the biochemistry of tumor and normal human brain, in vivo pool sizes of purine nucleotides, nucleosides, and nucleobases and of purine metabolizing enzymes in biopsy material from 14 grade IV astrocytomas and 4 normal temporal lobe samples were analyzed. Specimens were collected during surgery using the freeze-clamp sampling technique and analyzed by high pressure liquid chromatography. Total purine nucleotides, adenylates, and guanylates in the tumors were 2186, 1865, and 310 nmol/g (wet weight), respectively, which corresponds to 61, 60, and 71% of normal brain tissue concentrations. Relative to normal brain the tumors had significantly lower ATP and GTP levels, essentially normal pool sizes of purine nucleosides and bases, unchanged activities of the salvage enzymes hypoxanthine-guanine phosphoribosyltransferase, adenine phosphoribosyltransferase, and adenosine kinase (659, 456, and 98 nmol/h/mg protein, respectively) and 4-fold higher activities of IMP dehydrogenase (11.6 nmol/h/mg protein); the latter is the rate limiting enzyme for guanylate de novo synthesis. IMP pools in the tumors were 64% of values in normal brain. Modulation of the guanylate pathway in glioblastoma by inhibition of IMP dehydrogenase with tumor specific agents such as tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) appears to be a rational therapeutic approach. Preliminary in vitro experiments with normal and malignant tissue specimens from 2 additional patients revealed that significant amounts of the active metabolite thiazole-4-carboxamide adenine dinucleotide are formed from tiazofurin. At a concentration of 200 microM this drug was able to deplete guanylate pools in the tumors to a median of 54% of phosphate buffered saline treated controls. Flux studies with [14C]formate showed that tiazofurin strongly inhibited de novo synthesis of guanylates in glioblastoma to an average of 10% of controls. This effect was more pronounced in the tumors as compared to normal brain. No inhibition of salvage of [14C]guanine by tiazofurin could be observed in normal and malignant tissues. Supportive measures have to be considered to inhibit the highly active salvage enzyme hypoxanthine-guanine phosphoribosyltransferase that can partly antagonize a tiazofurin induced decrease in guanine nucleotides.

Topics: Brain; Brain Neoplasms; Female; Glioblastoma; Humans; Male; Middle Aged; Purine Nucleosides; Purine Nucleotides; Ribavirin