In vivo NMR spectroscopic studies on the bioenergetic changes induced by metabolic modulators in Ehrlich ascites...

Changes in the energy metabolism of Ehrlich ascites tumour (EAT) cells induced by treatment with 2-deoxy-D-glucose (2-DG) alone and in combination with other metabolic modulators, were studied using in vivo nuclear magnetic resonance (NMR) spectroscopy. Accumulation of 2-DG-6-phosphate (2-DG-6-P) and cellular energy status as reflected in the ratio of beta ATP to inorganic phosphate (beta-ATP/Pi) in cells could be monitored as a function of time using P-31 NMR spectroscopy. Presence of 2-DG induced a significant decrease in the levels of nucleotide triphosphates, which continued to reduce for some time even after removing 2-DG from the vicinity of cells. When administered along with 3-O-methyl-D-glucose (3-O-MG), 2-DG phosphorylated at a slower rate and the resultant 2-DG-6-P accumulated to a lesser extent than that obtained with 2-DG alone. Treatment with Photosan II, a haematoporphyrin derivative (Hpd), has been reported to increase the glucose utilisation and rate of glycolysis. Upon concomitant administration of 2-DG along with Hpd (after Hpd pretreatment for 1-2 hr), the extent of phosphorylation of 2-DG increased. The combination of 2-DG with 3-O-MG or Hpd reduced the energy status (beta-ATP/Pi) to a greater extent and the recovery was considerably less upon removal of the treatment, compared to the effects of either drug administered separately. Since metabolic depletion of ATP is known to inhibit the post-irradiation DNA repair processes, it is hypothesized that the use of these drug combinations, as adjuvants to tumour radiotherapy, should enhance the therapeutic efficacy and selectivity.