Effects of hyperglycemia on lonidamine‐induced acidification and de‐energization of human melanoma xenografts and sensitization to melphalan

摘要: We seek to exploit the natural tendency of melanomas and other tumors convert glucose lactate as a method for selective intracellular acidification cancer cells potentiation activity nitrogen-mustard antineoplastic agents. performed this study evaluate whether induction hyperglycemia (26 mM) could enhance effects lonidamine (LND, 100 mg/kg; intraperitoneally) on acidification, bioenergetic decline melphalan (LPAM) against DB-1 melanoma xenografts in mice. Intracellular pH (pHi), extracellular (pHe) bioenergetics (β-nucleoside triphosphate inorganic phosphate ratio, β-NTP/Pi) were reduced by 0.7 units (p 0.05) 51.4% < 0.05), respectively. The therapeutic response LPAM (7.5 intravenously) + LND (100 was about factor three under hyperglycemic conditions relative normoglycemia, producing growth delay 7.76 days (tumor doubling time, 5.31 days; cell kill, 64%) compared with alone 1.70 0.29 days. Under normoglycemic conditions, plus produced 17.75 days, corresponding kill 90% at same dose each these decrease tumor correlates an increase ATP levels resulting from increased glycolytic activity. However, substantially increases lactic acid production approximately six but did not tumor, most probably because strong buffering action carbon dioxide (the pKa carbonic is 6.4). Therefore, demonstrates that addition during treatment diminishes agent. Copyright © 2015 John Wiley & Sons, Ltd.