Defining the pH_i-hyperthermia sensitivity relationship for the RIF-1 tumor in vivo: A³¹P MR spectroscopy study

This study quantifies the enhancement of the therapeutic efficacy of hyperthermia resulting from an acutely acidified and accurately monitored intracellular pH (pH_i) in a mouse tumor model in vivo. Metabolic manipulation of the physiology of RIF-1 tumor (subcutaneous, on the hind flanks of female C3H/HeJ mice) achieved by i.p. bolus injection of glucose (glycolytic tumor acidification) or 3-O-methylglucose (non-glycolytic tumor acidification) was monitored by ³¹P magnetic resonance (³¹P MR) prior to, during and up to 1 h after localized hyperthermia. The pre-hyperthermia ³¹P MR-observable metabolic parameter that correlates most strongly with thermal sensitivity is pH_i. Thermal sensitivity increases linearly with decreasing pH, regardless of the mechanism (glycolytic or non-glycolytic) of metabolic manipulation. The quantitative relationship is described by log₁₀(SF)/EQ43 = 0.0079 pH_i,preHT -0.0606 (R = 0.63, P < 0.0001), where EQ43 is the thermal heat dose delivered to the tumor (in units of equivalent minutes at 42.5°C), pH_i,preHT is the intracellular pH immediately prior to hyperthermia, and SF is the surviving fraction. The therapeutic enhancement is not as dramatic as expected based upon previously reported in vitro studies but is generally consistent with other in vivo studies. The method still represents a viable strategy for enhancing the therapeutic efficacy of hyperthermia, especially when used in combination with other therapeutic modalities.