title: Growth-inhibitory and chemosensitizing effects of the glutathione-S-transferase-π-activated nitric oxide donor PABA/NO in malignant gliomas.
abstract: Glutathione-S-transferases (GSTs) are upregulated in malignant gliomas and contribute to their chemoresistance. The nitric oxide (NO) donor PABA/NO (O(2) -{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) generates NO upon selective enzymatic activation by GST-π-inducing selective biological effects in tumors. Tumor cell killing and chemosensitization were observed in a variety of tumors after exposure to GST-activated NO donor drugs. In our project, cytotoxic and chemosensitizing effects of PABA/NO in combination with carboplatin (CPT) and temozolomide (TMZ) were studied in human U87 glioma cells in vitro and in vivo. U87 glioma cells were exposed to PABA/NO alone or in combination with CPT or TMZ for 24 hr. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after 24-hr incubation and 48 hr after drug removal. The antiproliferative effect of PABA/NO was assessed in an intracranial U87 glioma nude rat model comparing subcutaneous administration and intratumoral delivery by convection-enhanced delivery. PABA/NO monotherapy showed a strong dose-dependent growth-inhibitory effect in U87 glioma cells in vitro, and a strong synergistic effect was observed after concomitant treatment with TMZ, but not with CPT. Systemic and intratumoral PABA/NO administration significantly reduced cell proliferation, but this did not result in prolonged survival in nude rats with intracranial U87 gliomas. PABA/NO has potent antiproliferative effects, sensitizes U87 glioma cells to TMZ in vitro and shows some in vivo efficacy. Further studies are still required to consolidate the role of NO donor therapy in glioma treatment.
authors: Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany.
authors: Evangelos
authors: E
authors: Kogias
authors: Nadja
authors: N
authors: Osterberg
authors: Brunhilde
authors: B
authors: Baumer
authors: Nikolaos
authors: N
authors: Psarras
authors: Christoph
authors: C
authors: Koentges
authors: Anna
authors: A
authors: Papazoglou
authors: Joseph E
authors: JE
authors: Saavedra
authors: Larry K
authors: LK
authors: Keefer
authors: Astrid
authors: A
authors: Weyerbrock
mesh_terms: D010129:4-Aminobenzoic Acid / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001391:Azo Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016190:Carboplatin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D051549:Glutathione S-Transferase pi / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000627:therapeutic use; D006801:Humans; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D051381:Rats; D011923:Rats, Nude; D000077204:Temozolomide; D062366:para-Aminobenzoates
chemical_list: D001391:Azo Compounds; D006131:Growth Inhibitors; D020030:Nitric Oxide Donors; C485370:O(2)-(2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino)phenyl 1-N,N-dimethylamino)diazen-1-ium-1,2-diolate; D062366:para-Aminobenzoates; D003606:Dacarbazine; D016190:Carboplatin; D051549:Glutathione S-Transferase pi; D010129:4-Aminobenzoic Acid; D000077204:Temozolomide