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Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy.

van Asten JJ, Vettukattil R, Buckle T, Rottenberg S, van Leeuwen F, Bathen TF, Heerschap A - J Transl Med (2015)

Bottom Line: The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples.Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel.Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Sjaak.vanAsten@radboudumc.nl.

ABSTRACT

Background: Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer.

Methodology: High resolution magic angle spinning (HRMAS) (1)H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25 mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6 ppm.

Results: The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6 ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation.

Conclusions: Relative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

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Related in: MedlinePlus

Principal Component Analysis (PCA) biplots[42]of the sensitive (A) and resistant (B) strains of mouse models. Plots show the differences in the metabolic profiles depending on the number of days after the administration of docetaxel. The sensitive strain shows distinct clusters based on the number of days after treatment (A) while the resistant strain does not (B) show such clusters.
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Fig3: Principal Component Analysis (PCA) biplots[42]of the sensitive (A) and resistant (B) strains of mouse models. Plots show the differences in the metabolic profiles depending on the number of days after the administration of docetaxel. The sensitive strain shows distinct clusters based on the number of days after treatment (A) while the resistant strain does not (B) show such clusters.

Mentions: As previously reported, tumor growth after docetaxel treatment significantly decreased in the sensitive tumors, and TUNEL staining showed a significant increase of apoptotic cells in these tumors with the highest increase at day 1-2, while this was not the case in the resistant tumors [15]. The biopsies from sensitive and resistant strains were evaluated separately by principal component analysis. PCA score plots of the sensitive strains (Figure 3A) showed a trend towards clustering based on the post treatment interval. The metabolic profiles of sensitive tumor samples obtained within 48 hours of treatment were characterized by higher levels of PCho compared to untreated controls. At 3-5 days post treatment, samples contained higher amounts of lactate, but for samples obtained at 6-7 days post treatment there was no difference with pre-treatment and 1-2 day post treatment groups. PCA of the resistant strain showed no tendency toward clustering based on the post treatment intervals (Figure 3B).Figure 3


Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy.

van Asten JJ, Vettukattil R, Buckle T, Rottenberg S, van Leeuwen F, Bathen TF, Heerschap A - J Transl Med (2015)

Principal Component Analysis (PCA) biplots[42]of the sensitive (A) and resistant (B) strains of mouse models. Plots show the differences in the metabolic profiles depending on the number of days after the administration of docetaxel. The sensitive strain shows distinct clusters based on the number of days after treatment (A) while the resistant strain does not (B) show such clusters.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4404119&req=5

Fig3: Principal Component Analysis (PCA) biplots[42]of the sensitive (A) and resistant (B) strains of mouse models. Plots show the differences in the metabolic profiles depending on the number of days after the administration of docetaxel. The sensitive strain shows distinct clusters based on the number of days after treatment (A) while the resistant strain does not (B) show such clusters.
Mentions: As previously reported, tumor growth after docetaxel treatment significantly decreased in the sensitive tumors, and TUNEL staining showed a significant increase of apoptotic cells in these tumors with the highest increase at day 1-2, while this was not the case in the resistant tumors [15]. The biopsies from sensitive and resistant strains were evaluated separately by principal component analysis. PCA score plots of the sensitive strains (Figure 3A) showed a trend towards clustering based on the post treatment interval. The metabolic profiles of sensitive tumor samples obtained within 48 hours of treatment were characterized by higher levels of PCho compared to untreated controls. At 3-5 days post treatment, samples contained higher amounts of lactate, but for samples obtained at 6-7 days post treatment there was no difference with pre-treatment and 1-2 day post treatment groups. PCA of the resistant strain showed no tendency toward clustering based on the post treatment intervals (Figure 3B).Figure 3

Bottom Line: The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples.Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel.Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Sjaak.vanAsten@radboudumc.nl.

ABSTRACT

Background: Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer.

Methodology: High resolution magic angle spinning (HRMAS) (1)H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25 mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6 ppm.

Results: The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6 ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation.

Conclusions: Relative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

Show MeSH
Related in: MedlinePlus