PARENT SESSION
2:30 PM to 3:30 PM
Monday, April 22, 2002
Poster Session 5 Heat Combined with Drugs
Room: Nevada 4-5
(MP05-43) Tumor oxygenation and acidification are increased in melanoma after exposure to meta-iodo-benzylguanidine and hyperglycemia.
Burd, Randy*,1, Wachsberger, Phyllis1, Daskalakis, Constantine1, Biaglow, John2, Stephens, Craig3, Leeper, Dennis1, 1 Thomas Jefferson University, Philadelphia, PA2 University of Pennsylvania, Philadelphia, PA3 M. D. Anderson Cancer Inst., Houston, TX
ABSTRACT-
Tumor oxygen tension and extracellular pH (pHe) are physiological parameters that can be manipulated to improve therapies such as hyperthermia, radiation, and alkylating agents. Many tumors consist of cells that are chronically exposed to low extracellular pH (pHe). Exposure of tumor cells in culture to glucose results in increased glycolysis and the inhibition of respiration (oxygen sparing effect). However, we have shown that when melanoma cells in culture are adapted to growth at low pH and exposed to glucose, respiration is stimulated (oxygen consumption). The effects of hyperglycemia and the respiratory inhibitor meta-iodo-benzylguanidine (MIBG) on tumor oxygen tension and pH were investigated in human melanoma xenografts in SCID mice. An oral gavage of 2M glucose (2g/kg) increased the average blood glucose concentration from 125 to 400 mg/dL. No change in oxygen tension above the steady state of about 1 mm Hg was observed, although tumor pHe decreased from a steady state of pH 6.7 to pH 6.5 (p < 0.01) after about 75 minutes. When MIBG (15mg/kg) was administered with oral glucose, blood glucose concentration increased again from 150 to 400 mg/dL. Oxygen tension increased from a steady state of 1.5 mm Hg to 15 mm Hg (p < 0.01), and tumor pHe decreased from a steady state of pH 6.7 to pH 6.3 (p < 0.01) after about 110 minutes. When the blood glucose concentration decreased to about 250 mg/dL, the tumor pHe began to recover, although tumor oxygen tension remained elevated. The hyperglycemia plus MIBG group exhibited more pronounced changes in oxygen tension and acidification (p < 0.01 and p = 0.09, respectively) when compared to the hyperglycemia alone group. In addition, the changes in blood glucose levels, oxygen tension, and tumor pHe all persisted longer in the hyperglycemia plus MIBG group. Acidification was extended by approximately 30-45 min. Administration of 15 mg/kg MIBG alone did not increase tumor oxygen tension or decrease tumor pHe. These results indicate that hyperglycemia alone does not affect tumor oxygen, as observed in cells adapted to growth at low pH in culture. However, addition of MIBG to hyperglycemia increases tumor oxygen tension as well as the magnitude and duration of acidification. Therefore, hyperglycemia plus MIBG may improve radiation therapy as well some chemotherapies and hyperthermia.
KEYWORDS: meta-iodo-benzylguanidine (MIBG), oxygenation, acidification, pH