The main goal when treating malignancies with radiation therapy is to deprive tumor cells of their reproductive potential. One approach to achieve this is by inducing tumor cell apoptosis. Accumulating evidences suggest that induction of apoptosis alone is insufficient to account for the therapeutic effect of radiotherapy. It has become obvious in the last few years that inhibition of the proliferative capacity of malignant cells following irradiation, especially with solid tumors, can occur via alternative cell death modalities or permanent cell cycle arrests, i.e., senescence. In this review, apoptosis and mitotic catastrophe, the two major cell deaths induced by radiation, are described and dissected in terms of activating mechanisms. Furthermore, treatment-induced senescence and its relevance for the outcome of radiotherapy of cancer will be discussed. The importance of p53 for the induction and execution of these different types of cell deaths is highlighted. The efficiency of radiotherapy and radioimmunotherapy has much to gain by understanding the cell death mechanisms that are induced in tumor cells following irradiation. Strategies to use specific inhibitors that will manipulate key molecules in these pathways in combination with radiation might potentiate therapy and enhance tumor cell kill.

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CSF levels of neurofilament light and glial fibrillary acidic protein may have prognostic value in multiple sclerosis.

The human tissue nonspecific alkaline phosphatase (TNAP) is found in liver, kidney, and bone. Mutations in the TNAP gene can lead to Hypophosphatasia, a rare inborn disease that is characterized by defective bone mineralization. TNAP is 74% homologous to human placental alkaline phosphatase (PLAP) whose crystal structure has been recently determined at atomic resolution (Le Du, M. H., Stigbrand, T., Taussig The alkaline phosphatases (EC 3.1.3.1) (APs) 1 form a large family of dimeric enzymes common to all organisms. They catalyze the hydrolysis of phosphomonoesters (1) with release of inorganic phosphate. Mammalian APs have low sequence identity with the Escherichia coli enzyme (25-30%), although the residues involved in the active site of the enzyme and the ligands coordinating the two zinc atoms and the magnesium ion are largely conserved. Therefore, the catalytic mechanism deduced from the structure of the E. coli AP is believed to be similar in eukaryotic APs (2). This mechanism involves the activation of the catalytic serine by a zinc atom, the formation of a covalent phosphoseryl intermediate, the hydrolysis of the phosphoseryl by a water molecule activated by a second zinc atom, and the release of the phosphate product or its transfer to a phosphate acceptor (3).In humans, three out of four AP isozymes are tissue-specific: one is placental (PLAP), the second appears in germ cells (GCAP), and the third in the intestine (IAP). They are 90 -98% homologous, and their genes are clustered on chromosome 2q37.1. The fourth, TNAP, 50% identical to the other three, is nonspecific and can be found in bone, liver, and kidney (4, 5, 6). Its gene is located on chromosome 1p34 -36 (7), and mutations in the TNAP gene have been associated with hypophosphatasia, a rare inherited disorder, characterized by defective bone mineralization. The disease is highly variable in its clinical expression, due to the strong allelic heterogeneity in the TNAP gene. Such expression ranges from stillbirth without mineralized bone to pathological fractures developing only late in adulthood (8). Depending on the age of onset, five clinical forms are currently recognized: perinatal, infantile, childhood, adult, and odontohypophosphatasia. To date, 89 different mutations associated with this disease have been characterized (9 -22). Correlation between genotype and phenotype are difficult to establish, because most patients are compound heterozygous for missense mutations, making difficult the determination of the respective roles of each mutation.This difficulty arises mainly from the lack of data concerning the precise role that TNAP plays in bone mineralization. This may be partly solved by the use of site-directed mutagenesis of TNAP cDNA and cell transfection to assay residual activity of the mutant AP enzyme (16,18,20,(23)(24)(25). However, this only measures the ability of the enzyme to hydrolyze phosphomonoesters. Transfection assays cannot distinguish structural mutations from functional ones, and mutations that exhibit residual activi...

Human placental alkaline phosphatase (PLAP) is one of three tissue-specific human APs extensively studied because of its ectopic expression in tumors. The crystal structure, determined at 1.8-Å resolution, reveals that during evolution, only the overall features of the enzyme have been conserved with respect to Escherichia coli. The surface is deeply mutated with 8% residues in common, and in the active site, only residues strictly necessary to perform the catalysis have been preserved. Additional structural elements aid an understanding of the allosteric property that is specific for the mammalian enzyme (Hoylaerts, M. F., Manes, T., and Millá n, J. L. (1997) J. Biol. Chem. 272, 22781-22787). Allostery is probably favored by the quality of the dimer interface, by a long N-terminal ␣-helix from one monomer that embraces the other one, and similarly by the exchange of a residue from one monomer in the active site of the other. In the neighborhood of the catalytic serine, the orientation of Glu-429, a residue unique to PLAP, and the presence of a hydrophobic pocket close to the phosphate product, account for the specific uncompetitive inhibition of PLAP by L-amino acids, consistent with the acquisition of substrate specificity. The location of the active site at the bottom of a large valley flanked by an interfacial crown-shaped domain and a domain containing an extra metal ion on the other side suggest that the substrate of PLAP could be a specific phosphorylated protein.