Detection of tumour treatment response using hyperpolarized 13C pyruvate

The exchange reaction between hyperpolarized 1-¹³C pyruvate and lactate, catalysed by the enzyme lactate dehydrogenase (LDH), can now be measured in real-time with ¹³C nuclear magnetic resonance spectroscopy and imaged in tissues using ¹³C MRI. EL-4 murine lymphoma cells catalyse this pyruvate-lactate exchange in a substrate-dependent fashion, and we demonstrate that the reaction is inhibited following treatment with chemotherapeutic drugs both in vitro and in vivo. The LDH reaction specifically labels the intratumoural lactate pool present within solid EL-4 murine lymphoma tumours, and this exchange was reduced following treatment with the chemotherapeutic drug etoposide. This novel metabolic imaging technique can be predictive of therapeutic success. The C6 intracranial rat glioma faithfully reproduces many morphological aspects of the human disease, and can be used as a model for the study of human brain tumours. When hyperpolarized pyruvate was administered to C6 glioma bearing rats, there was specific labelling of intratumoural lactate, and little to no polarized substrate in the normal brain. Following radiation therapy of these glioma bearing rats, the exchange of label between pyruvate and lactate was reduced as measured using chemical-shift imaging and was predictive of therapeutic success. Taken together, these results demonstrate the potential for hyperpolarized ¹³C pyruvate imaging to detect treatment response in vivo in different models of cancer. This work details initial studies into what might be a potentially valuable metabolic imaging tool. Hopefully this tool may one day be used by clinicians to improve the management of human cancer patients.