Application of the multicellular tumour spheroid model to screen PET tracers for analysis of early response of chemotherapy in breast cancer

Monazzam, Azita; Josephsson, Raymond; Blomqvist, Carl; Carlsson, Jörgen; Långström, Bengt; Bergström, Mats

doi:10.1186/bcr1747

Cited by 29 publications

(28 citation statements)

References 19 publications

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“…Therefore, FLT uptake predominately reflects the fraction of proliferating cells. As has been reported frequently, docetaxel alone induced significant inhibition of [ 18 F]FLT uptake in tumor cells (41,42). Our study results (Fig.…”

Section: Discussionsupporting

confidence: 61%

PF-00477736 Mediates Checkpoint Kinase 1 Signaling Pathway and Potentiates Docetaxel-Induced Efficacy in Xenografts

Zhang¹,

Yan²,

Painter³

et al. 2009

Clinical Cancer Research

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Purpose: Checkpoint kinase 1 (Chk1) plays a critical role in the activation of mitotic spindle checkpoint and DNA damage checkpoint. We examined the preclinical use of the Chk1 inhibitor PF-00477736 as a docetaxel-sensitizing agent. Specifically, we investigated the correlation between PF-00477736^mediated modulation of biomarkers and the sensitization of docetaxel efficacy. Experimental Design: In vitro and in vivo studies using COLO205 and other cell lines were done to assess PF-00477736^induced enhancement of docetaxel efficacy and effects on associated biomarkers. Conclusions: Docetaxel triggers mitotic spindle checkpoint activation at low concentrations and activates both the DNA damage checkpoint and the spindle checkpoint at high concentrations. In combination with docetaxel, PF-00477736 abrogates the mitotic checkpoint, as well as the DNA damage checkpoint, and results in sensitization to docetaxel. Chk1inhibitor PF-00477736 offers a therapeutic potential for the enhancement of taxane therapy.

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Section: Discussionsupporting

confidence: 61%

PF-00477736 Mediates Checkpoint Kinase 1 Signaling Pathway and Potentiates Docetaxel-Induced Efficacy in Xenografts

Zhang¹,

Yan²,

Painter³

et al. 2009

Clinical Cancer Research

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“…Tam has been shown to decrease glycolysis [19,24,25] and inhibit GLUT 1 in vitro in tam-sensitive cells [19]. Previous studies have also shown a decrease in glycolysis after tam treatment by imaging FDG uptake [26,27]. Uptake of 2-NBDG significantly decreased after treatment in MCF7 cells, but did not change in the MDA-MB-435 cell line.…”

Section: Discussionmentioning

confidence: 96%

Uptake of 2-NBDG as a method to monitor therapy response in breast cancer cell lines

Millon

Ostrander

Brown

et al. 2010

Breast Cancer Res Treat

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This study quantifies uptake of a fluorescent glucose analog, (2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose) (2-NBDG), in a large panel of breast cancer cells and demonstrates potential to monitor changes in glycolysis caused by anticancer and endocrine therapies. Expressions of glucose transporter (GLUT 1) and hexokinase (HK I), which phosphorylates 2-NBDG, were measured via western blot in two normal mammary epithelial and eight breast cancer cell lines of varying biological subtype. Fluorescence intensity of each cell line labeled with 100 lM 2-NBDG for 20 min or unlabeled control was quantified. A subset of cancer cells was treated with anticancer and endocrine therapies, and 2-NBDG fluorescence changes were measured. Expression of GLUT 1 was necessary for uptake of 2-NBDG, as demonstrated by lack of 2-NBDG uptake in normal human mammary epithelial cells (HMECs). GLUT 1 expression and 2-NBDG uptake was ubiquitous among all breast cancer lines. Reduction and stimulation of 2-NBDG uptake was demonstrated by perturbation with anticancer agents, lonidamine (LND), and a-cyano-hydroxycinnamate (a-Cinn), respectively. LND directly inhibits HK and significantly reduced 2-NBDG fluorescence in a subset of two breast cancer cell lines. Conversely, when cells were treated with a-Cinn, a drug used to increase glycolysis, 2-NBDG uptake was increased. Furthermore, tamoxifen (tam), a common endocrine therapy, was administered to estrogen receptor positive and negative (ER?/-) breast cells and demonstrated a decreased 2-NBDG uptake in ER? cells, reflecting a decrease in glycolysis. Results indicate that 2-NBDG uptake can be used to measure changes in glycolysis and has potential for use in early drug development.

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“…We have therefore previously advocated an empiric approach, in which the appropriate PET tracer is selected on the basis of cellular uptake studies performed in a spheroid cell culture model (8,9). The model presented here is optimized for this type of in vitro work.…”

Section: Discussionmentioning

confidence: 99%

“…The first part of this concept is illustrated by studies performed in multicellular cell aggregates (i.e., spheroids) (5)(6)(7)(8)(9). This cell culture mode was selected because it mimics better the cellular physiology of in vivo tumors than do monolayer cells, allows an easy application of pulse treatment or drug exposure mimicking the in vivo exposure, allows follow-up of drug effects during a longer time span than do monolayer cells (typically days to weeks), is practical for evaluation of effects on growth, is practical for application of PET tracers, and allows an assessment of PET tracer uptake and an evaluation of secreted or tissue biomarkers in the same sample.…”

mentioning

confidence: 99%

Modeling Spheroid Growth, PET Tracer Uptake, and Treatment Effects of the Hsp90 Inhibitor NVP-AUY922

Bergström

Monazzam²,

Razifar³

et al. 2008

J Nucl Med

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For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drugdevelopment program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials. Methods: The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growthinhibitory effect was described mathematically by a combined E max and time course model fitted to the data. The model was then used to simulate a once-per-week treatment; in these experiments the uptake of the PET tracers 18 F-FDG and 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT) was determined at different doses and different time points. Results: A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of 18 F-FDG per viable tumor volume was minimally affected by the treatment, whereas the 18 F-FLT uptake decreased in correlation with the growth inhibition. Conclusion: The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. 18 F-FLT is a suitable tracer for the monitoring of effect, and the 18 F-FLT PET study might be performed within 3 d after dosing.

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Application of the multicellular tumour spheroid model to screen PET tracers for analysis of early response of chemotherapy in breast cancer

Cited by 29 publications

References 19 publications

PF-00477736 Mediates Checkpoint Kinase 1 Signaling Pathway and Potentiates Docetaxel-Induced Efficacy in Xenografts

PF-00477736 Mediates Checkpoint Kinase 1 Signaling Pathway and Potentiates Docetaxel-Induced Efficacy in Xenografts

Uptake of 2-NBDG as a method to monitor therapy response in breast cancer cell lines

Modeling Spheroid Growth, PET Tracer Uptake, and Treatment Effects of the Hsp90 Inhibitor NVP-AUY922

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