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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. (Bröstgruppen)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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2007 (English)In: Breast Cancer Research, ISSN 1465-542X, Vol. 9, no 4, R45- p.Article in journal (Refereed) Published
Abstract [en]

Introduction

Positron emission tomography (PET) is suggested for early monitoring of treatment response, assuming that effective anticancer treatment induces metabolic changes that precede morphology alterations and changes in growth. The aim of this study was to introduce multicellular tumour spheroids (MTS) to study the effect of anticancer drugs and suggest an appropriate PET tracer for further studies.

Methods

MTS of the breast cancer cell line MCF7 were exposed to doxorubicin, paclitaxel, docetaxel, tamoxifen or imatinib for 7 days for growth pattern studies and for 3 or 5 days for PET tracer studies. The effect on growth was computed using the semi-automated size determination method (SASDM). The effect on the uptake of PET tracers [18F]3'-deoxy-3'-fluorothymidine (FLT), [1-11C]acetate (ACE), [11C]choline (CHO), [11C]methionine (MET), and 2-[18F]fluoro-2-deoxyglucose (FDG) was calculated in form of uptake/viable volume of the MTS at the end of the drug exposures, and finally the uptake was related to effects on growth rate.

Results

The drugs paclitaxel, docetaxel and doxorubicin gave severe growth inhibition, which correlated well with inhibition of the FLT uptake. FLT had, compared with ACE, CHO, MET and FDG, higher sensitivity in monitoring the therapy effects.

Conclusion

SASDM provides an effective, user-friendly, time-saving and accurate method to record the growth pattern of the MTS, and also to calculate the effect of the drug on PET tracer uptake. This study demonstrate the use of MTS and SASDM in combination with PET tracers as a promising approach to probe and select PET tracer for treatment monitoring of anticancer drugs and that can hopefully be applied for optimisation in breast cancer treatment.

Place, publisher, year, edition, pages
2007. Vol. 9, no 4, R45- p.
Keyword [en]
Cancer, Tumor, Radiation, Therapy
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96170DOI: 10.1186/bcr1747ISI: 000250883100013PubMedID: 17659092OAI: oai:DiVA.org:uu-96170DiVA: diva2:170655
Available from: 2007-09-12 Created: 2007-09-12 Last updated: 2014-04-15Bibliographically approved
In thesis
1. Multicellular Tumour Spheroids in a Translational PET Imaging Strategy
Open this publication in new window or tab >>Multicellular Tumour Spheroids in a Translational PET Imaging Strategy
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Positron Emission Tomography (PET) has gained an important roll in clinical for diagnosis, staging and prognosis of a range of cancer types. Utilization of PET for monitoring and evaluation of cancer treatment is an attractive but almost new concept. The proper choice of PET-tracer as a biomarker for treatment follow-up is crucial. The important characteristic for a suitable tracer is its ability to reflect the response to a treatment at an early stage, before any morphologically changes occurs. It would be an advantage to screen a battery of PET tracers in a preclinical model and introduce a few potential tracers in clinical trial.

The most conventional pre-clinical approach in PET-oncology utilizes xenografts in mice or rats and requires a large number of subjects. It would be a great advantage to introduce a less demanding but still reliable preclinical method for a more efficient planning of studies in animal model and then in human trials.

The Multicellular Tumour Spheroid (MTS) system represents an intermediary level between cells growing as monolayer and solid tumours in experimental animals or patients. It mimics the growth of naturally occurring human tumours before neovascularization and appears to be more informative than monolayer and more economical and more ethical than animal models.

The aim of this work was to establish, refine and evaluate the application of MTS model as a preclinical approach in PET oncology. The vision was to introduce a preclinical method to probe and select PET tracer for treatment monitoring of anticancer drugs, which can hopefully be applied for optimization in breast cancer treatment.

In this thesis, a number of basic experiments were performed to explore the character of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) uptake in MTS. FDG as the most established PET tracer was an obvious initial option for the evaluation of the model. For further assess-ment, we studied effects on FDG uptake in MTS treated with five routinely used chemother-apy agents. For association of PET tracer uptake to size change of MTS, we developed a reliable and user-friendly method for size determination of MTS. The next step was to apply the MTS model to screen PET tracers for analysis of early response of chemotherapy in breast cancer. Finally the method was utilized for translational imaging exemplified with a new chemotherapy agent.

The results were encouraging and the MTS model was introduced and evaluated as a preclini-cal tool in PET oncology. The method was implicated to in vitro quickly assess a therapy profile of existing and newly developed anticancer drugs in order to investigate the effects of candidate drugs on tumour-growth, selection of appropriate PET tracer for treatment monitor-ing and finally understanding relation between growth inhibition and biomarkers as part of translational imaging activities.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 273
Keyword
Oncology, Positron Emission Tomography, Multicellular Tumour Spheroid, Translational Research, Onkologi
Identifiers
urn:nbn:se:uu:diva-8196 (URN)978-91-554-6959-7 (ISBN)
Public defence
2007-10-05, IX, Universitetshuset, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-09-12 Created: 2007-09-12 Last updated: 2013-06-10Bibliographically approved

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Monazzam, AzitaBlomqvist, CarlCarlsson, Jörgen

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