The effect of hypoxia and hyperoxia on nucleoside triphosphate/inorganic phosphate, pO2 and radiation response in an experimental tumour model

Abstract

Summary This study has evaluated the effect of breathing 100% oxygen, carbogen and carbon monoxide (at 660 p.p.m.) on the bioenergetic and oxygenation status and the radiation response of 200-mm3 C3H mammary carcinomas grown in the feet of CDF mice. Bioenergetic status was assessed by 31p magnetic resonance spectroscopy (MRS) using a 7-tesla spectrometer with both short (2 s) and long (6 s) pulse repetition times. Tumour partial pressure of oxygen (P02) was measured with an Eppendorf polarographic electrode; the oxygenation parameters were the median P02 and fraction of p02 values < 2.5 mmHg. The radiation response was estimated using a tumour growth delay assay (time to grow three times treatment volume). Carbon monoxide breathing decreased tumour P02 and compromised the radiation response, but the l-nucleoside triphosphate (NTP)/Pi ratio was unchanged. Both carbogen and oxygen (100%) increased tumour P02 and P-NTP/Pi and enhanced the radiation response, the effects being similar under the two gassing conditions and dependent on the gas breathing time. Thus, in this tumour model, 31P-MRS can detect hyperoxic changes, but because cells can remain metabolically active even at low oxygen tensions the 3-NTP/P1 did not correlate with low tissue oxygenation. An analysis of variance showed that gas breathing time induced a significant systematic effect on 1-NTP/Pi, the MRS pulse repetition time had a significant effect on 3-NTP/P1 change under hypoxic but not under hyperoxic conditions and the type of gas that was inhaled had a significant effect on J-NTP/Pi.Keywords: C3H mammary carcinoma; hyperoxia; hypoxia; 31P-NMR spectroscopy; NTP/P1; polarographic oxygen electrode; tumour oxygenation, radiation response There is both experimental and clinical evidence that hypoxic tumour cells cause resistance to certain types of cancer therapy (Moulder and Rockwell, 1984;Teicher et al, 1981; Grau and Overgaard, 1988;Durand, 1991;Overgaard and Horsman, 1996). Considerable effort is now being made to identify those human tumours that contain hypoxic cells (for review see Stone et al, 1993, Raleigh et al, 1996. Direct Previous studies in experimental tumours showed a significant positive correlation between 31P-MRS energy measurements and oxygen status (Vaupel et al, 1989;Sostman et al, 1991), intracapillary oxyhaemoglobin saturation (Rofstad et al, 1988a), blood supply (Lyng et al, 1993) or radiobiological hypoxic fraction in three of four tumour lines (Rofstad et al, 1988b). In addition, a positive correlation was found between the fraction of radiobiological hypoxic cells and polarographic oxygen electrode measurements after manipulation of oxygen levels within tumours of a particular model and tumour size . The 31P-MRS energy status and the fraction of radiobiological hypoxic cells were compared under identical conditions and no correlation was found . Moreover, no correlation was found in experimental studies that compared radiobiological hypoxia and oxygen electrode measurements or 31P-MRS energy assessments (Rofstad et...

The effects of host carbogen (95% oxygen/5% carbon dioxide) breathing on metabolic characteristics of Morris hepatoma 9618a

“…Increases in NTP/Pi and pO2 similar to those seen in hepatoma 9618A, have been seen in a CH3 mammary adenocarcinoma in response to host carbogen breathing (Nordsmark et al, 1997). In a study of four rat tumours (including hepatoma 9618a) and 17 mouse tumours measured polarographically and reported elsewhere (Collingridge, 1997), hepatoma 9618a had one of the highest median pO2 values of all tumours studied, consistent with its status as a well-differentiated tumour type.…”

Dynamic in vivo oxymetry using overhauser enhanced MR imaging

“…Suggested areas of applications where in vivo oxygen concentration measurements could be of clinical importance are: Determination of pO 2 in tumors before and during radiation therapy. The importance of pO 2 for survival of the irradiated cells has been extensively discussed in the literature (45–47) and it is a general consensus that cell survival can vary with a factor of ≈3 depending on the pO 2 level. It seems most urgent to be able to determine low values of pO 2 in the range 0–30 mmHg.…”

Electron paramagnetic resonance imaging of tumor hypoxia: Enhanced spatial and temporal resolution for in vivo pO2 determination

“…The assessment of tissue oxygen concentration is an important factor in the outcome of radiation therapy and/or chemotherapy for cancer (1, 2). Hence there is great interest in developing noninvasive methods to measure in vivo oxygen concentration in tumors.…”