RESUMO
BACKGROUND: The development of therapeutics is often characterized by promising animal research that fails to translate into clinical efficacy; this holds for the development of gene therapy in glioma. We tested the hypothesis that this is because of limitations in the internal and external validity of studies reporting the use of gene therapy in experimental glioma. METHOD: We systematically identified studies testing gene therapy in rodent glioma models by searching three online databases. The number of animals treated and median survival were extracted and studies graded using a quality checklist. We calculated median survival ratios and used random effects meta-analysis to estimate efficacy. We explored effects of study design and quality and searched for evidence of publication bias. RESULTS: We identified 193 publications using gene therapy in experimental glioma, including 6,366 animals. Overall, gene therapy improved median survival by a factor of 1.60 (95% CI 1.53-1.67). Study quality was low and the type of gene therapy did not account for differences in outcome. Study design characteristics accounted for a significant proportion of between-study heterogeneity. We observed similar findings in a data subset limited to the most common gene therapy. CONCLUSION: As the dysregulation of key molecular pathways is characteristic of gliomas, gene therapy remains a promising treatment for glioma. Nevertheless, we have identified areas for improvement in conduct and reporting of studies, and we provide a basis for sample size calculations. Further work should focus on genes of interest in paradigms recapitulating human disease. This might improve the translation of such therapies into the clinic.
RESUMO
Clinically, amantadine and memantine are drugs whose therapeutic utility is linked to their ability to block N-methyl-D-aspartate receptors (NMDARs) in a voltage-dependent manner. Nevertheless many studies that have characterized the pharmacological actions of amantadine and memantine have done so in the absence of physiological levels of Mg(2+) ions. This study quantifies the extent to which Mg(2+) alters the potency of the block produced by both amantadine and memantine at human recombinant GluN1/GluN2A NMDARs. Human recombinant GluN1/GluN2A NMDARs were expressed in Xenopus laevis oocytes and two-electrode voltage-clamp recordings were made at -80, -60 and -40 mV to quantify amantadine and memantine block in the absence and presence of Mg(2+). Amantadine and memantine blocked human GluN1/GluN2A NMDARs in a voltage-dependent manner with IC(50) values (at -80 mV) of 49 ± 6 µM (n = 7) and 1.0 ± 0.3 µM (n = 7), respectively. In the presence of Mg(2+) (1mM) the equivalent IC(50) values were 165 ± 10 µM (n=6) and 6.6 ± 0.3 µM (n = 5). Similarly in the presence of amantadine or memantine the potency of Mg(2+) in blocking GluN1/GluN2A NMDARs was reduced. The decrease in the potencies of both amantadine and memantine in the presence of physiological concentrations of Mg(2+) indicates that other targets (e.g. α7-nicotinic acetylcholine receptors and 5-HT(3) receptors) in addition to NMDARs may well be sites of the therapeutic action of these channel blockers.