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Monazzam, Azita
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Publications (10 of 16) Show all publications
Monazzam, A., Lau, J., Velikyan, I., Li, S.-C., Razmara, M., Rosenström, U., . . . Skogseid, B. (2018). Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET. Scientific Reports, 8, Article ID 748.
Open this publication in new window or tab >>Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 748Article in journal (Refereed) Published
Abstract [en]

Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment. Glucagon-like peptide 1 (GLP-1) pathway is essential in islet regeneration, i.e. inhibition of β-cell apoptosis and enhancement of β-cell proliferation, yet involvement of GLP-1 in MEN1 related P-NET has not yet been demonstrated. The objective of this work was to investigate if normal sized islets of Men1 heterozygous mice have increased Glucagon-like peptide-1 receptor (GLP-1R) expression compared to wild type islets, and if this increase is detectable in vivo with positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 (68Ga-Exendin-4). 68Ga-Exendin-4 showed potential for early lesion detection in MEN1 pancreas due to increased GLP1R expression.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-342327 (URN)10.1038/s41598-017-18855-0 (DOI)000422637200007 ()29335487 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-28Bibliographically approved
Razmara, M., Monazzam, A. & Skogseid, B. (2018). Reduced menin expression impairs rapamycin effects as evidenced by an increase in mTORC2 signaling and cell migration. Cell Communication and Signaling, 16, Article ID 64.
Open this publication in new window or tab >>Reduced menin expression impairs rapamycin effects as evidenced by an increase in mTORC2 signaling and cell migration
2018 (English)In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 16, article id 64Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Mammalian target of rapamycin (mTOR) is a master regulator of various cellular responses by forming two functional complexes, mTORC1 and mTORC2. mTOR signaling is frequently dysregulated in pancreatic neuroendocrine tumors (PNETs). mTOR inhibitors have been used in attempts to treat these lesions, and prolonged progression free survival has been recorded. If this holds true also for the multiple endocrine neoplasia type 1 (MEN1) associated PNETs is yet unclear. We investigated the relationship between expression of the MEN1 protein menin and mTOR signaling in the presence or absence of the mTOR inhibitor rapamycin.

METHODS: In addition to use of menin wild type and menin-null mouse embryonic fibroblasts (MEFs), menin was silenced by siRNA in pancreatic neuroendocrine tumor cell line BON-1. Panels of protein phosphorylation, as activation markers downstream of PI3k-mTOR-Akt pathways, as well as menin expression were evaluated by immunoblotting. The impact of menin expression in the presence and absence of rapamycin was determinate upon Wound healing, migration and proliferation in MEFs and BON1 cells.

RESULTS: PDGF-BB markedly increased phosphorylation of mTORC2 substrate Akt, at serine 473 (S473) and threonine 450 (T450) in menin-/- MEFs but did not alter phosphorylation of mTORC1 substrates ribosomal protein S6 or eIF4B. Acute rapamycin treatment by mTORC1-S6 inhibition caused a greater enhancement of Akt phosphorylation on S473 in menin-/- cells as compared to menin+/+ MEFs (116% vs 38%). Chronic rapamycin treatment, which inhibits both mTORC1and 2, reduced Akt phosphorylation of S473 to a lesser extent in menin-/- MEFs than menin+/+ MEFs (25% vs 75%). Silencing of menin expression in human PNET cell line (BON1) also enhanced Akt phosphorylation at S473, but not activation of mTORC1. Interestingly, silencing menin in BON1 cells elevated S473 phosphorylation of Akt in both acute and chronic treatments with rapamycin. Finally, we show that the inhibitory effect of rapamycin on serum mediated wound healing and cell migration is impaired in menin-/- MEFs, as well as in menin-silenced BON1 cells.

CONCLUSIONS: Menin is involved in regulatory mechanism between the two mTOR complexes, and its reduced expression is accompanied with increased mTORC2-Akt signaling, which consequently impairs anti-migratory effect of rapamycin.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Akt, MEN1, PI3K, PNET, Rapamycin, mTOR
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-363616 (URN)10.1186/s12964-018-0278-2 (DOI)000446362600001 ()30285764 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014/895
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2018-12-03Bibliographically approved
Hall, H., Velikyan, I., Blom, E., Ulin, J., Monazzam, A., Påhlman, L., . . . Långström, B. (2012). In vitro autoradiography of carcinoembryonic antigen in tissue from patients with colorectal cancer using multifunctional antibody TF2 and 67/68Ga-labeled haptens by pretargeting. American journal of nuclear medicine and molecular imaging, 2(2), 141-150
Open this publication in new window or tab >>In vitro autoradiography of carcinoembryonic antigen in tissue from patients with colorectal cancer using multifunctional antibody TF2 and 67/68Ga-labeled haptens by pretargeting
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2012 (English)In: American journal of nuclear medicine and molecular imaging, ISSN 2160-8407, Vol. 2, no 2, p. 141-150Article in journal (Refereed) Published
Abstract [en]

The carcinoembryonic antigen (CEA) was visualized in vitro in tissue from patients with colorectal cancer with trivalent bispecific antibody TF2 and two hapten molecules, [67/68Ga]Ga-IMP461 and [67/68Ga]Ga-IMP485 by means of pretargeting. Colorectal cancer tissue samples obtained from surgery at Uppsala University Hospital, were frozen fresh and cryosectioned. The two hapten molecules comprising 1,4,7-triazacyclononanetriacetic acid chelate moiety (NOTA) were labeled with 67Ga or 68Ga. The autoradiography was conducted by incubating the tissue samples with the bispecific antibody TF2, followed by washing and incubation with one of the radiolabeled hapten molecules. After washing, drying and exposure to phosphor imager plates, the autoradiograms were analyzed and compared to standard histochemistry (hematoxylin-eosin). Pronounced binding was found in the tissue from colorectal cancer using the bispecific antibody TF2 and either of the haptens [67/68Ga]Ga-IMP461 and [67/68Ga]Ga-IMP485. Distinct binding was also detected in the epithelium of most samples of neighboring tissue, taken at a minimum of 10 cm from the site of the tumor. It is concluded that pretargeting CEA with the bispecific antibody TF2 followed by the addition of 67/68Ga-labeled hapten is extremely sensitive for visualizing this marker for colorectal cancer. This methodology is therefore a very specific complement to other histochemical techniques in the diagnosis of biopsies or in samples taken from surgery. Use of the pretargeting technique in vivo may also be an advance in diagnosing patients with colorectal cancer, either using 67Ga and SPECT or 68Ga and PET.

National Category
Medicinal Chemistry Pharmaceutical Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-188959 (URN)23133809 (PubMedID)
Available from: 2012-12-21 Created: 2012-12-21 Last updated: 2018-02-01Bibliographically approved
Blom, E., Velikyan, I., Monazzam, A., Razifar, P., Nair, M., Razifar, P., . . . Långström, B. (2011). Synthesis and characterization of scVEGF-PEG-[68Ga]NOTA and scVEGF-PEG-[68Ga]DOTA PET tracers. Journal of labelled compounds & radiopharmaceuticals, 54(11), 685-692
Open this publication in new window or tab >>Synthesis and characterization of scVEGF-PEG-[68Ga]NOTA and scVEGF-PEG-[68Ga]DOTA PET tracers
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2011 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 54, no 11, p. 685-692Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor (VEGF) signaling via vascular endothelial growth factor receptor 2 (VEGFR-2) on tumor endothelial cells is a critical driver of tumor angiogenesis. Novel anti-angiogenic drugs target VEGF/VEGFR-2 signaling and induce changes in VEGFR-2 prevalence. To monitor VEGFR-2 prevalence in the course of treatment, we are evaluating (68)Ga positron emission tomography imaging agents based on macrocyclic chelators, site-specifically conjugated via polyethylene glycol (PEG) linkers to engineered VEGFR-2 ligand, single-chain (sc) VEGF. The (68)Ga-labeling was performed at room temperature with NOTA (2,2', 2 ''-(1,4,7-triazonane-1,4,7-triyl) triacetic acid) conjugates or at 90 degrees C by using either conventional or microwave heating with NOTA and DOTA (2,2', 2 '', 2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl) tetraacetic acid) conjugates. The fastest (similar to 2min) and the highest incorporation (>90%) of (68)Ga into conjugate that resulted in the highest specific radioactivity (similar to 400MBq/nmol) was obtained with microwave heating of the conjugates. The bioactivity of the NOTA-and DOTA-containing tracers was validated in 3-D tissue culture model of 293/KDR cells engineered to express high levels of VEGFR-2. The NOTA-containing tracer also displayed a rapid accumulation (similar to 20s after intravenous injection) to steady-state level in xenograft tumor models. A combination of high specific radioactivity and maintenance of functional activity suggests that scVEGF-PEG-[(68)Ga] NOTA and scVEGF-PEG-[(68)Ga] DOTA might be promising tracers for monitoring VEGFR-2 prevalence and should be further explored.

Keywords
scVEGF, (68)Ga, radiolabeling, angiogenesis, VEGFR-2, PET
National Category
Organic Chemistry Medical Image Processing
Identifiers
urn:nbn:se:uu:diva-108589 (URN)10.1002/jlcr.1909 (DOI)000297987200001 ()
Available from: 2009-10-10 Created: 2009-09-23 Last updated: 2017-12-13Bibliographically approved
Åberg, O., Stevens, M., Lindh, J., Wallinder, C., Hall, H., Monazzam, A., . . . Långström, B. (2010). Synthesis and evaluation of a 11C-labelled angiotensin II AT2 receptor ligand. Journal of labelled compounds & radiopharmaceuticals, 53(10), 616-624
Open this publication in new window or tab >>Synthesis and evaluation of a 11C-labelled angiotensin II AT2 receptor ligand
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2010 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 53, no 10, p. 616-624Article in journal (Refereed) Published
Abstract [en]

Three C-11-radiolabelled high-affinity nonpeptide AT(2) receptor-selective ligands were synthesized and one of these was evaluated as positron emission tomography (PET) tracer. The labelling reaction was performed via palladium(0)-mediated aminocarbonylation of the aryl iodide substrate using [C-11] carbon monoxide as the labelled precursor. As an example, starting with 10.0 GBq [C-11] carbon monoxide, 1.10 GBq of the product N-butoxycarbonyl-3-[4-(N-benzyl-[C-11] carbamoyl)phenyl]-5-isobutylthiophene-2-sulphonamide [C-11]4d was obtained in 36% decay-corrected radiochemical yield (from [C-11] carbon monoxide), 42 min from end of bombardment with a specific activity of 110 GBq.mu mol(-1). The N-isopropyl-[C-11] carbamoyl-analogue [C-11]4c (radiochemical purity >95%) was studied employing autoradiography, organ distribution, and small animal PET. In vitro autoradiography showed specific binding in the pancreas and kidney. Organ distribution in six rats revealed a high uptake in the liver, intestine, kidney, and adrenals. Small animal PET showed rapid and reversible uptake in the kidneys followed by accumulation in the urinary bladder suggesting fast renal excretion of the tracer. In addition, high accumulation was also seen in the liver. For future studies, more metabolically stable tracers will need to be developed. To the best of our knowledge, this is the first attempt of the use of PET imaging for the detection of expressed, fully functional AT(2) receptors in living subjects.

Keywords
angiotensin II, AT2, PET, 11C, aminocarbonylation, [11C]carbon monoxide
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-98914 (URN)10.1002/jlcr.1793 (DOI)000282667600004 ()
Available from: 2009-03-05 Created: 2009-03-05 Last updated: 2017-12-13Bibliographically approved
Monazzam, A., Razifar, P., Ide, S., Rugaard Jensen, M., Josephsson, R., Blomqvist, C., . . . Bergström, M. (2009). Evaluation of the Hsp90 inhibitor NVP-AUY922 in multicellular tumour spheroids with respect to effects on growth and PET tracer uptake. Nuclear Medicine and Biology, 36(3), 335-342
Open this publication in new window or tab >>Evaluation of the Hsp90 inhibitor NVP-AUY922 in multicellular tumour spheroids with respect to effects on growth and PET tracer uptake
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2009 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 36, no 3, p. 335-342Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Molecular targeting has become a prominent concept in cancer treatment and heat shock protein 90 (Hsp90) inhibitors are suggested as promising anticancer drugs. The Hsp90 complex is one of the chaperones that facilitate the refolding of unfolded or misfolded proteins and plays a role for key oncogenic proteins such as Her2, Raf-1, Akt/PKB, and mutant p53. NVP-AUY922 is a novel low-molecular Hsp90 inhibitor, currently under clinical development as an anticancer drug. Disruption of the Hsp90-client protein complexes leads to proteasome-mediated degradation of client proteins and cell death. The aim of the current study was to use a combination of the multicellular tumour spheroid (MTS) model and positron emission tomography (PET) to investigate the effects of NVP-AUY922 on tumour growth and its relation to PET tracer uptake for the selection of appropriate PET tracer. A further aim was to evaluate the concentration and time dependence in the relation between growth inhibition and PET tracer uptake as part of translational imaging activities. METHODS: MTS of two breast cancer cell lines (MCF-7 and BT474), one glioblastoma cell line (U87MG) and one colon carcinoma cell line (HCT116) were prepared. Initially, we investigated MTS growth pattern and (3)H-thymidine incorporation in MTS after continuous exposure to NVP-AUY922 in order to determine dose response. Then the short-term effect of the drug on the four PET tracers 2-[(18)F] fluoro-2-deoxyglucose (FDG), 3'-deoxy-3'-fluorothymidine (FLT), methionine and choline was correlated to the long-term effect (changes in growth pattern) to determine the adequate PET tracer with high predictability. Next, the growth inhibitory effect of different dose schedules was evaluated to determine the optimal dose and time. Finally, the effect of a 2-h exposure to the drug on growth pattern and FDG/FLT uptake was evaluated. RESULTS: A dose-dependent inhibition of growth and decrease of (3)H-thymidine uptake was observed with 100% growth cessation in the dose range 7-52 nM and 50% (3)H-thymidine reduction in the range of 10-23 nM, with the most pronounced effect on BT474 cells. The effect of the drug was best detected by FLT. The results suggested that a complete cessation of growth of the viable cell volume was achieved with about 50% inhibition of FLT uptake 3 days after continuous treatment. Significant growth inhibition was observed at all doses and all exposure time spans. Two-hour exposure to NVP-AUY922 generated a growth inhibition which persisted dose dependently up to 10 days. The uptake of FDG per viable tumour volume was reduced by just 25% with 300 nM treatment of the drug, whereas the FLT uptake decreased up to 75% in correlation with the growth inhibition and recovery. CONCLUSIONS: Our results indicate a prolonged action of NVP-AUY922 in this cell culture, FLT is a suitable tracer for the monitoring of the effect and a FLT PET study within 3 days after treatment can predict the treatment outcome in this model. If relevant in vivo, this information can be used for efficient planning of animal PET studies and later human PET trial.

Keywords
Multicellular spheroids, Positron Emission Tomography, HSP90, Breast cancer, Growth inhibition
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-105530 (URN)10.1016/j.nucmedbio.2008.12.009 (DOI)000265130000012 ()19324279 (PubMedID)
Available from: 2009-06-04 Created: 2009-06-04 Last updated: 2017-12-13Bibliographically approved
Razifar, P., Hennings, J., Monazzam, A., Hellman, P., Långström, B. & Sundin, A. (2009). Masked volume wise Principal Component Analysis of small adrenocortical tumours in dynamic [11C]-metomidate Positron Emission Tomography. BMC Medical Imaging, 9:6
Open this publication in new window or tab >>Masked volume wise Principal Component Analysis of small adrenocortical tumours in dynamic [11C]-metomidate Positron Emission Tomography
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2009 (English)In: BMC Medical Imaging, ISSN 1471-2342, E-ISSN 1471-2342, Vol. 9:6Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In previous clinical Positron Emission Tomography (PET) studies novel approaches for application of Principal Component Analysis (PCA) on dynamic PET images such as Masked Volume Wise PCA (MVW-PCA) have been introduced. MVW-PCA was shown to be a feasible multivariate analysis technique, which, without modeling assumptions, could extract and separate organs and tissues with different kinetic behaviors into different principal components (MVW-PCs) and improve the image quality. METHODS: In this study, MVW-PCA was applied to 14 dynamic 11C-metomidate-PET (MTO-PET) examinations of 7 patients with small adrenocortical tumours. MTO-PET was performed before and 3 days after starting per oral cortisone treatment. The whole dataset, reconstructed by filtered back projection (FBP) 0-45 minutes after the tracer injection, was used to study the tracer pharmacokinetics. RESULTS: Early, intermediate and late pharmacokinetic phases could be isolated in this manner. The MVW-PC1 images correlated well to the conventionally summed image data (15-45 minutes) but the image noise in the former was considerably lower. PET measurements performed by defining "hot spot" regions of interest (ROIs) comprising 4 contiguous pixels with the highest radioactivity concentration showed a trend towards higher SUVs when the ROIs were outlined in the MVW-PC1 component than in the summed images. Time activity curves derived from "50% cut-off" ROIs based on an isocontour function whereby the pixels with SUVs between 50 to 100% of the highest radioactivity concentration were delineated, showed a significant decrease of the SUVs in normal adrenal glands and in adrenocortical adenomas after cortisone treatment. CONCLUSION: In addition to the clear decrease in image noise and the improved contrast between different structures with MVW-PCA, the results indicate that the definition of ROIs may be more accurate and precise in MVW-PC1 images than in conventional summed images. This might improve the precision of PET measurements, for instance in therapy monitoring as well as for delineation of the tumour in radiation therapy planning.

National Category
Radiology, Nuclear Medicine and Medical Imaging Medical Image Processing
Research subject
Computerized Image Analysis
Identifiers
urn:nbn:se:uu:diva-104646 (URN)10.1186/1471-2342-9-6 (DOI)19386097 (PubMedID)
Available from: 2009-04-22 Created: 2009-05-29 Last updated: 2017-12-13Bibliographically approved
Lendvai, G., Monazzam, A., Velikyan, I., Eriksson, B., Josephsson, R., Långström, B., . . . Estrada, S. (2009). Non-hybridisation saturable mechanisms play a role in the uptake of 68Ga-labelled LNA-DNA mixmer antisense oligonucleotides in rats. Oligonucleotides, 19(3), 223-231
Open this publication in new window or tab >>Non-hybridisation saturable mechanisms play a role in the uptake of 68Ga-labelled LNA-DNA mixmer antisense oligonucleotides in rats
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2009 (English)In: Oligonucleotides, ISSN 1545-4576 (Print), Vol. 19, no 3, p. 223-231Article in journal (Refereed) Published
Abstract [en]

Oligonucleotides (ODN) are key molecules for the aim of preventing   translation of a gene product or monitoring gene expression in tissues.   However, multiple methodological and biological hurdles need to be   solved before in vivo application in humans will be possible. For   positron emission tomography (PET) investigations, a 20-mer DNA-locked   nucleic acid (LNA) mixmer ODN specifi c for rat chromogranin-A mRNA was   labeled with Ga-68 and its uptake was examined in vivo in rats with and   without blocking of scavenger receptors by polyribo-nucleotides. In   addition, uptake studies of Ga-68-LNA were performed with respect to   time and concentration in human and rat cell lines. The human cell   lines did not express the target mRNA. Both polyinosinic acid (poly-I)   and polyadenylic acid (poly-A) reduced the uptake in rat tissues and in   human cell lines. Poly-I was found to be more effective in the liver   whereas poly-A was more effective in the kidney. In addition, the   blockade by poly-I was statistically significant in the pancreas,   adrenal gland, bone marrow, intestine, testis, urinary bladder, muscle,   parotid gland, and heart, whereas poly-A also caused significant   reduction in pancreas, adrenal gland, and bone marrow but not as much   as in kidney. Cell culture study showed a 2-phase dose-dependent uptake   characteristic with a saturable and a passive diffusion-like phase;   however, these 2 phases were not so well expressed in the rat cell   line. The results suggest that scavenger receptors or other saturable   processes unrelated to hybridization may be involved in the tissue   uptake of Ga-68-LNA and in the clearance of antisense ODN through the   liver, kidney, spleen, and bone marrow. The fact that these processes   may be sequence-dependent suggests that proof of in vivo hybridization   through imaging may not be obtained by only comparing sense and   antisense sequences and proving dose-dependency.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-96301 (URN)10.1089/oli.2009.0192 (DOI)000270785700002 ()
Available from: 2007-10-18 Created: 2007-10-18 Last updated: 2014-04-15Bibliographically approved
Bergström, M., Monazzam, A., Razifar, P., Ide, S., Josephsson, R. & Långström, B. (2008). Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922. Journal of Nuclear Medicine, 49(7), 1204-1210
Open this publication in new window or tab >>Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922
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2008 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 49, no 7, p. 1204-1210Article in journal (Refereed) Published
Abstract [en]

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 drug-development 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 growth-inhibitory 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 F-18-FDG and 3'-deoxy-3'-F-18-fluorothymidine (F-18-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 F-18-FDG per viable tumor volume was minimally affected by the treatment, whereas the F-18-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. F-18-FLT is a suitable tracer for the monitoring of effect, and the F-18-FLT PET study might be performed within 3 d after dosing.

Keywords
spheroids, antitumoral treatment, modeling, FLT, Hsp90
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-109984 (URN)10.2967/jnumed.108.050799 (DOI)000257599700029 ()18552146 (PubMedID)
Available from: 2009-11-02 Created: 2009-11-02 Last updated: 2017-12-12Bibliographically approved
Monazzam, A., Josephsson, R., Blomqvist, C., Carlsson, J., Långström, B. & Bergström, M. (2007). Application of the multicellular tumour spheroid model to screen PET tracers for analysis of early response of chemotherapy in breast cancer. Breast Cancer Research, 9(4), R45
Open this publication in new window or tab >>Application of the multicellular tumour spheroid model to screen PET tracers for analysis of early response of chemotherapy in breast cancer
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2007 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 9, no 4, p. R45-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.

Keywords
Cancer, Tumor, Radiation, Therapy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-96170 (URN)10.1186/bcr1747 (DOI)000250883100013 ()17659092 (PubMedID)
Available from: 2007-09-12 Created: 2007-09-12 Last updated: 2017-12-14Bibliographically approved
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