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• W2088687690 abstract "The extracellular pH (pHe) in solid tumours is frequently lower than the pHe in normal tissues. Cells within an acidic environment depend on mechanisms which regulate intracellular pH (pHi) for their survival, including the Na+/H+ antiport which exports protons in exchange for Na+ ions. Amiloride and its analogues DMA (5-(N,N-dimethyl)amiloride), MIBA (5-(N-methyl-N-isobutyl)amiloride) and EIPA (5-(N-ethyl-N-isopropyl)amiloride) are known to inhibit the Na+/H+ antiport and therefore decrease the cells ability to regulate pHi. All three analogues were found to be potent inhibitors of the antiport in human MGH-U1 and murine EMT-6 cells, with DMA being approximately 20, MIBA 100 and EIPA 200-fold as potent as amiloride; EIPA also gave more complete suppression of the Na+/H+ antiport. These agents were not toxic to cells when used alone; however, in combination with nigericin, an agent which acidifies cells, all three analogues were toxic to cells at pHe < 7.0, and markedly enhanced the toxicity of nigericin alone. Cell killing was greatest for nigericin used with EIPA or MIBA. None of the agents were toxic to cells at pHe 7.0 or above. When used against variant cells lacking the Na+/H+ antiport (PS-120 cells) EIPA did not enhance the cytotoxicity of nigericin alone, suggesting that the observed effect was due to inhibition of Na+/H+ exchange, rather than due to non-specific effects. The combination of EIPA and nigericin gave similar cell killing in previously dissociated and intact MGH-U1 spheroids, suggesting that the agents have good penetration of solid tissue. Preliminary experiments using EMT-6 tumours in mice suggested that EIPA and nigericin were able to enhance the toxicity of radiation in vivo, presumably through selective effects against the hypoxic (and probably acidic) subpopulation of cells that is resistant to radiation." @default.
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• W2088687690 date "1993-02-01" @default.
• W2088687690 modified "2023-10-06" @default.
• W2088687690 title "Therapeutic potential of analogues of amiloride: inhibition of the regulation of intracellular pH as a possible mechanism of tumour selective therapy" @default.
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• W2088687690 doi "https://doi.org/10.1038/bjc.1993.56" @default.
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