Abstract
[1-13C]pyruvate, the most widely used compound in dissolution-dynamic nuclear polarization (dDNP) magnetic resonance (MR), enables the visualization of lactate dehydrogenase (LDH) activity. This activity had been demonstrated in a wide variety of cancer models, ranging from cultured cells, to xenograft models, to human tumors in situ. Here we quantified the LDH activity in precision cut tumor slices (PCTS) of breast cancer xenografts. The Michigan Cancer Foundation-7 (MCF7) cell-line was chosen as a model for the luminal breast cancer type which is hormone responsive and is highly prevalent. The LDH activity, which was manifested as [1-13C]lactate production in the tumor slices, ranged between 3.8 and 6.1 nmole/nmole adenosine tri-phosphate (ATP) in 1 min (average 4.6 ± 1.0) on three different experimental set-ups consisting of arrested vs. continuous perfusion and non-selective and selective RF pulsation schemes and combinations thereof. This rate was converted to an expected LDH activity in a mass ranging between 3.3 and 5.2 µmole/g in 1 min, using the ATP level of these tumors. This indicated the likely utility of this approach in clinical dDNP of the human breast and may be useful as guidance for treatment response assessment in a large number of tumor types and therapies ex vivo.
Highlights
It is recognized that the varying clinicopathological phenotype of breast malignancy closely parallels at least four intrinsic molecular subtypes: luminal A, luminal B, HER2 positive with estrogen receptor negative disease, and triple negative disease [1]
We have developed a new model consisting of viable precision-cut tissue slices of a xenograft tumor
With regard to tissues that cannot be perfused ex vivo via their own vasculature, we have recently developed a dissolution-dynamic nuclear polarization (dDNP)-magnetic resonance (MR) set-up for precision cut tissue slices [51,52]
Summary
It is recognized that the varying clinicopathological phenotype of breast malignancy closely parallels at least four intrinsic molecular subtypes: luminal A, luminal B, HER2 positive with estrogen receptor negative disease, and triple negative disease [1]. These parameters influence treatment choices, such as anti-hormonal therapy for luminal A and B or specific antibody treatment for Her 2 positive cancers. A and B is largely based on tumor biology as currently defined by immunohistochemistry, multigene testing plays a role in categorizing the two as well [2] These characterizations further influence treatment choices, as it is in these patients that uncertainty about optimal treatment most commonly arises, as clinicians seek to avoid over- or under-treatment [3].
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