Early detection of response to experimental chemotherapeutic Top216 with [18F]FLT and [18F]FDG PET in human ovary cancer xenografts in mice

Mette Munk Jensen; Kamille Dumong Erichsen; Fredrik Björkling; Jacob Madsen; Peter Buhl Jensen; Liselotte Højgaard; Maxwell Sehested; Andreas Kjær

doi:10.1371/journal.pone.0012965

Early detection of response to experimental chemotherapeutic Top216 with [¹⁸F]FLT and [¹⁸F]FDG PET in human ovary cancer xenografts in mice

Mette Munk Jensen, Kamille Dumong Erichsen, Fredrik Björkling, Jacob Madsen, Peter Buhl Jensen, Liselotte Højgaard, Maxwell Sehested, Andreas Kjær

35 Citations (Scopus)

Abstract

Background:3'-deoxy-3'-[¹⁸F]fluorothymidine (¹⁸F-FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use ¹⁸F-FLT positron emission tomography (PET) to study treatment responses to a new anti-cancer compound. To do so, we studied early anti-proliferative effects of the experimental chemotherapy Top216 non-invasively by PET. Methodology/Principal Findings:In vivo uptake of ¹⁸F-FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after Top216 treatment (50 mg/kg i.v. at 0 and 48 hours) was initiated. Baseline ¹⁸F-FLT scans were made before either Top216 (n = 7-10) or vehicle (n = 5-7) was injected and repeated after 2 and 6 hours and 1 and 5 days of treatment. A parallel study was made with 2'-deoxy-2'-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) (n = 8). Tracer uptake was quantified using small animal PET/CT. Imaging results were validated by tumor volume changes and gene-expression of Ki67 and TK1. Top216 (50 mg/kg 0 and 48 hours) inhibited the growth of the A2780 tumor compared to the control group (P<0.001). ¹⁸F-FLT uptake decreased significantly at 2 hours (-52%; P<0.001), 6 hours (-49%; P = 0.002) and Day 1 (-47%; P<0.001) after Top216 treatment. At Day 5 18F-FLT uptake was comparable to uptake in the control group. Uptake of 18F-FLT was unchanged in the control group during the experiment. In the treatment group, uptake of 18F-FDG was significantly decreased at 6 hours (-21%; P = 0.003), Day 1 (-29%; P<0.001) and Day 5 (-19%; P = 0.05) compared to baseline. Conclusions/Significance:One injection with Top216 initiated a fast and significant decrease in cell-proliferation assessable by ¹⁸F-FLT after 2 hours. The early reductions in tumor cell proliferation preceded changes in tumor size. Our data indicate that ¹⁸F-FLT PET is promising for the early non-invasive assessment of chemotherapy effects in both drug development and for tailoring therapy in patients.

Original language	English
Journal	P L o S One
Volume	5
Issue number	9
Pages (from-to)	e12965
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0012965
Publication status	Published - 1 Jan 2010

Keywords

Animals
Antineoplastic Agents
Cell Proliferation
Dideoxynucleosides
Disease Models, Animal
Drug Monitoring
Female
Fluorodeoxyglucose F18
Humans
Mice
Mice, Nude
Ovarian Neoplasms
Positron-Emission Tomography
Radiopharmaceuticals
Xenograft Model Antitumor Assays

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pone.0012965

Cite this

@article{146a30aed92c4965bccb29126f50c239,

title = "Early detection of response to experimental chemotherapeutic Top216 with [18F]FLT and [18F]FDG PET in human ovary cancer xenografts in mice",

abstract = "Background:3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use 18F-FLT positron emission tomography (PET) to study treatment responses to a new anti-cancer compound. To do so, we studied early anti-proliferative effects of the experimental chemotherapy Top216 non-invasively by PET. Methodology/Principal Findings:In vivo uptake of 18F-FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after Top216 treatment (50 mg/kg i.v. at 0 and 48 hours) was initiated. Baseline 18F-FLT scans were made before either Top216 (n = 7-10) or vehicle (n = 5-7) was injected and repeated after 2 and 6 hours and 1 and 5 days of treatment. A parallel study was made with 2'-deoxy-2'-[18F]fluoro-D-glucose (18F-FDG) (n = 8). Tracer uptake was quantified using small animal PET/CT. Imaging results were validated by tumor volume changes and gene-expression of Ki67 and TK1. Top216 (50 mg/kg 0 and 48 hours) inhibited the growth of the A2780 tumor compared to the control group (P<0.001). 18F-FLT uptake decreased significantly at 2 hours (-52%; P<0.001), 6 hours (-49%; P = 0.002) and Day 1 (-47%; P<0.001) after Top216 treatment. At Day 5 18F-FLT uptake was comparable to uptake in the control group. Uptake of 18F-FLT was unchanged in the control group during the experiment. In the treatment group, uptake of 18F-FDG was significantly decreased at 6 hours (-21%; P = 0.003), Day 1 (-29%; P<0.001) and Day 5 (-19%; P = 0.05) compared to baseline. Conclusions/Significance:One injection with Top216 initiated a fast and significant decrease in cell-proliferation assessable by 18F-FLT after 2 hours. The early reductions in tumor cell proliferation preceded changes in tumor size. Our data indicate that 18F-FLT PET is promising for the early non-invasive assessment of chemotherapy effects in both drug development and for tailoring therapy in patients.",

keywords = "Animals, Antineoplastic Agents, Cell Proliferation, Dideoxynucleosides, Disease Models, Animal, Drug Monitoring, Female, Fluorodeoxyglucose F18, Humans, Mice, Mice, Nude, Ovarian Neoplasms, Positron-Emission Tomography, Radiopharmaceuticals, Xenograft Model Antitumor Assays",

author = "Jensen, {Mette Munk} and Erichsen, {Kamille Dumong} and Fredrik Bj{\"o}rkling and Jacob Madsen and Jensen, {Peter Buhl} and Liselotte H{\o}jgaard and Maxwell Sehested and Andreas Kj{\ae}r",

year = "2010",

month = jan,

day = "1",

doi = "10.1371/journal.pone.0012965",

language = "English",

volume = "5",

pages = "e12965",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "9",

}

TY - JOUR

T1 - Early detection of response to experimental chemotherapeutic Top216 with [18F]FLT and [18F]FDG PET in human ovary cancer xenografts in mice

AU - Jensen, Mette Munk

AU - Erichsen, Kamille Dumong

AU - Björkling, Fredrik

AU - Madsen, Jacob

AU - Jensen, Peter Buhl

AU - Højgaard, Liselotte

AU - Sehested, Maxwell

AU - Kjær, Andreas

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Background:3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use 18F-FLT positron emission tomography (PET) to study treatment responses to a new anti-cancer compound. To do so, we studied early anti-proliferative effects of the experimental chemotherapy Top216 non-invasively by PET. Methodology/Principal Findings:In vivo uptake of 18F-FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after Top216 treatment (50 mg/kg i.v. at 0 and 48 hours) was initiated. Baseline 18F-FLT scans were made before either Top216 (n = 7-10) or vehicle (n = 5-7) was injected and repeated after 2 and 6 hours and 1 and 5 days of treatment. A parallel study was made with 2'-deoxy-2'-[18F]fluoro-D-glucose (18F-FDG) (n = 8). Tracer uptake was quantified using small animal PET/CT. Imaging results were validated by tumor volume changes and gene-expression of Ki67 and TK1. Top216 (50 mg/kg 0 and 48 hours) inhibited the growth of the A2780 tumor compared to the control group (P<0.001). 18F-FLT uptake decreased significantly at 2 hours (-52%; P<0.001), 6 hours (-49%; P = 0.002) and Day 1 (-47%; P<0.001) after Top216 treatment. At Day 5 18F-FLT uptake was comparable to uptake in the control group. Uptake of 18F-FLT was unchanged in the control group during the experiment. In the treatment group, uptake of 18F-FDG was significantly decreased at 6 hours (-21%; P = 0.003), Day 1 (-29%; P<0.001) and Day 5 (-19%; P = 0.05) compared to baseline. Conclusions/Significance:One injection with Top216 initiated a fast and significant decrease in cell-proliferation assessable by 18F-FLT after 2 hours. The early reductions in tumor cell proliferation preceded changes in tumor size. Our data indicate that 18F-FLT PET is promising for the early non-invasive assessment of chemotherapy effects in both drug development and for tailoring therapy in patients.

AB - Background:3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use 18F-FLT positron emission tomography (PET) to study treatment responses to a new anti-cancer compound. To do so, we studied early anti-proliferative effects of the experimental chemotherapy Top216 non-invasively by PET. Methodology/Principal Findings:In vivo uptake of 18F-FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after Top216 treatment (50 mg/kg i.v. at 0 and 48 hours) was initiated. Baseline 18F-FLT scans were made before either Top216 (n = 7-10) or vehicle (n = 5-7) was injected and repeated after 2 and 6 hours and 1 and 5 days of treatment. A parallel study was made with 2'-deoxy-2'-[18F]fluoro-D-glucose (18F-FDG) (n = 8). Tracer uptake was quantified using small animal PET/CT. Imaging results were validated by tumor volume changes and gene-expression of Ki67 and TK1. Top216 (50 mg/kg 0 and 48 hours) inhibited the growth of the A2780 tumor compared to the control group (P<0.001). 18F-FLT uptake decreased significantly at 2 hours (-52%; P<0.001), 6 hours (-49%; P = 0.002) and Day 1 (-47%; P<0.001) after Top216 treatment. At Day 5 18F-FLT uptake was comparable to uptake in the control group. Uptake of 18F-FLT was unchanged in the control group during the experiment. In the treatment group, uptake of 18F-FDG was significantly decreased at 6 hours (-21%; P = 0.003), Day 1 (-29%; P<0.001) and Day 5 (-19%; P = 0.05) compared to baseline. Conclusions/Significance:One injection with Top216 initiated a fast and significant decrease in cell-proliferation assessable by 18F-FLT after 2 hours. The early reductions in tumor cell proliferation preceded changes in tumor size. Our data indicate that 18F-FLT PET is promising for the early non-invasive assessment of chemotherapy effects in both drug development and for tailoring therapy in patients.

KW - Animals

KW - Antineoplastic Agents

KW - Cell Proliferation

KW - Dideoxynucleosides

KW - Disease Models, Animal

KW - Drug Monitoring

KW - Female

KW - Fluorodeoxyglucose F18

KW - Humans

KW - Mice

KW - Mice, Nude

KW - Ovarian Neoplasms

KW - Positron-Emission Tomography

KW - Radiopharmaceuticals

KW - Xenograft Model Antitumor Assays

U2 - 10.1371/journal.pone.0012965

DO - 10.1371/journal.pone.0012965

M3 - Journal article

C2 - 20885974

SN - 1932-6203

VL - 5

SP - e12965

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 9

ER -