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Lani · 12-22-2006, 04:26 PM

directly convert GABA and glutamate into sources of energy. Moreover, glycine was involved in a mechanism that increased the amount of fatty acids - an important source of energy - in the bloodstream of the lab mice.

‘We showed that the neurotramsitters GABA, glycine and gluatate not only stimulate proliferation of the tumor cells, but they also are able secure sources of energy for the cells,’ Ippolito says. ‘In a way, the tumor cells eat their own words.’

‘Having identified a key vulnerability in these aggressive neuroendicrine tumor cells, the researchers looked for a way to exploit it. They selected agents already approved for medical use by the Food and Drug Administration.

Two drugs - amiloride, a diuretic and carbidopa, used to treat Parkinson’s disease - exert their effects by inhibiting the very same mechanisms the research group had identified as important for the tumor cells’ energy-gathering reactions.

They combined these two drugs with a third drug, flumazenil, which is ordinarily used to reverse the effects of sedatives. Flumazenil binds to GABA receptors on the surface of nerve cells, and the researchers theorized that it could also inhibit GABA signaling between tumor cells.

‘We propose that this might be a potential therapeutic regimen for patients with aggressive neuroendocrine tumors,’ says Ippolito. ‘Since the drugs are already FDA approved, they could be more quickly used as experimental therapeutics.’

Examination of gene expression profiles of more than 400 human cancers showed that the genes encoding the enzymes vital to these aggressive neuroendocrine tumors were also expressed at high levels in some non-neuroendocrine cancers. This suggests that the three-drug therapy could work for many kinds of cancers, according to the study authors.

‘This approach is very powerful,’ says Gordon. ‘By combining a variety of experiemental and computational methods that monitor the expression of genes encoding enzymes and their biochemical products, we can explore the metabolism of these cells, looking for unusual pathways that might reveal their potenial vulnerabilities. Then we can see if medications already exist - ones whose mechanism of action is known and whose safety has been established - that can be used to target components of these unusual pathways, test them in animal models of human cancer, and if the results look promising, bring them to the patient’s bedside as part of a carefully controlled clinical trial.’

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Ippolito JE, Merritt ME, Backhed F, Moulder KL, Mennerick S, Manchester JK, Gammon ST, Piwnica-Worms D, Gordon JI, Linkage between cellular communications, energy utilization and proliferation in metastatic neuroendocrine cancers. Proceedings of the National Academy of Sciences 2006 AUG 15; 103(33):12505-10

12-22-2006, 04:26 PM	#5
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	continued..... directly convert GABA and glutamate into sources of energy. Moreover, glycine was involved in a mechanism that increased the amount of fatty acids - an important source of energy - in the bloodstream of the lab mice. ‘We showed that the neurotramsitters GABA, glycine and gluatate not only stimulate proliferation of the tumor cells, but they also are able secure sources of energy for the cells,’ Ippolito says. ‘In a way, the tumor cells eat their own words.’ ‘Having identified a key vulnerability in these aggressive neuroendicrine tumor cells, the researchers looked for a way to exploit it. They selected agents already approved for medical use by the Food and Drug Administration. Two drugs - amiloride, a diuretic and carbidopa, used to treat Parkinson’s disease - exert their effects by inhibiting the very same mechanisms the research group had identified as important for the tumor cells’ energy-gathering reactions. They combined these two drugs with a third drug, flumazenil, which is ordinarily used to reverse the effects of sedatives. Flumazenil binds to GABA receptors on the surface of nerve cells, and the researchers theorized that it could also inhibit GABA signaling between tumor cells. ‘We propose that this might be a potential therapeutic regimen for patients with aggressive neuroendocrine tumors,’ says Ippolito. ‘Since the drugs are already FDA approved, they could be more quickly used as experimental therapeutics.’ Examination of gene expression profiles of more than 400 human cancers showed that the genes encoding the enzymes vital to these aggressive neuroendocrine tumors were also expressed at high levels in some non-neuroendocrine cancers. This suggests that the three-drug therapy could work for many kinds of cancers, according to the study authors. ‘This approach is very powerful,’ says Gordon. ‘By combining a variety of experiemental and computational methods that monitor the expression of genes encoding enzymes and their biochemical products, we can explore the metabolism of these cells, looking for unusual pathways that might reveal their potenial vulnerabilities. Then we can see if medications already exist - ones whose mechanism of action is known and whose safety has been established - that can be used to target components of these unusual pathways, test them in animal models of human cancer, and if the results look promising, bring them to the patient’s bedside as part of a carefully controlled clinical trial.’ ### Ippolito JE, Merritt ME, Backhed F, Moulder KL, Mennerick S, Manchester JK, Gammon ST, Piwnica-Worms D, Gordon JI, Linkage between cellular communications, energy utilization and proliferation in metastatic neuroendocrine cancers. Proceedings of the National Academy of Sciences 2006 AUG 15; 103(33):12505-10