Kavindra Nath1,
David S. Nelson1, Andrew M. Ho1, Stephen B. Pickup1,
Christina Gustafson1, Cory Alvey2, Rong Zhou1,
Dennis B. Leeper3, Jerry D. Glickson1
1Radiology,
University of Pennsylvania, Philadelphia, PA, United States; 2Pharmacology,
University of Pennsylvania, Philadelphia, PA, United States; 3Radiation
Oncology, Thomas Jefferson University, Philadelphia, PA, United States
Synopsis: We seek to employ the natural tendency of melanomas and other tumors to convert glucose to lactate as a method for selective intracellular acidification of cancer cells and to exploit this effect in potentiating the activity of N-mustard and anthracycline antineoplastic agents.. We performed this study to evaluate whether induction of hyperglycemia could enhance the effects of lonidamine (LND) on inducing intracellular acidification, bioenergetic decline and potentiation of the activity of melphalan (LPAM) against DB1 melanoma xenografts in mice.. Intracellular pH and the bioenergetics were reduced by 0.7 units (p<0.001) and 51.4% (p>0.05), respectively, under hyperglycemic conditions, which is very similar to the effects of LND under normoglycemic conditions. This study demonstrates that while hyperglycemia substantially increases lactic acid production by the tumor, it does not increase the effects of LND on acidification of the tumor because of the strong buffering action of carbon dioxide (the pKa of carbonic acid is 6.39).