There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A (LDHA) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the Warburg effect); however, it has multiple additional functions in non-neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The Warburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic. LACTATE DEHYDROGENASELactate dehydrogenase (LDH) is a tetrameric enzyme, belonging to the 2-hydroxy acid oxidoreductase family, which increases the rate of the simultaneous inter-conversion of pyruvate to lactate and nicotinamide adenine dinucleotide (NAD)H to NAD + by 14 orders of magnitude (10) (Figure 1). The reaction involves the transfer of a hydride ion from NADH to the C2 carbon of pyruvate (99) and is commonly used by cells for anaerobic respiration. There are four LDH genes: LDHA, LDHB, LDHC and LDHD (Figure 2). LDHA, LDHB and LDHC are L isomers, whereas LDHD is a D isomer. The L isomers use or produce L-lactate, which is the major enantiomer found in vertebrates.The human LDHA gene is located on chromosome 11p15.4, the transcribed protein has 332 amino acids, a predicted molecular weight of 37 kDa and 24 splice variants; the human genome also contains several non-transcribed LDHA pseudogenes (32, 126). Evolutionarily, LDHA and LDHB are thought to have arisen from the duplication of a single LDHA-like LDH gene (82). LDHC, a testes-specific gene, is also thought to have evolved in mammals from the duplication of the LDHA gene after the A-B duplication (82).LDHA is also known as the M subunit as it is predominantly found in skeletal muscle, and LDHB is also known as the H subunit as it is predominantly found in the heart. Unlike the other LDH genes, which can form only homotetramers, LDHA and LDHB can form homo-or heterotetramers. There are five isoenzymes of LDH that can be made from the M and H subunits: LDH-1 (4H), LDH-2 (3H, 1M), LDH-3 (2H, 2M), LDH-4 (1H, 3M), and LDH-5 (5M) (Figure 2). LDH-1 and LDH-5 have identical active site regions and only differ in 81 out of 332 amino acid positions, mo...

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In this communication, we describe the successful encapsulation of (177)Lu into the endohedral metallofullerene (177)Lu(x)Lu(3-x)N@C(80) (x = 1-3) starting with (177)LuCl(3) in a modified quartz Kraschmer-Huffman electric generator. We demonstrate that the (177)Lu (beta-emitter) in this fullerene cage is not significantly released for a period of up to at least one-half-life (6.7 days). We also demonstrate that this agent can be conjugated with an interleukin-13 peptide that is designed to target an overexpressed receptor in glioblastoma multiforme tumors. This nanoparticle delivery platform provides flexibility for a wide range of radiotherapeutic and radiodiagnostic multimodal applications.

Glioblastoma multiforme (GBM) is one of the most highly vascularized of all human tumors. Our objective was to characterize a 3-dimensional (3-D) in vitro angiogenesis model by co-culturing HUVEC and GBM cells, and to study the role of VEGF in mediating capillary tubule formation in this model. HUVEC-coated dextran beads were suspended in fibrin gel with human glioma cells on top. The number of sprouts and the length of the processes were measured. HUVEC can be induced to form sprouts and longer processes with lumens, in co-culture with glioma cells that secrete VEGF. Addition of exogenous VEGF enhances this effect. In the absence of glioma cells, many single HUVEC migrate away from the beads, without significant tubule formation. Hypoxia further stimulated sprout formation by 50-100%. Anti-VEGF neutralizing antibody suppressed HUVEC sprouting by 75% in co-culture with glioma cells. This 3-D in vitro co-culture system provides a robust and useful model for analysis of the major steps of glioma-induced angiogenesis.

These studies demonstrate that IL-13 peptide-conjugated gadolinium metallofullerenes could serve as a platform to deliver imaging and therapeutic agents to tumor cells.