Kinetic modelling of dissolution dynamic nuclear polarisation C magnetic resonance spectroscopy data for analysis of pyruvate delivery and fate in tumours.

Dissolution dynamic nuclear polarisation (dDNP) of C-labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of hyperpolarised C-labelled pyruvate ( C -pyruvate) and urea ( C-urea), a nonmetabolised marker. A general mathematical model of pyruvate-lactate exchange, incorporating an arterial input function (AIF), enabled the losses of pyruvate and lactate from tumour to be estimated, in addition to the clearance rate of pyruvate signal from blood into tumour, K , and the forward and reverse fractional rate constants for pyruvate-lactate signal exchange, k and k .

Evaluation of Sydnone-Based Analogues of Combretastatin A-4 Phosphate (CA4P) as Vascular Disrupting Agents for Use in Cancer Therapy.

The combretastatins have attracted significant interest as small-molecule therapies for cancer due to their ability to function as vascular disrupting agents. We have successfully prepared a range of combretastatin analogues that are based on a novel sydnone heterocycle core, and their potential as tubulin binders has been assessed in vitro and in vivo. The most potent candidate was found to disrupt microtubules and affect cellular morphology at sub-micromolar levels.

Targeting the vasculature of tumours: combining VEGF pathway inhibitors with radiotherapy.

The development of blood vessels by the process of angiogenesis underpins the growth and metastasis of many tumour types. Various angiogenesis inhibitors targeted against vascular endothelial growth factor A (VEGF-A) and its receptors have entered the clinic more than a decade ago. However, despite substantial clinical improvements, their overall efficacy proved to be significantly lower than many of the pre-clinical studies had predicted.