Neuroblastomas biology

Brodeur GM. Neuroblastoma biological insights into a clinical enigma. Nat Rev Cancer. 2003 3 203-216. 

Tamplin et. al. (54) observed that V. cholerae and A. hydrophila cell extracts contained substances with TTX-like biological activity in tissue culture assay, counteracting the lethal effect of veratridine on ouabain-treated mouse neuroblastoma cells. Concentrations of TTX-like activity ranged from 5 to 100 ng/L of culture when compared to standard TTX. The same bacterial extracts also displaced radiolabelled STX from rat brain membrane sodium channel receptors and inhibited the compound action potential of frog sciatic nerve. However, the same extracts did not show TTX-like blocking events of sodium current when applied to rat sarcolemmal sodium channels in planar lipid bilayers. 

Apart from AP-A, the best characterized of these polypeptides with respect to its biological activity is Anemonia sulcata toxin II (ATX II) [19]. This molecule is also cardioactive [28], as would be expected from its similarity to AP-A. Renaud et al. [29] have compared the activities of a number of sea anemone and scorpion toxins on isolated rat atria and found that anthopleurin-B (AP-B, also known as Ax II) had the highest potency and the greatest margin between the concentrations necessary for maximal inotropic activity and for provoking arrhythmias (0.3 versus 10 n . It was also found that sodium channels of rat cardiac cells in culture, which have a low affinity for tetrodotoxin (TTX), have a particularly high affinity for Type 1 anemone toxins [29], whereas Type 2 toxins [30] and scorpion toxins [31] had similar affinities for TTX-sensitive and TTX-insensitive channels in rat neuroblastoma cells and skeletal myotubes, respectively. 

Before implantation several in vitro tests were performed. For evaluation of a possible toxic reaction, we investigated the material and the whole devices in vitro with cell culture methods. Direct contact and extraction tests with a mouse fibroblasts cell line (L 929) and a neuroblastoma cell line (neuro-2-a) were performed according to the international standard ISO 10993 ( Biological Evaluation of Medical Devices ). The materials and devices showed no toxicity, i.e. no significant differences in membrane integrity of the cell membranes, mitochondrial activity and DNA synthesis rate. The neuro-2-a cell line is so sensitive that even small changes in process technology are detectable. The flexible polyimide structures proved to be non toxic. 

Urine creatinine is used to adjust the values of urinary biological indicators for example, creatinine measurements are necessary for correction of vanilmandelic and homovanillic acids, which indicate neuroblastoma and pheochromocytoma, when excreted in urine in abnormally increased concentrations. Ratios of vanilmandelic and homovanillic acids to creatinine have been utilized as a diagnostic index of these diseases. 

The analysis of ganglioneuroblastomas and neuroblastomas indicates that the level of N-wyc expression is highest in the most undifferentiated cells, which show atypical aggressive biological behavior. 

Hachitanda Y, Hata J. Stage IVS neuroblastoma A clinical, histological, and biological analysis of 45 cases. Hum Pathol. 1996 27 1135-1138. 

Brodeur GM, Maris JM, Yamashiro DJ, et al. Biology and genetics of human neuroblastomas. J Pediatr Hematol Oncol. 1997 19 93-101. 

An allosteric model. J Biol Chem 252 8669-8676 Catterall WA (1980) Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes. Annu Rev Pharmacol Toxicol 20 15-43 Catterall WA (1981) Inhibition of voltage-sensitive sodium channels in neuroblastoma cells by antiarrhythmic drugs. Mol Pharmacol 20 356-362 Catterall WA (1992) Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev 72 [Suppl] S15-S48... 

Intraperitoneal toxicity to mice was used to establish a structure-activity relationship since this was the piece of information available for the highest number of PTX analogues. The scarce amounts of pure PTXs has precluded the inclusion of several analogues in studies of other PTX biological activities. In every in vitro study that includes more than one analogue, the structure-activity relationship is similar to that obtained in vivo [4,19]. The in vitro study that includes more analogues compares the effects on actin cytoskeleton of PTX-1, -2, -11, and -2SA in human neuroblastoma and rat hepatocarcinoma cells, and the results resemble in vivo toxicity, with PTX-2 and -11 being the more potent compounds, followed by PTX-1 [19]. In the same experiments, PTX-2SA had no effect [19]. 

Figure 69 The Biology of the Neuroblastoma Cell Accommodates Malignant Transformation and Reversal to Full Differentiation. Reference Appendix 2, Explanations to the Figures...

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