phosphocreatine and Fibrosarcoma

The effects of pentobarbital anesthetic and physical restraint have been evaluated in murine RIF-1 tumors in terms of their suitability in providing minimal temporal variations in core and tumor temperatures, intracellular (pHMR) and extracellular (pHF) tumor pH, and tumor bioenergetics. pHF was measured using a fibreoptic pH probe. The implications of the changes in these parameters on the combined studies of in vivo MRS and hyperthermia have been discussed. The temporal variations of core and tumor temperatures, pHF and pHMR between the anesthetised and restrained mice were statistically significant (p < 0.0001, p < 0.005, and p < 0.0001, respectively). Differences in the temperatures between the two groups varied with time, and were maximum at about 2 h after pentobarbital. In the anesthetised mice, while there was a net increase of 0.28 pH units in pHF, there was a drop by 0.32 pH units in pHMR (p < 0.001). Temporal variations of both pHF and pHMR in the restrained mice were relatively constant. In light of these findings, wherever possible, physical restraint in a suitably designed holder is suggested for immobilizing animals for magnetic resonance spectroscopy studies.

Topics: Adjuvants, Anesthesia; Animals; Energy Metabolism; Fibrosarcoma; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C3H; Neoplasms, Experimental; Pentobarbital; Phosphates; Phosphocreatine; Restraint, Physical; Temperature

Bioenergetic and metabolic status of murine FSaII tumours were evaluated using 31P MRS, acid extracts ('global' techniques) and quantitative bioluminescence ('microregional' assay). Data obtained from s.c. tumours of varying sizes (44-600 mm3) have been correlated with the oxygenation status evaluated using O2-sensitive needle electrodes. beta-NTP/Pi and phosphocreatine (PCr)/Pi ratios derived from 31P MRS were positively correlated to the median tissue pO2 values. pH declined during growth with intracellular acidosis being evident in tumours > 350 mm3. Whereas lactic acid formation greatly contributed to this decline in small- and medium-sized tumours, ATP hydrolysis and slowing down of the activities of pumps involved in pHi regulation seem to be major factors responsible for intracellular acidification in bulky tumours. PCr levels decreased at an early growth stage, whilst ATP concentrations dropped in bulky malignancies only, coinciding with a decrease in adenylate energy charge and a substantial rise in the levels of total Pi. MRS observable (mobile) Pi was consistently lower than [Pi] measured in acid extracts. On average, median pO2 values of ca 10 mmHg represent a critical threshold for energy metabolism. At higher median O2 tensions, levels of ATP, phosphomonoester and total Pi were relatively constant. This coincided with intracellular alkalosis or neutrality and stable adenylate ratios. On average, median pO2 values < 10 mmHg coincided with intracellular acidosis, ATP depletion, a drop in energy charge and rising Pi levels.

Topics: Acidosis; Adenosine Triphosphate; Animals; Cell Hypoxia; Energy Metabolism; Female; Fibrosarcoma; Glucose; Hydrogen-Ion Concentration; Lactates; Lactic Acid; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C3H; Oxygen; Phosphates; Phosphocreatine

Topics: Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Chromatography, High Pressure Liquid; Energy Metabolism; Fibrosarcoma; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C3H; Oxygen Consumption; Phosphates; Phosphocreatine; Ribonucleotides; Sarcoma, Experimental

In order to examine the mechanisms underlying radiation-induced changes in phosphorus metabolite levels observed in RIF-1 tumors in vivo, RIF-1 cells in culture were perfused for up to 70 h following gamma-irradiation with 0-25 Gy and monitored continuously by 31P NMR spectroscopy at 8.5 T. Cells immobilized in the sample volume by incorporation into calcium alginate beads were bioenergetically stable, but did not replicate at the cell density used. Following an initial increase in PCr and NTP, which occurred in both control and irradiated cells, a dramatic decline in high-energy phosphates was detected beginning 24-30 h after irradiation with 15 or 25 Gy. In contrast, unirradiated cells or cells treated with 10 Gy remained metabolically stable for up to 72 h. The metabolic changes induced by irradiation of the cultured cells, which reflected cell death and lysis, were distinctly different from those observed in RIF-1 tumors in vivo during the same postirradiation time interval--an increase in high-energy relative to low-energy phosphates. This suggests that the spectral changes in vivo do not result from direct modification of cellular energy metabolism by radiation injury.

Topics: Animals; Energy Metabolism; Fibrosarcoma; G1 Phase; Gamma Rays; Magnetic Resonance Spectroscopy; Mice; Nucleotides; Oxygen Consumption; Phosphates; Phosphocreatine; Phosphorus; Radiation Dosage; Resting Phase, Cell Cycle; Tumor Cells, Cultured

The effects of 3-O-methyl-D-glucose (3-OMG) on subcutaneously implanted murine radiation-induced fibrosarcoma 1 tumor were examined with 2H, 13C, and 31P nuclear magnetic resonance (NMR) in situ. Using 31P NMR, changes in tumor high-energy phosphate metabolism were monitored for 2.5 h after i.p. administration of 3-OMG (8.1 g/kg body weight); tumor pH decreased by a mean maximum of 0.52 +/- 0.05 (SE) (n = 10), [PCr] decreased by 54%, [NTP] decreased by 35%, and [Pi] increased by 36%. Tumor blood flow, as measured by 2H NMR monitoring of D2O washout kinetics, decreased by 40% at 1 h and by 47% at 2 h after 3-OMG injection (n = 4). This substantial tumor acidification (pH decrease much greater than 0.1), expected to require a glycolytic substrate (Hwang et al., Cancer Res., 51: 3108-3118, 1991), is surprising in light of the previously documented metabolically inert nature of 3-OMG. In situ 13C NMR spectroscopy, following [6-13C]3-OMG i.p. injection, examined the possibility of the glycolytic metabolism of 3-OMG. However, only the C-6 resonance of 3-OMG was detected (n = 6); no resonances from [6-13C]3-OMG-6-phosphate or [3-13C]lactate were observed. These results confirmed that 3-OMG was not metabolized in radiation-induced fibrosarcoma 1 tumor. At the completion of the in situ 13C NMR experiments, tumors were freeze clamped, and perchloric acid extraction was performed. High-resolution 1H NMR measurement of lactate concentrations showed no statistically significant difference in control tumor extracts (from mice not receiving i.p. injection; n = 5) and in tumor extracts from mice administered i.p. [6-13C]3-OMG (n = 5), indicating that there was no significant increase in lactate level in the tumor extracts from mice administered i.p. 3-OMG due to increased plasma glucose concentration. The results of these 1H and 13C NMR studies indicated that the radiation-induced fibrosarcoma 1 tumor acidification caused by i.p. administration of 3-OMG was not due to a direct (3-OMG----lactate) or an indirect (systemic glucose----lactate) increase in tumor lactic acid levels.

Topics: 3-O-Methylglucose; Animals; Blood Glucose; Carbon Radioisotopes; Deuterium; Female; Fibrosarcoma; Glucose; Hematocrit; Hydrogen-Ion Concentration; Lactates; Lactic Acid; Magnetic Resonance Spectroscopy; Mannitol; Methylglucosides; Mice; Mice, Inbred C3H; Neoplasms, Radiation-Induced; Nucleosides; Phosphates; Phosphocreatine

Experimental tumors growing in irradiated tissue have been used to study the biological differences characteristic of locally recurrent tumors. Since the hypoxic cell fraction of tumors growing in irradiated tissue is increased and growth rate is slowed, these tumors are assumed to be metabolically deprived with hypoperfusion. In this study, we directly measured the effect of tumor bed irradiation on blood flow, growth rate, rate of nucleoside triphosphate (NTP) turnover, and metabolic state using 31P and 2H nuclear magnetic resonance, and an intradermal assay for angiogenesis. (NTP turnover refers to ATP-synthetase mediated NTP turnover that is visible to 31P nuclear magnetic resonance using the technique of saturation transfer.) A decrease in the number of small blood vessels perfusing tumors in a preirradiated bed was found. Most of the decrease was due to a loss of vessels with diameters less than 0.04 mm. When tumors growing in preirradiated tissue reached approximately 100 mm3 in volume, a high frequency of gross and microscopic necrosis and hemorrhage was already observed in most tumors. Consistent with these observations, the phosphocreatine/inorganic phosphate and nucleoside triphosphate/inorganic phosphate ratios were significantly lower in the tumors growing in a preirradiated bed compared with tumors in a nonirradiated bed. The blood flow rate was similar to control for tumors less than 100 mm3 (45.8 versus 40.5 ml/100 g/min, P = not significant), but was significantly lower than control for tumors greater than 100 mm3 (40.4 versus 12.2 ml/100 g/min, P less than 0.01). The NTP turnover rates correlated (P less than 0.005, r = 0.66) with the volume doubling rate (1/tumor volume doubling time), but for tumors approximately 100 mm3 in size neither the volume doubling rate nor the NTP turnover rate of tumors growing in an irradiated bed was statistically lower than control [NTP turnover: 14 +/- 3%/s versus 9 +/- 2%/s; volume doubling rate: 0.47 +/- 0.07/day versus 0.33 +/- 0.04/day (mean +/- SE)]. A large intertumor variability of all metabolic parameters was observed.

Topics: Adenosine Triphosphatases; Animals; Cell Division; Deuterium; Fibrosarcoma; Kinetics; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C3H; Mice, Nude; Muscles; Neovascularization, Pathologic; Phosphates; Phosphocreatine; Phosphorus; Regional Blood Flow; Ribonucleotides; Sarcoma, Experimental

The hyperglycemia-induced in situ metabolism and blood flow changes produced in s.c. implanted murine radiation-induced fibrosarcoma-1 tumors, grown on the flanks of female C3H/HeJ mice, were examined with 31P and 2H nuclear magnetic resonance. Initial experiments verified a hyperglycemic tumor acidification similar to that reported earlier with a different substrain of mice, C3H/AnF (J.L. Evelhoch et al., Proc. Natl. Acad. Sci. USA, 81: 6496-6500, 1984). Changes in the tumor pH, phosphorus metabolites, and blood flow were then compared after administration of saline, glucose, or mannitol (a nonmetabolizable glucose analogue) using a mole-equivalent dose of the sugars (i.e., 0.8 mmol/20g mouse). Neither saline (n = 8) nor mannitol (n = 6) administration had any marked effect upon tumor pH, whereas glucose administration produced a mean maximum tumor pH reduction of 0.74 +/- 0.09 (SE; n = 9) during the 2.5 h post-glucose injection. No significant changes in high energy phosphate concentrations were observed during the same period after saline injection. After glucose injection, the [phosphocreatine] gradually decreased by 64% (P = 0.0001). After the initial 1 h post-glucose injection, the [inorganic phosphate] increased by 58% (P = 0.0001), and the [nucleoside triphosphates] decreased by 29% (P = 0.0001) during the following 1.5 h. After mannitol injection, while there was no change in [inorganic phosphate] over time (P = 0.37), the [phosphocreatine] decreased by 33% (P = 0.0001) and the [nucleoside triphosphates] decreased by 21% (P = 0.0015) within 20 min, then both the [phosphocreatine] and [nucleoside triphosphates] remained at constant levels during the following 2 h. In parallel experiments, the volumetric rate of tumor blood flow and perfusion was measured by 2H nuclear magnetic resonance monitoring of 2H2O washout kinetics (S-G. Kim and J. J. H. Ackerman, Cancer Res., 48: 3449-3453, 1988); tumor blood flow decreased by 80% (P = 0.0001, n = 11), 60% (P = 0.0031, n = 4), and 20% (P = 0.058, n = 10) at 2 h after glucose, mannitol, or saline injections, respectively. These results suggest that anaerobic glycolysis is a requirement for hyperglycemic tumor acidification. However, the decrease in tumor blood flow accompanying hyperglycemic acidification suggests that flow reduction also may be a contributing or a required cofactor for acidification via inhibition of lactic acid egress.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Blood Glucose; Carbon Dioxide; Deuterium; Female; Fibrosarcoma; Glucose; Hematocrit; Hydrogen-Ion Concentration; Kinetics; Magnetic Resonance Spectroscopy; Mannitol; Mice; Mice, Inbred C3H; Neoplasms, Radiation-Induced; Oxygen; Partial Pressure; Phosphocreatine; Phosphorus; Regional Blood Flow; Ribonucleotides; Sarcoma, Experimental

The metabolic response of the RIF-1 tumor to 5-fluorouracil (a single dose of 260 mg 5FU/kg, ip) was monitored in 10 mice using 19F and 31P MR spectroscopy. 19F MRS revealed a continuous drop in tumor 5FU level and an increase in the fluoronucleotide (Fnuc) signal to a plateau value of 50% of the initial 5FU level, during the first 2 h after chemotherapy. Although the 31P MR spectra of the tumors showed no significant initial changes, the total level of MR visible tumor phosphate decreased and tumor pH increased during the subsequent days. The changes in phosphate metabolism and tumor pH did not correlate with the detected fluorine levels or tumor response. However, the pretreatment Pi level, the plateau Fnuc level, and the 5FU induced decrease in tumor volume showed significant correlation. This indicates that both 19F and 31P MR spectroscopy have potential for predicting response to 5FU chemotherapy.

Topics: Animals; beta-Alanine; Female; Fibrosarcoma; Fluorine; Fluorouracil; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Phosphates; Phosphocreatine; Phosphorus; Regression Analysis; Remission Induction; Skin Neoplasms

Previous studies have reported significant radiobiological and hemodynamic effects associated with sodium pentobarbital (PB) anesthetization. The present work contrasts the effects of PB with azaperone-ketamine (AZ) in RIF-1 and KHT tumors while animal body core temperature is maintained at 37 degrees C. The primary aims were to evaluate both agents in terms of: (i) duration of anesthetic; (ii) effect on absolute levels of 31P NMR phosphocreatine (PCr) + beta-nucleoside triphosphate (beta-NTP)/inorganic phosphate (Pi) ratios; and (iii) effect on temporal variability of PCr + beta-NTP/Pi ratios. In terms of overall duration, AZ was the clear preference. Although the maintenance of 37 degrees C core temperature significantly reduced overall durations for both anesthetics, AZ animals invariably remained immobile for a minimum of 80 min. For PB, durations were highly unpredictable. With AZ, mean PCr + beta-NTP/Pi ratios were constant over the entire 80 min period for both lines. With PB, PCr + beta-NTP/Pi ratios were lower in relation to AZ for KHT at select timepoints, but highly variable among RIF-1 tumours. Since ratios under PB varied substantially with time for RIF-1 lines, measurements taken with PB are clearly not representative of the control state. Furthermore, in light of the consistent and reproducible results obtained with AZ, this anesthetic is considered a marked improvement over PB for animal studies of this nature.

Topics: Anesthetics; Animals; Azaperone; Energy Metabolism; Fibrosarcoma; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Mice; Phenobarbital; Phosphates; Phosphocreatine; Time Factors

In vivo 31P nuclear magnetic resonance (31P NMR) spectroscopy has been used to compare metabolic profiles with tumor radiosensitivity. A radioresistant mammary carcinoma (MCa) and a radiosensitive methylcholanthrene-induced fibrosarcoma (Meth-A) were studied by 31P NMR spectroscopy in the tumor volume range of approximately 100-1200 mm3. The MCa showed a constant pH in this volume range; the ratio of phosphocreatine to inorganic phosphate (PCr/Pi) for 160-300 mm3 tumors was 0.33 +/- 0.11 (mean +/- standard deviation) and did not change (0.29 +/- .09) for tumors in the volume range of 600-1200 mm3. In comparison, the Meth-A showed a decrease in tumor pH as volume increased from 160-300 mm3 (pH 7.16 +/- 0.4) to 600-1200 mm3 (pH 6.94 +/- .07). Tumor PCr/Pi decreased from 0.70 +/- .16 (160-300 mm3) to 0.33 +/- .16 (600-1200 mm3). The radiation doses for control of MCa-induced tumors in 50% of the treated tumors ranged from 65 (150-250 mm3) to 71 Gy (1000-1300 mm3) and for the Meth-A-induced tumors ranged from 35 (150-250 mm3) to 38 Gy (1000-1300 mm3). These results suggest that 31P NMR spectra may be a qualitative predictor of tumor hypoxia, although further studies of human and rodent tumors are necessary to support this hypothesis.

Topics: Animals; Fibrosarcoma; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Mammary Neoplasms, Experimental; Methylcholanthrene; Mice; Neoplasm Transplantation; Nucleotides; Phosphocreatine; Radiation Tolerance

The relative concentrations of nucleotide triphosphates, creatine phosphate, inorganic phosphate, and pH have been evaluated as a function of tumor volume in a murine fibrosarcoma (FSaII) by 31P NMR spectroscopy. As the tumor volume increased from 60-1250 mm3, the ratio of phosphocreatine to inorganic phosphate systemically decreased. This decrease paralleled a decrease in the ratio of nucleotide triphosphate to inorganic phosphate in the same tumor volume range. The tumor pH as measured by 31P NMR decreased slightly with tumor growth. A pH of 7.17 +/- 0.07 (n = 17) was found for tumors between 60 and 150 mm3, whereas for tumors greater than 900 mm3, a pH of 7.05 +/- .03 (n = 6) was noted. Intermediate size tumors (151-900) had a pH of 7.12 +/- 0.09 (n = 18). The change in tumor energy status with tumor volume inversely paralleled the change in tumor radiobiologic hypoxic cell fraction and suggested a causal relationship between tumor nutrient status and energy status. Tumor thermal sensitivity also increased with tumor volume, suggesting a relationship between pH, energy status, and thermal sensitivity, as has been demonstrated under in vitro conditions. Each NMR parameter was found to correlate significantly with tumor volume independent of the other NMR parameters.

Topics: Adenosine Triphosphate; Animals; Cell Hypoxia; Energy Metabolism; Fibrosarcoma; Hydrogen-Ion Concentration; Hyperthermia, Induced; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Phosphates; Phosphocreatine

Size-dependent changes in therapeutically relevant and interrelated metabolic parameters of a murine fibrosarcoma (FSaII) were investigated in vivo using conscious (unanesthetized) animals and tumor sizes less than or equal to 2% of body weight. Tumor pH and bioenergetics were evaluated by 31P nuclear magnetic resonance spectroscopy (31P-MRS), and tumor tissue oxygen tension (pO2) distribution was examined using O2-sensitive needle electrodes. During growth FSaII tumors showed a progressive loss of phosphocreatine (PCr) and nucleoside triphosphate (NTP) with increasing inorganic phosphate (Pi) and phosphomonoester (PME) signals. Ratios for PCr/Pi, PME/Pi, NTP/Pi, and phosphodiester/inorganic phosphate (PDE/Pi) as well as pH determined by 31P-NMR (pHNMR) and the mean tissue pO2 progressively declined as the tumors increased in size. The only relevant ratio increasing with tumor growth was PME/NTP. When the mean tissue pO2 value was plotted against pHNMR, NTP/Pi, PCr/Pi, PME/Pi, and PDE/Pi for tumor groups of similar mean volumes, a highly significant positive correlation was observed. There was a negative correlation between mean tumor tissue pO2 values and PME/NTP. From these results we concluded that 31P-MRS can detect changes in tumor bioenergetics brought about by changes in tumor oxygenation. Furthermore, the close correlation between oxygenation and energy status suggests that the microcirculation in FSaII tumors yields an O2-limited energy metabolism. Finally, a correlation between the proportion of pO2 readings between 0 and 2.5 mmHg and the radiobiologically hypoxic cell fraction in FSaII tumors was observed. The latter finding might be of particular importance for radiation therapy.

Topics: Animals; Energy Metabolism; Fibrosarcoma; Magnetic Resonance Spectroscopy; Mice; Neoplasm Transplantation; Oxygen Consumption; Partial Pressure; Phosphates; Phosphocreatine

In vivo 31P nuclear magnetic resonance spectroscopy has been used to examine the RIF-1 fibrosarcoma in mice during untreated growth and following chemotherapy with cyclophosphamide. Levels of inorganic phosphate increase relative to phosphocreatine or nucleoside triphosphates during early untreated growth. After the tumor reaches a volume of approximately 1 g, no further decrease in energy level is observed. Following treatment with cyclophosphamide, tumor phosphorus metabolite ratios and pH are significantly altered, compared to untreated age-matched controls. During the growth delay period following chemotherapy there is a significant reduction in the ratio of inorganic phosphate to other phosphate metabolites, compared to age-matched controls. In addition, a more alkaline pH is observed in the tumors of treated animals. When the growth delay period ends, nuclear magnetic resonance spectra return to pretreatment patterns. The magnitude of the differences in 31P nuclear magnetic resonance spectral parameters between treated animals and untreated controls is dose dependent. However, doses of cyclophosphamide above 200 mg/kg do not result in earlier spectroscopic alterations, nor in larger effects by Day 3 after treatment, even though clonogenic cell killing and growth delay are greater at these higher doses.

Topics: Animals; Cyclophosphamide; Dose-Response Relationship, Drug; Fibrosarcoma; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C3H; Neoplasms, Radiation-Induced; Phosphates; Phosphocreatine

Tumor tissue contains viable hypoxic regions that are radioresistant and often chemoresistant and may therefore be responsible for some treatment failures. A subject of general interest has been the development of non-invasive means of monitoring tissue oxygen. Pulse Fourier transform 31P NMR spectroscopy can be used to estimate intracellular nucleotide triphosphates (NTP), phosphocreatinine (PCr), inorganic phosphate (Pi) and pH. We have obtained 31P NMR spectra as an indirect estimate of tissue oxygen and metabolic status in a C3H mouse fibrosarcoma FSaII. Sequential spectra were studied during tumor growth in a cohort of animals and peak area ratios for several metabolites were computed digitally by computer. During growth, tumors showed a progressive loss of PCr with increasing Pi, and most tumors greater than 250 mm3 in volume had little or no measurable PCr. The smallest tumors (38 mm3 average volume) had PCr/Pi ratios of 1.03 +/- .24, whereas tumors 250 mm3 or more had an average PCr/Pi ratio of 0.15 +/- .04. Similarly derived NTP/Pi ratios decreased with tumor size, but this change was not significant (p = .17). Radiobiologic hypoxic cell fractions were estimated using the radiation dose required to control tumor in 50% of animals (TCD50) or by the lung colony technique. Tumors less than 100 mm3 had a hypoxic cell fraction of 4% (TCD50) while tumors 250 mm3 had a 40% hypoxic cell fraction (lung colony assay). These hypoxic fraction determinations correlated well with the depletion of PCr and decline in NTP/Pi ratios seen at 250 mm3 tumor volumes. Tumor spectral changes with acute ischemia were studied after ligation of the tumor bearing limb and were similar to changes seen with tumor growth. PCr was lost within 7 minutes, with concurrent increase in Pi and loss of NTP. Complete loss of all high energy phosphates occurred by 40 minutes of occlusion. In vivo tumor 31P NMR spectroscopy can be used to estimate tissue metabolic status and may be useful in non-invasive prediction of hypoxic cell fraction, reoxygenation, and radiation treatment response.

Topics: Animals; Energy Metabolism; Female; Fibrosarcoma; Hydrogen-Ion Concentration; Hypoxia; Ischemia; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C3H; Nucleotides; Phosphates; Phosphocreatine; Sarcoma, Experimental

The hyperglycemia-induced in vivo metabolic changes produced in subcutaneous murine RIF-1 tumors, grown on female C3H/Anf mice, were examined with 31P surface-coil NMR. Serum glucose levels were elevated 4-fold by bolus intraperitoneal injection of 0.3 ml of an aqueous 50% glucose solution. Tumor pH was calculated from the chemical shift of Pi and relative phosphocreatine and ATP concentrations were determined by Simpson's rule integration of the peak areas. Tumor pH decreased by ca. 0.45 unit over 2 hr while phosphocreatine concentrations decreased by ca. 50% over the same time period (n = 9). Initial tumor pH correlated inversely with the initial peak intensity ratio of Pi:ATP (r = -0.77). In a significant number of tumors (n = 4), two pH populations were observed. In these tumors, one population was unaffected by hyperglycemia and the other showed a decrease in pH. In the other tumors (n = 5), the pH distribution broadened as the pH decreased. In these tumors, the observed decreased in phosphocreatine concentration correlated with that calculated from the effect of measured tumor pH on the intracellular creatine kinase equilibrium (n = 18, r = 0.91). This correlation and consideration of the Pi distribution in the tumor suggest that the pH measured by 31P NMR is weighted heavily by intracellular pH for the RIF-1 tumor. The presence of two distinct tumor pH populations or a broadened pH distribution likely reflects variations in tumor microcellular environment. Control experiments showed negligible changes in tumor pH and high energy phosphate concentrations after bolus intraperitoneal injection of 0.3 ml of isotonic saline. In addition, negligible changes in leg muscle pH and high energy phosphate concentrations were observed after glucose injection into mice with or without tumors. These results indicate that hyperglycemia induced by intraperitoneal glucose injection is effective in lowering the tumor pH of the murine RIF-1 tumor.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Fibrosarcoma; Hydrogen-Ion Concentration; Hyperglycemia; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C3H; Phosphates; Phosphocreatine; Sarcoma, Experimental