Tumor lactate content predicts for response to fractionated irradiation of human squamous cell carcinomas in nude mice - ScienceDirect

Radiotherapy and Oncology

Volume 81, Issue 2, November 2006, Pages 130-135

Radiotherapy and Oncology

https://doi.org/10.1016/j.radonc.2006.08.012 Get rights and content

Abstract

Background and purpose

The present study was performed to test the hypothesis that lactate accumulation correlates with the radioresistance of malignant tumors due to the radical scavenging capacity of lactate or metabolic intermediates of glycolysis, such as pyruvate.

Materials and methods

Five human head and neck squamous cell carcinoma cell lines (HNSCCs) xenografted in nude mice were treated with a clinically relevant irradiation protocol with 30 fractions within 6 weeks. The radiation dose necessary to locally control 50% of the tumors (TCD₅₀) ranged from 47.4 to 129.8 Gy. Concentrations of glucose, lactate, and ATP in viable tumor regions as potential indicators of glycolytic activity were assessed with structure-associated quantitative bioluminescence imaging.

Results

Mean lactate concentrations of the different tumor cell lines were in the range of 7.3–25.9 μmol/g. TCD₅₀ values were positively correlated with tumor lactate levels (R = 0.9824, p = 0.0028).

Conclusions

The data obtained support the hypothesis that tissue lactate content correlates with radioresistance in solid human tumors. Furthermore, the results suggest that tumor lactate content determined non-invasively by proton magnetic resonance spectroscopy imaging may be used to predict for radioresistance of malignancies in the clinic; the data also imply that transient inhibition of glycolysis during treatment might possibly sensitize tumors to irradiation.

Section snippets

Animals and tumor models

The study was performed using five lines of human squamous cell carcinomas (HNSCC) of the head and neck region xenografted in nude mice. Details of the animals, tumor lines and the local tumor control assay are described in Yaromina et al., this issue. In brief, tumors were transplanted subcutaneously into the right hind leg of nude mice whole body irradiated with 4 Gy (200 kV X-rays, 0.5 mm Cu filter) 2 days before transplantation. Tumors were either excised for histological studies and

Results

The process of structure-associated metabolic imaging is illustrated by Fig. 1 showing sequential cryosections through a human HNSCC (UT-SCC-15) xenograft representing the color-coded concentration distribution of lactate (a), the anti-mouse staining (b) and the hematoxylin and eosin (H&E) staining (c). The anti-mouse staining allows for an unequivocal discrimination between the human tumor xenograft (unstained) and the host murine tissue (dark brown staining). Using interactive image analysis,

Discussion

Structure-associated and quantitative metabolic imaging with bioluminescence is a unique technology for the assessment of quantitative information regarding the metabolic status of selected tissue areas. This is important for studies on solid tumors, since most cancers are heterogeneous containing viable tumor regions, more or less extended necrosis, stromal elements and a variable proportion of infiltrated immune cells. The current study has been focussed on the interaction between radiation

Acknowledgements

The authors thank Mrs. E. Wenzel, Mrs. S. Balschukat, Mrs. D. Pfitzmann, Mrs. K. Schumann and Mrs. M. Oelsner for excellent technical assistance.

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^☆: Financial support: This investigation was supported by grants of the Deutsche Forschungsgemeinschaft to W.M.K. (Mu 576/14-1) and to M.B. and D.Z. (Ba 1433/4-2).

¹: Shared first authorship.

²: Shared senior authorship.

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