[Show abstract][Hide abstract] ABSTRACT: High pretreatment tumor lactate content is associated with poor outcome after fractionated irradiation in human squamous cell carcinoma (hSCC) xenografts. Therefore, decreasing lactate content might be a promising approach for increasing tumor radiosensitivity. As the basis for such experiments, the effects of the biochemical inhibitors pyruvate dehydrogenase kinase dichloroacetate (DCA), lactate dehydrogenase oxamate, and monocarboxylic acid transporter-1 α-cyano-4-hydroxycinnamate (CHC) on tumor micromilieu and growth were investigated.
Oxygen consumption (OCR) and extracellular acidification rates (ECAR) were measured in FaDu and UT-SCC-5 hSCC in response to DCA in vitro. Mice bearing FaDu, UT-SCC-5, and WiDr colorectal adenocarcinoma received either DCA in drinking water or DCA injected twice a day, or CHC injected daily. WiDr was also treated daily with oxamate. FaDu and UT-SCC-5 were either excised 8 days after treatment for histology or tumor growth was monitored. WiDr tumors were excised at 8 mm. Effect of inhibitors on ATP, lactate, hypoxia, and Ki67 labeling index (LI) was evaluated.
DCA increased OCR and decreased ECAR in vitro. None of the treatments with inhibitors significantly changed lactate content, hypoxia levels, and Ki67 LI in the three tumor lines in vivo. ATP concentration significantly decreased after only daily twice injections of DCA in FaDu accompanied by a significant increase in necrotic fraction. Tumor growth was not affected by any of the treatments.
Overall, tumor micromilieu and tumor growth could not be changed by glycolysis modifiers in the three tumor cell lines in vivo. Further studies are necessary to explore the impact of metabolic targets on radiation response.
Strahlentherapie und Onkologie 02/2012; 188(5):431-7. DOI:10.1007/s00066-011-0054-3 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bone marrow derived CD11b+ myelomonocytes have been shown to be recruited by the tumour and to promote tumour regrowth after irradiation. Here we investigated in a panel of well characterised hSCC tumour models the number of tumour-infiltrating CD11b+ cells and the association with response to clinically relevant fractionated irradiation.
Six hSCC tumour models (UT-SCC-5, -14, -15, XF354, FaDu, SAS) xenografted in nude mice were excised after injection of pimonidazole hypoxia marker before irradiation and after 5 and 10 fractions. In parallel, TCD(50) (dose to cure 50% of the tumours) assays were performed to determine the response to 30 fractions within 6 weeks. The TCD(50) values have been previously published . Double staining of CD11b and pimonidazole was performed using immunofluorescence. CD11b+ cells were counted in viable pimonidazole-negative areas (non-hypoxic) and pimonidazole-positive areas (hypoxic) of whole tumour cross-sections.
The median number of tumour-infiltrating CD11b+ cells either decreased or remained unchanged after 5 and 10 fractions in most of the tumour models. The density of CD11b+ cells in hypoxic areas was similar or lower than in non-hypoxic regions independently on treatment in majority of the tumour models. After 10 fractions the median CD11b+ cell density was significantly associated with the TCD(50) values after 30 fractions.
The data from our exploratory study suggest that tumour-infiltrating CD11b+ cells may contribute to local tumour control after fractionated irradiation, which supports to further study their prognostic value and to evaluate specific myelomonocyte targeting strategies to overcome radiation resistance.
Radiotherapy and Oncology 07/2011; 101(1):80-5. DOI:10.1016/j.radonc.2011.05.054 · 4.36 Impact Factor