Detecting treatment response in a model of human breast adenocarcinoma using hyperpolarised [1-13C]pyruvate and [1,4-13C2]fumarate.

摘要: There has been substantial growth and investment in drug discovery development programmes oncology recent years, with the aim of producing therapeutics targeted at spectrum genetic abnormalities found cancer (Hu et al, 2000; Semenza, 2003; Bryant 2005). This rapid expansion moved field clinical closer to realisation personalised medicine, which patients receive drugs, individually or combination, that are tailored their specific disease. The delivery this approach should be facilitated by noninvasive imaging methods allow an early assessment treatment response, identifying unsuccessful treatments stage enabling selection more effective (reviewed Brindle (2008a)). Currently, tumour responses assessed from reductions size (Eisenhauer 2009). However, lacks sensitivity many weeks may elapse before a change is detected (Neves Brindle, 2006; Weissleder Pittet, 2008; 2008a). In some cases, for example cytostatic therapies, there no despite positive response (Brindle, Measurements physiology biochemistry, however, can give much earlier indication response. Positron emission tomography (PET) measurements uptake glucose analogue [18F] 2-fluoro-2-deoxy--glucose (FDG) being used increasingly clinic disease provide evidence 2009). MRS, particularly 1H MRS, also detect metabolic changes accompany (Aboagye Bhujwalla, 1999; Glunde 2006). relative lack limits spatial temporal resolution spectroscopic experiments cases only single voxel studies performed Although MRS widely clinic, limited routine use. situation introduction dynamic nuclear polarisation (DNP) technique increase solution state 13C experiment >10 000-fold (Ardenkjaer-Larsen 2003). enormous gain means that, following injection hyperpolarised 13C-labelled cell substrate, sufficient signal image molecule vivo, and, importantly, its conversion into other metabolites. Whereas largely static picture levels tissue metabolites, labelling enables cellular metabolism. principal drawback method, short half-life polarisation; [1-13C]pyruvate ∼30 s material must injected imaged within ∼5 min. Thus, order metabolism using technique, substrate taken up rapidly subsequent very fast. Even then, it often possible monitor enzyme-catalysed reaction (Gallagher 2009a). Nevertheless, already shown promise detecting tumours (Day 2007; Witney 2009). The exchange label between lactate, catalysed lactate dehydrogenase (LDH), was decrease drug-treated murine lymphoma vivo 2007), where decreased flux due number factors, including: DNA damage-mediated activation polyADP-ribose polymerase (PARP) consequent depletion NAD(H) coenzyme pool, loss LDH activity, reduction cellularity A similar study same model [1,4-13C2]fumarate, showed rate fumarase fumarate malate measure drug-induced necrosis 2009b). With trial about start prostate 2008b), reasonable expectation could translate offers new functional treatment. We show here, human breast adenocarcinoma, combination [1,4-13C2]fumarate doxorubicin any detectable size. labelled production, reflecting damage initiation apoptotic program, onset necrosis.