{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T12:48:19Z","timestamp":1772542099332,"version":"3.50.1"},"reference-count":36,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,2,22]],"date-time":"2015-02-22T00:00:00Z","timestamp":1424563200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-CA129544"],"award-info":[{"award-number":["R01-CA129544"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["NMR in Biomedicine"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:p>We seek to exploit the natural tendency of melanomas and other tumors to convert glucose to lactate as a method for the selective intracellular acidification of cancer cells and for the potentiation of the activity of nitrogen\u2010mustard antineoplastic agents. We performed this study to evaluate whether the induction of hyperglycemia (26 mM) could enhance the effects of lonidamine (LND, 100 mg\/kg; intraperitoneally) on the induction of intracellular acidification, bioenergetic decline and potentiation of the activity of melphalan (LPAM) against DB\u20101 melanoma xenografts in mice. Intracellular pH (pH<jats:sub>i<\/jats:sub>), extracellular pH (pH<jats:sub>e<\/jats:sub>) and bioenergetics (\u03b2\u2010nucleoside triphosphate to inorganic phosphate ratio, \u03b2\u2010NTP\/Pi) were reduced by 0.7 units (<jats:italic>p<\/jats:italic> &lt; 0.001), 0.3 units (<jats:italic>p<\/jats:italic> &gt; 0.05) and 51.4% (<jats:italic>p<\/jats:italic> &lt; 0.05), respectively. The therapeutic response to LPAM (7.5 mg\/kg; intravenously) + LND (100 mg\/kg; intraperitoneally) was reduced by about a factor of three under hyperglycemic conditions relative to normoglycemia, producing a growth delay of 7.76 days (tumor doubling time, 5.31 days; cell kill, 64%) compared with LND alone of 1.70 days and LPAM alone of 0.29 days. Under normoglycemic conditions, LND plus LPAM produced a growth delay of 17.75 days, corresponding to a cell kill of 90% at the same dose for each of these agents. The decrease in tumor cell kill under hyperglycemic conditions correlates with an increase in tumor ATP levels resulting from increased glycolytic activity. However, hyperglycemia substantially increases lactic acid production in tumors by a factor of approximately six (<jats:italic>p<\/jats:italic> &lt; 0.05), but hyperglycemia did not increase the effects of LND on acidification of the tumor, most probably because of the strong buffering action of carbon dioxide (the p<jats:italic>K<\/jats:italic><jats:sub>a<\/jats:sub> of carbonic acid is 6.4). Therefore, this study demonstrates that the addition of glucose during treatment with LND diminishes the activity of this agent. Copyright \u00a9 2015 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/nbm.3260","type":"journal-article","created":{"date-parts":[[2015,2,22]],"date-time":"2015-02-22T22:34:12Z","timestamp":1424644452000},"page":"395-403","source":"Crossref","is-referenced-by-count":18,"title":["Effects of hyperglycemia on lonidamine\u2010induced acidification and de\u2010energization of human melanoma xenografts and sensitization to melphalan"],"prefix":"10.1002","volume":"28","author":[{"given":"Kavindra","family":"Nath","sequence":"first","affiliation":[{"name":"Department of Radiology University of Pennsylvania  Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David S.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Pennsylvania  Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel F.","family":"Heitjan","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Epidemiology University of Pennsylvania  Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Pennsylvania  Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis B.","family":"Leeper","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Thomas Jefferson University  Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerry D.","family":"Glickson","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Pennsylvania  Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,2,22]]},"reference":[{"key":"e_1_2_7_2_1","unstructured":"American Cancer Society.Cancer Facts and Figures\u20142014. 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