Tumor retention of 5-fluorouracil following irradiation observed using 19F nuclear magnetic resonance spectroscopy

A. William Blackstock; Lester Kwock; Craig Branch; Elaine M. Zeman; Joel E. Tepper

doi:10.1016/S0360-3016(96)00356-2

Tumor retention of 5-fluorouracil following irradiation observed using ¹⁹F nuclear magnetic resonance spectroscopy

A. William Blackstock, Lester Kwock, Craig Branch, Elaine M. Zeman, Joel E. Tepper

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Purpose: The combination of 5-fluorouracil (5FU) and radiation results in improved tumor control in a variety of gastrointestinal cancers. We propose the enhancement is related to radiation potentiating the antitumor effects of 5FU. To better understand the mechanism of the 5FU-radiation interaction, ¹⁹F nuclear magnetic resonance (NMR) spectroscopy experiments were performed to observed the tumor clearance and metabolism of 5FU. Methods and Materials: Experiments were performed on 10 3-6-week-old female (Nu/Nu) athymic nude mice. Flank tumors measuring approximately 1.0 cm in diameter 3 weeks following a subcutaneous injection of 1 x 10⁶ human colon adenocarcinoma (HT-29) cells were studied. In our first group, all animals received an intravenous bolus injection of 5FU (100 mg/kg) immediately before spectroscopic analysis. Animals in the second group were first treated with a single tumor radiation dose of 10 Gy just before the 5FU injection and subsequent spectroscopy. Spectroscopic analysis was performed with a 2.0-T NMR spectroscopy system. Results: The tumor retention of 5FU was prolonged in animals receiving radiation before the drug infusion. The tumor clearance rate of the 5FU for nonirradiated animals was 0.0178 ± 0.0082/min vs. 0.0055 ± 0.0027/min for irradiated animals, reflecting a threefold reduction in drug clearance in the irradiated tumors. The difference was significant alp < 0.005. Conclusion: Our preliminary experiments suggest the enhanced cytotoxicity seen with concurrent 5FU and radiation is related to prolonged tumor retention of 5FU induced by radiation. This is consistent with the hypothesis that radiation is potentiating the cytotoxic effects of 5FU.

Original language	English (US)
Pages (from-to)	641-648
Number of pages	8
Journal	International Journal of Radiation Oncology Biology Physics
Volume	36
Issue number	3
DOIs	https://doi.org/10.1016/S0360-3016(96)00356-2
State	Published - Oct 1 1996
Externally published	Yes

Keywords

5-Fluorouracil
F
NMR spectroscopy

ASJC Scopus subject areas

Radiation
Oncology
Radiology Nuclear Medicine and imaging
Cancer Research

UN SDGs

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

Access to Document

10.1016/S0360-3016(96)00356-2

Cite this

@article{6c299f4367bd45e7a37b279ab13eb7e6,

title = "Tumor retention of 5-fluorouracil following irradiation observed using 19F nuclear magnetic resonance spectroscopy",

abstract = "Purpose: The combination of 5-fluorouracil (5FU) and radiation results in improved tumor control in a variety of gastrointestinal cancers. We propose the enhancement is related to radiation potentiating the antitumor effects of 5FU. To better understand the mechanism of the 5FU-radiation interaction, 19F nuclear magnetic resonance (NMR) spectroscopy experiments were performed to observed the tumor clearance and metabolism of 5FU. Methods and Materials: Experiments were performed on 10 3-6-week-old female (Nu/Nu) athymic nude mice. Flank tumors measuring approximately 1.0 cm in diameter 3 weeks following a subcutaneous injection of 1 x 106 human colon adenocarcinoma (HT-29) cells were studied. In our first group, all animals received an intravenous bolus injection of 5FU (100 mg/kg) immediately before spectroscopic analysis. Animals in the second group were first treated with a single tumor radiation dose of 10 Gy just before the 5FU injection and subsequent spectroscopy. Spectroscopic analysis was performed with a 2.0-T NMR spectroscopy system. Results: The tumor retention of 5FU was prolonged in animals receiving radiation before the drug infusion. The tumor clearance rate of the 5FU for nonirradiated animals was 0.0178 ± 0.0082/min vs. 0.0055 ± 0.0027/min for irradiated animals, reflecting a threefold reduction in drug clearance in the irradiated tumors. The difference was significant alp < 0.005. Conclusion: Our preliminary experiments suggest the enhanced cytotoxicity seen with concurrent 5FU and radiation is related to prolonged tumor retention of 5FU induced by radiation. This is consistent with the hypothesis that radiation is potentiating the cytotoxic effects of 5FU.",

keywords = "5-Fluorouracil, F, NMR spectroscopy",

author = "Blackstock, {A. William} and Lester Kwock and Craig Branch and Zeman, {Elaine M.} and Tepper, {Joel E.}",

note = "Funding Information: Several hypotheses have been suggested to explain this interaction. It has been postulated that 5FU interferes with the repair of sublethal radiation damage, perhaps secondary to the incorporation of the fluorinated pyrimidine into DNA (8). Prior experiments performed by Byfield et al., however, did not support this proposed mechanism (5). Miller and Kinsella noted that cells exposed to the 5FU derivative 5-fluoro-2{\textquoteright}-deoxyuridine (FUdR) were arrested in early S-phase of the cell cycle for up to 48 h, suggesting that the mechanism of the interaction was related to cell synchrony (18). Yet, in further investigation using centrifugal elutriation to obtain populations enriched in various phases of the cell cycle, the cells revealed no difference in radiation sensitivity as a function of cell age (26). A third hypothesis is that radiation sensitization depends toral candidate in the UNC Department of English, for editorial support. This study was supported in part by NIH Grant NC1 ROI CA 39633 (L.K.) and the American Cancer Society. Accepted for publication 5 July 1996.",

year = "1996",

month = oct,

day = "1",

doi = "10.1016/S0360-3016(96)00356-2",

language = "English (US)",

volume = "36",

pages = "641--648",

journal = "International Journal of Radiation Oncology Biology Physics",

issn = "0360-3016",

publisher = "Elsevier Inc.",

number = "3",

}

TY - JOUR

T1 - Tumor retention of 5-fluorouracil following irradiation observed using 19F nuclear magnetic resonance spectroscopy

AU - Blackstock, A. William

AU - Kwock, Lester

AU - Branch, Craig

AU - Zeman, Elaine M.

AU - Tepper, Joel E.

N1 - Funding Information: Several hypotheses have been suggested to explain this interaction. It has been postulated that 5FU interferes with the repair of sublethal radiation damage, perhaps secondary to the incorporation of the fluorinated pyrimidine into DNA (8). Prior experiments performed by Byfield et al., however, did not support this proposed mechanism (5). Miller and Kinsella noted that cells exposed to the 5FU derivative 5-fluoro-2’-deoxyuridine (FUdR) were arrested in early S-phase of the cell cycle for up to 48 h, suggesting that the mechanism of the interaction was related to cell synchrony (18). Yet, in further investigation using centrifugal elutriation to obtain populations enriched in various phases of the cell cycle, the cells revealed no difference in radiation sensitivity as a function of cell age (26). A third hypothesis is that radiation sensitization depends toral candidate in the UNC Department of English, for editorial support. This study was supported in part by NIH Grant NC1 ROI CA 39633 (L.K.) and the American Cancer Society. Accepted for publication 5 July 1996.

PY - 1996/10/1

Y1 - 1996/10/1

N2 - Purpose: The combination of 5-fluorouracil (5FU) and radiation results in improved tumor control in a variety of gastrointestinal cancers. We propose the enhancement is related to radiation potentiating the antitumor effects of 5FU. To better understand the mechanism of the 5FU-radiation interaction, 19F nuclear magnetic resonance (NMR) spectroscopy experiments were performed to observed the tumor clearance and metabolism of 5FU. Methods and Materials: Experiments were performed on 10 3-6-week-old female (Nu/Nu) athymic nude mice. Flank tumors measuring approximately 1.0 cm in diameter 3 weeks following a subcutaneous injection of 1 x 106 human colon adenocarcinoma (HT-29) cells were studied. In our first group, all animals received an intravenous bolus injection of 5FU (100 mg/kg) immediately before spectroscopic analysis. Animals in the second group were first treated with a single tumor radiation dose of 10 Gy just before the 5FU injection and subsequent spectroscopy. Spectroscopic analysis was performed with a 2.0-T NMR spectroscopy system. Results: The tumor retention of 5FU was prolonged in animals receiving radiation before the drug infusion. The tumor clearance rate of the 5FU for nonirradiated animals was 0.0178 ± 0.0082/min vs. 0.0055 ± 0.0027/min for irradiated animals, reflecting a threefold reduction in drug clearance in the irradiated tumors. The difference was significant alp < 0.005. Conclusion: Our preliminary experiments suggest the enhanced cytotoxicity seen with concurrent 5FU and radiation is related to prolonged tumor retention of 5FU induced by radiation. This is consistent with the hypothesis that radiation is potentiating the cytotoxic effects of 5FU.

AB - Purpose: The combination of 5-fluorouracil (5FU) and radiation results in improved tumor control in a variety of gastrointestinal cancers. We propose the enhancement is related to radiation potentiating the antitumor effects of 5FU. To better understand the mechanism of the 5FU-radiation interaction, 19F nuclear magnetic resonance (NMR) spectroscopy experiments were performed to observed the tumor clearance and metabolism of 5FU. Methods and Materials: Experiments were performed on 10 3-6-week-old female (Nu/Nu) athymic nude mice. Flank tumors measuring approximately 1.0 cm in diameter 3 weeks following a subcutaneous injection of 1 x 106 human colon adenocarcinoma (HT-29) cells were studied. In our first group, all animals received an intravenous bolus injection of 5FU (100 mg/kg) immediately before spectroscopic analysis. Animals in the second group were first treated with a single tumor radiation dose of 10 Gy just before the 5FU injection and subsequent spectroscopy. Spectroscopic analysis was performed with a 2.0-T NMR spectroscopy system. Results: The tumor retention of 5FU was prolonged in animals receiving radiation before the drug infusion. The tumor clearance rate of the 5FU for nonirradiated animals was 0.0178 ± 0.0082/min vs. 0.0055 ± 0.0027/min for irradiated animals, reflecting a threefold reduction in drug clearance in the irradiated tumors. The difference was significant alp < 0.005. Conclusion: Our preliminary experiments suggest the enhanced cytotoxicity seen with concurrent 5FU and radiation is related to prolonged tumor retention of 5FU induced by radiation. This is consistent with the hypothesis that radiation is potentiating the cytotoxic effects of 5FU.

KW - 5-Fluorouracil

KW - F

KW - NMR spectroscopy

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M3 - Article

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JO - International Journal of Radiation Oncology Biology Physics

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