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Title: Preclinical evaluation of 18F-ML-10 to determine timing of apoptotic response to chemotherapy in solid tumors

Abstract

Here, we investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid ( 18F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment. As a result, treated mice demonstrated increased 18F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline ( P > .05); however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment ( P < .05), but no significant difference at 1 day posttreatment. In conclusion, 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has themore » potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.« less

Authors:
 [1];  [2];  [3];  [2];  [2];  [2];  [2];  [2];  [2]
  1. Univ. of Pittsburgh, Pittsburgh, PA (United States); Sisli Etfal Training and Research Hospital, Istanbul (Turkey)
  2. Univ. of Pittsburgh, Pittsburgh, PA (United States)
  3. Univ. of Pittsburgh, Pittsburgh, PA (United States); Istanbul Univ., Istanbul (Turkey)
Publication Date:
Research Org.:
Univ. of Pittsburgh, Pittsburgh, PA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1366738
Grant/Contract Number:
SC0008833
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Molecular Imaging
Additional Journal Information:
Journal Volume: 16; Journal ID: ISSN 1536-0121
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; molecular imaging; apoptosis; early response; 18F-ML-10; PET

Citation Formats

Demirci, Emre, Ahmed, Rafay, Ocak, Meltem, Latoche, Joseph, Radelet, April, DeBlasio, Nicole, Mason, N. Scott, Anderson, Carolyn J., and Mountz, James M.. Preclinical evaluation of 18F-ML-10 to determine timing of apoptotic response to chemotherapy in solid tumors. United States: N. p., 2017. Web. doi:10.1177/1536012116685941.
Demirci, Emre, Ahmed, Rafay, Ocak, Meltem, Latoche, Joseph, Radelet, April, DeBlasio, Nicole, Mason, N. Scott, Anderson, Carolyn J., & Mountz, James M.. Preclinical evaluation of 18F-ML-10 to determine timing of apoptotic response to chemotherapy in solid tumors. United States. doi:10.1177/1536012116685941.
Demirci, Emre, Ahmed, Rafay, Ocak, Meltem, Latoche, Joseph, Radelet, April, DeBlasio, Nicole, Mason, N. Scott, Anderson, Carolyn J., and Mountz, James M.. Tue . "Preclinical evaluation of 18F-ML-10 to determine timing of apoptotic response to chemotherapy in solid tumors". United States. doi:10.1177/1536012116685941. https://www.osti.gov/servlets/purl/1366738.
@article{osti_1366738,
title = {Preclinical evaluation of 18F-ML-10 to determine timing of apoptotic response to chemotherapy in solid tumors},
author = {Demirci, Emre and Ahmed, Rafay and Ocak, Meltem and Latoche, Joseph and Radelet, April and DeBlasio, Nicole and Mason, N. Scott and Anderson, Carolyn J. and Mountz, James M.},
abstractNote = {Here, we investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment. As a result, treated mice demonstrated increased 18F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline (P > .05); however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment (P < .05), but no significant difference at 1 day posttreatment. In conclusion, 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.},
doi = {10.1177/1536012116685941},
journal = {Molecular Imaging},
number = ,
volume = 16,
place = {United States},
year = {Tue Jan 10 00:00:00 EST 2017},
month = {Tue Jan 10 00:00:00 EST 2017}
}

Journal Article:
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  • Purpose: Several individual clinical and preclinical studies have shown the possibility of evaluating tumor hypoxia by using noninvasive positron emission tomography (PET). The current study compared 3 hypoxia PET tracers frequently used in the clinic, [{sup 18}F]FMISO, [{sup 18}F]FAZA, and [{sup 18}F]HX4, in a preclinical tumor model. Tracer uptake was evaluated for the optimal time point for imaging, tumor-to-blood ratios (TBR), spatial reproducibility, and sensitivity to oxygen modification. Methods and Materials: PET/computed tomography (CT) images of rhabdomyosarcoma R1-bearing WAG/Rij rats were acquired at multiple time points post injection (p.i.) with one of the hypoxia tracers. TBR values were calculated, andmore » reproducibility was investigated by voxel-to-voxel analysis, represented as correlation coefficients (R) or Dice similarity coefficient of the high-uptake volume. Tumor oxygen modifications were induced by exposure to either carbogen/nicotinamide treatment or 7% oxygen breathing. Results: TBR was stabilized and maximal at 2 hours p.i. for [{sup 18}F]FAZA (4.0 ± 0.5) and at 3 hours p.i. for [{sup 18}F]HX4 (7.2 ± 0.7), whereas [{sup 18}F]FMISO showed a constant increasing TBR (9.0 ± 0.8 at 6 hours p.i.). High spatial reproducibility was observed by voxel-to-voxel comparisons and Dice similarity coefficient calculations on the 30% highest uptake volume for both [{sup 18}F]FMISO (R = 0.86; Dice coefficient = 0.76) and [{sup 18}F]HX4 (R = 0.76; Dice coefficient = 0.70), whereas [{sup 18}F]FAZA was less reproducible (R = 0.52; Dice coefficient = 0.49). Modifying the hypoxic fraction resulted in enhanced mean standardized uptake values for both [{sup 18}F]HX4 and [{sup 18}F]FAZA upon 7% oxygen breathing. Only [{sup 18}F]FMISO uptake was found to be reversible upon exposure to nicotinamide and carbogen. Conclusions: This study indicates that each tracer has its own strengths and, depending on the question to be answered, a different tracer can be put forward.« less
  • In this paper, a novel 18F-labeled α,α-disubstituted amino acid-based tracer, 2-amino-5-[ 18F]fluoro-2-methylpentanoic acid ([ 18F]FAMPe), has been developed for brain tumor imaging with a longer alkyl side chain than previously reported compounds to increase brain availability via system L amino acid transport. Both enantiomers of [ 18F]FAMPe were obtained in good radiochemical yield (24–52% n = 8) and high radiochemical purity (>99%). In vitro uptake assays in mouse DBT gliomas cells revealed that ( S)-[ 18F]FAMPe enters cells partly via sodium-independent system L transporters and also via other nonsystem A transport systems including transporters that recognize glutamine. Biodistribution and smallmore » animal PET/CT studies in the mouse DBT model of glioblastoma showed that both ( R)- and ( S)-[ 18F]FAMPe have good tumor imaging properties with the ( S)-enantiomer providing higher tumor uptake and tumor to brain ratios. Finally, comparison of the SUVs showed that ( S)-[ 18F]FAMPe had higher tumor to brain ratios compared to ( S)-[ 18F]FET, a well-established system L substrate.« less
  • Purpose: To determine whether the response of human head and neck cancer xenografts to cisplatin (CIS) could be enhanced with 2-deoxy-D-glucose (2DG); whether 2-[{sup 18}F]-fluoro-2-deoxy-D-glucose (FDG) uptake correlated with responses to this drug combination; and whether 2DG would enhance CIS-induced radiosensitization. Methods and Materials: Clonogenic survival responses to CIS + 2DG were determined in FaDu and Cal-27 cells and reduced/oxidized glutathione levels were monitored as parameters indicative of oxidative stress. The efficacy of CIS + 2DG was determined in FaDu and Cal-27 xenografts, and FDG uptake was determined by using positron emission tomography. Results: Use of CIS + 2DG enhancedmore » cell killing of FaDu and Cal-27 cells compared with either drug alone while increasing the percentage of oxidized glutathione in vitro. Use of CIS + 2DG inhibited FaDu and Cal-27 tumor growth and increased disease-free survival compared with either drug alone. The Cal-27 tumors showed greater pretreatment FDG uptake and increased disease-free survival when treated with 2DG + CIS relative to FaDu tumors. Treatment with 2DG enhanced CIS-induced radiosensitization in FaDu tumor cells grown in vitro and in vivo and resulted in apparent cures in 50% of tumors. Conclusions: These results show the enhanced therapeutic efficacy of CIS + 2DG in human head and neck cancer cells in vitro and in vivo compared with either drug alone, as well as the potential for FDG uptake to predict tumor sensitivity to 2DG + CIS. These findings provide a strong rationale for evaluating 2DG + CIS in combined-modality head and neck cancer therapy with radiation in a clinical setting.« less
  • Hexane samples were irradiated from a Co/sup 60/ source at a small integral dose of 3 to l00 x l0/sup 18/ ev'/ml at a constant dose rate of 6.6 x l0/ sup 14/ ev/ml-sec. The gaseous radiolytic products (methane, ethane, ethylene, propane, propylene. butane, and butene-1) were determined by gaseous chromatography. The data were found to fit the relationship: lg P =lg k +lg D, that is, P = k D/sup a/, where P isthe yield of gaseous product and D is the dose. It was found that a(c/sub 1/ to c/sub 4/) = 0.92, a(c/sub 2/to c/sub 4/-the alkanes)more » =0.92 and a (c/sub 2/ to c/sub 4/- the alkenes) = 0.88. The difference in yields can be explained by hydrogenation of unsaturated compounds. The G yields (mols/l0O ev) for the gaseous hydrolytic products were found to be 0.4l for methane, 0.82 for ethane, 0.62 for ethylene, 0.68 for propane, 0.3l for propylene, 0.65 for butane, and 0.24 for butene-l. (TTT)« less