Measurement of the acute response to hypoxia in rat tumours in vivo using magnetic resonance spectroscopy and hyperpolarised pyruvate


Year:

Session type:

Steven Reynolds1, Joanne Bluff1, Tooba Alizadeh1, Samira Kazan1, Stephen Metcalf1, Emily Wholey1, Leigh Williams1, Adriana Bucur1, Becky Bibby1, Martyn Paley1, Gillian M Tozer1
1University of Sheffield, Sheffield, UK

Background

Vascular targeting of tumours represents a proven complementary approach to conventional cancer therapy. Vascular disrupting agents (VDAs) cause extensive oxygen and nutrient deprivation, leading to tumour cell death1. Therefore, monitoring oxygenation levels is vital in understanding this process. The influence of tumour oxygenation state on tumour metabolism was determined by administering hyperpolarised 13C1-pyruvic acid to BDIX rats bearing syngeneic subcutaneous P22 sarcomas and estimating the rate constant for conversion of pyruvate to lactate, kpl, using magnetic resonance spectroscopy.

Method

Tumor pO2 was manipulated by supplying either normal or hypoxic air (10-15% O2, 4% CO2, balance N2). 5ml/kg of hyperpolarised 13C1-pyruvate was injected and slice-localised 13C magnetic resonance (MR) spectra acquired using a 13C/1H surface coil positioned over the tumour in a 7T MRI system. Pyruvate and lactate integrals versus time were fitted, using Matlab, to a two-way exchange model and kpl values extracted2.

Results

kpl significantly increased from 0.031±0.007s-1 under normoxia to 0.049±0.019s-1 for hypoxic conditions (mean±SD for n=8 p<0.01). Control experiments of multiple pyruvate injections in air-breathing rats (n=7) demonstrated no significant change in the rate constant, kpl, between 1st injection (0.046±0.015s-1) and 2nd injection (0.051±0.015s-1). A significant correlation was also found between kpl versus combined mean arterial blood pressure (MABP) and arterial blood oxygenation, pO2 levels.

Conclusion

MR methods for in vivo monitoring of metabolism of a hyperpolarised substrate (pyruvate to lactate) in tumour tissue were developed. The increase in kpl indicates a shift away from oxidative phosphorylation under hypoxic conditions, suggesting that measurement of this parameter would be useful for monitoring the effects of tumour vascular disrupting agents. The strong correlation between kpl and MABP*pO2 is most likely due to MABP driving tumour blood flow and therefore influencing tumour pO2.