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Previously we reported that three imaging methods, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), T1ρ-MRI, and ultralow temperature NADH/flavoprotein fluorescence imaging (redox scanning), could differentiate the less metastatic human melanoma cell line A375P from a more metastatic line C8161 growing as mouse xenografts in nude mice (Li LZ et al. Adv. Exp. Med. Biol., 2007, 599:67-78; PNAS, 2009, 106:6608-6613). The more metastatic C8161 tumor was characterized by less blood perfusion/permeability, a more oxidized mitochondrial redox state in the tumor core, and a smaller T1ρ relaxation time constant averaged across the entire tumor section. In the current study, we have further probed the bioenergetic status and tissue microenvironment of these tumors by applying whole tumor phosphorous magnetic resonance spectroscopy (31P-MRS) to these two xenografts in a vertical bore 9.4-T Varian magnet. The phosphomonoester (PME)/βNTP ratio and intracellular pH value (pHi) were determined. The phosphomonoester (PME)/βNTP was higher in the more metastatic C8161 tumors (n=4) than in the less metastatic A375P tumors (n=4) (p < 0.1). No significant difference between the pHi of C8161 and A375P was observed.

Accurate prediction of tumor metastatic potential would be helpful in treatment planning and in the design of agents that modify the tumor phenotype. We report that three methods that are potentially transferable to the clinic – dynamic contrast enhanced MRI (DCE MRI), T(1ρ)-weighted imaging and low temperature fluorescence imaging (that could be performed on biopsy specimens) – distinguished between relatively indolent (A375P) and aggressive (C8161) metastatic human melanoma xenografts in nude mice, whereas T(1) and T(2) relaxation time measurements did not. DCE MRI data analyzed by the BOLus Enhanced Relaxation Overview (BOLERO) method in conjunction with concurrent measurements of the arterial input function yielded a blood transfer rate constant (K(trans)) which measures perfusion/permeability, that was significantly higher in the core of the indolent tumor than in the core of the aggressive tumor. Histological staining indicated that aggressive tumors had more blood vascular structure but fewer functional vascular structure than indolent tumors. Indolent tumors exhibited T(1ρ) values that were significantly higher than those of aggressive tumors at spin-locking frequencies >500Hz. The mitochondrial redox ratio, Fp/(Fp+NADH), where Fp and NADH are the fluorescence of oxidized flavoproteins and reduced pyridine nucleotides, respectively, of aggressive tumors was much higher (more oxidized) than that of indolent tumors and often showed a bimodal distribution with an oxidized core and a reduced rim. These differences observed between these two types of tumors, one indolent and one aggressive, if generalizable, would be very valuable in predicting human melanoma metastatic potential.

Clinical interest in hyperthermia as a safe and effective adjuvant to irradiation in cancer therapy continues to heighten. The review of experimental and clinical studies by Overgaard suggests that the optimal thermal enhancement ratio (TER) may be obtained by simultaneous administration of both modalities; however, an improvement in therapeutic ratio (tumor effect vs. skin effect) may be best attained by sequential administration of radiotherapy and hyperthermia and with sessions separated by intervals of three hours or longer. Most clinical studies have either administered the heat shortly before irradiation therapy (Kim et al., Marmor and Hahn, Manning et al.) or immediately after (Bicher et al., Perez et al., Arcangeli et al., and Luk).