Changes in 2-fluoro-2-deoxy-D-glucose incorporation, hexokinase activity and lactate production by breast cancer cells responding to treatment with the anti-HER-2 antibody trastuzumab

Richard, W. Cheyne, Laurent Alain Claude Trembleau, Abbie McLaughlin, Timothy Andrew Davies Smith

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Abstract

Changes in 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) incorporation by tumors, detected using positron emission tomography, during response to chemotherapy are utilized clinically in patient management. Here, the effect of treatment with growth-inhibitory doses of the anti-human epidermal growth factor receptor-2 antibody trastuzumab (Herceptin) on the incorporation of FDG by breast tumor cells was measured along with hexokinase (HK) and glucose transport to determine the potential of FDG-positron emission tomography in predicting response to these biological anti-cancer therapies and their modulatory effects on the steps involved in FDG incorporation. Methods: The sensitivity to trastuzumab of three breast tumor cell lines, SKBr3, MDA-MB-453 and MDA-MB-468, expressing human epidermal growth factor receptor-2 at high, medium and low levels, respectively, was determined using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay over a 6-day period, and a clonogenic assay was carried out after 7- and 10-day exposures. FDG incorporation by cells treated with growth-inhibitory doses of trastuzumab was carried out after 4 h and 2, 4 and 6 days of treatment. Glucose transport (rate of uptake of the non-metabolizable analogue [3H]O-methyl-d-glucose), HK activity and lactate production were measured on cells treated with inhibitory doses of trastuzumab for 6 days. Results: The IC50 doses for SKBr3 and MDA-MB-453 and the IC20 dose for MDA-MB-468 after 6 days of treatment with trastuzumab were 0.25, 1 and 170 µg/ml, respectively. FDG incorporation by SKBr3 and MDA-MB-453 cells was found to be decreased using IC50 doses of trastuzumab for 6 days. At the IC50 doses, FDG incorporation was also decreased at 4 days and, in the case of MDA-MB-453, even after 4 h of treatment. Decreased FDG incorporation corresponded with decreased HK activity in these cells. Lactate production, previously suggested to be a potential measure of response, was found to be significantly decreased by SKBr3 and MDA-MB-453 cells responding to trastuzumab. Conclusion: FDG incorporation at the tumor cell level is modulated by treatment with growth-inhibitory doses of trastuzumab due to modulation of HK activity. Changes in lactate production may also be a useful determinant of response to trastuzumab. © 2010 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)339-346
Number of pages8
JournalNuclear Medicine and Biology
Volume38
Issue number3
Early online date3 Dec 2010
DOIs
Publication statusPublished - Apr 2011

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Hexokinase
Fluorodeoxyglucose F18
Lactic Acid
Breast Neoplasms
Glucose
Antibodies
Therapeutics
Inhibitory Concentration 50
Positron-Emission Tomography
Trastuzumab
Growth
Neoplasms
Tumor Cell Line

Keywords

  • Trastuzumab
  • FDG
  • PET
  • Hexokinase
  • Lactate

Cite this

@article{37e3f3730ff649a0907ad1f73a384c37,
title = "Changes in 2-fluoro-2-deoxy-D-glucose incorporation, hexokinase activity and lactate production by breast cancer cells responding to treatment with the anti-HER-2 antibody trastuzumab",
abstract = "Changes in 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) incorporation by tumors, detected using positron emission tomography, during response to chemotherapy are utilized clinically in patient management. Here, the effect of treatment with growth-inhibitory doses of the anti-human epidermal growth factor receptor-2 antibody trastuzumab (Herceptin) on the incorporation of FDG by breast tumor cells was measured along with hexokinase (HK) and glucose transport to determine the potential of FDG-positron emission tomography in predicting response to these biological anti-cancer therapies and their modulatory effects on the steps involved in FDG incorporation. Methods: The sensitivity to trastuzumab of three breast tumor cell lines, SKBr3, MDA-MB-453 and MDA-MB-468, expressing human epidermal growth factor receptor-2 at high, medium and low levels, respectively, was determined using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay over a 6-day period, and a clonogenic assay was carried out after 7- and 10-day exposures. FDG incorporation by cells treated with growth-inhibitory doses of trastuzumab was carried out after 4 h and 2, 4 and 6 days of treatment. Glucose transport (rate of uptake of the non-metabolizable analogue [3H]O-methyl-d-glucose), HK activity and lactate production were measured on cells treated with inhibitory doses of trastuzumab for 6 days. Results: The IC50 doses for SKBr3 and MDA-MB-453 and the IC20 dose for MDA-MB-468 after 6 days of treatment with trastuzumab were 0.25, 1 and 170 µg/ml, respectively. FDG incorporation by SKBr3 and MDA-MB-453 cells was found to be decreased using IC50 doses of trastuzumab for 6 days. At the IC50 doses, FDG incorporation was also decreased at 4 days and, in the case of MDA-MB-453, even after 4 h of treatment. Decreased FDG incorporation corresponded with decreased HK activity in these cells. Lactate production, previously suggested to be a potential measure of response, was found to be significantly decreased by SKBr3 and MDA-MB-453 cells responding to trastuzumab. Conclusion: FDG incorporation at the tumor cell level is modulated by treatment with growth-inhibitory doses of trastuzumab due to modulation of HK activity. Changes in lactate production may also be a useful determinant of response to trastuzumab. {\circledC} 2010 Elsevier Inc. All rights reserved.",
keywords = "Trastuzumab, FDG, PET, Hexokinase, Lactate",
author = "Cheyne, {Richard, W.} and Trembleau, {Laurent Alain Claude} and Abbie McLaughlin and Smith, {Timothy Andrew Davies}",
year = "2011",
month = "4",
doi = "10.1016/j.nucmedbio.2010.09.005",
language = "English",
volume = "38",
pages = "339--346",
journal = "Nuclear Medicine and Biology",
issn = "0969-8051",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Changes in 2-fluoro-2-deoxy-D-glucose incorporation, hexokinase activity and lactate production by breast cancer cells responding to treatment with the anti-HER-2 antibody trastuzumab

AU - Cheyne, Richard, W.

AU - Trembleau, Laurent Alain Claude

AU - McLaughlin, Abbie

AU - Smith, Timothy Andrew Davies

PY - 2011/4

Y1 - 2011/4

N2 - Changes in 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) incorporation by tumors, detected using positron emission tomography, during response to chemotherapy are utilized clinically in patient management. Here, the effect of treatment with growth-inhibitory doses of the anti-human epidermal growth factor receptor-2 antibody trastuzumab (Herceptin) on the incorporation of FDG by breast tumor cells was measured along with hexokinase (HK) and glucose transport to determine the potential of FDG-positron emission tomography in predicting response to these biological anti-cancer therapies and their modulatory effects on the steps involved in FDG incorporation. Methods: The sensitivity to trastuzumab of three breast tumor cell lines, SKBr3, MDA-MB-453 and MDA-MB-468, expressing human epidermal growth factor receptor-2 at high, medium and low levels, respectively, was determined using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay over a 6-day period, and a clonogenic assay was carried out after 7- and 10-day exposures. FDG incorporation by cells treated with growth-inhibitory doses of trastuzumab was carried out after 4 h and 2, 4 and 6 days of treatment. Glucose transport (rate of uptake of the non-metabolizable analogue [3H]O-methyl-d-glucose), HK activity and lactate production were measured on cells treated with inhibitory doses of trastuzumab for 6 days. Results: The IC50 doses for SKBr3 and MDA-MB-453 and the IC20 dose for MDA-MB-468 after 6 days of treatment with trastuzumab were 0.25, 1 and 170 µg/ml, respectively. FDG incorporation by SKBr3 and MDA-MB-453 cells was found to be decreased using IC50 doses of trastuzumab for 6 days. At the IC50 doses, FDG incorporation was also decreased at 4 days and, in the case of MDA-MB-453, even after 4 h of treatment. Decreased FDG incorporation corresponded with decreased HK activity in these cells. Lactate production, previously suggested to be a potential measure of response, was found to be significantly decreased by SKBr3 and MDA-MB-453 cells responding to trastuzumab. Conclusion: FDG incorporation at the tumor cell level is modulated by treatment with growth-inhibitory doses of trastuzumab due to modulation of HK activity. Changes in lactate production may also be a useful determinant of response to trastuzumab. © 2010 Elsevier Inc. All rights reserved.

AB - Changes in 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) incorporation by tumors, detected using positron emission tomography, during response to chemotherapy are utilized clinically in patient management. Here, the effect of treatment with growth-inhibitory doses of the anti-human epidermal growth factor receptor-2 antibody trastuzumab (Herceptin) on the incorporation of FDG by breast tumor cells was measured along with hexokinase (HK) and glucose transport to determine the potential of FDG-positron emission tomography in predicting response to these biological anti-cancer therapies and their modulatory effects on the steps involved in FDG incorporation. Methods: The sensitivity to trastuzumab of three breast tumor cell lines, SKBr3, MDA-MB-453 and MDA-MB-468, expressing human epidermal growth factor receptor-2 at high, medium and low levels, respectively, was determined using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay over a 6-day period, and a clonogenic assay was carried out after 7- and 10-day exposures. FDG incorporation by cells treated with growth-inhibitory doses of trastuzumab was carried out after 4 h and 2, 4 and 6 days of treatment. Glucose transport (rate of uptake of the non-metabolizable analogue [3H]O-methyl-d-glucose), HK activity and lactate production were measured on cells treated with inhibitory doses of trastuzumab for 6 days. Results: The IC50 doses for SKBr3 and MDA-MB-453 and the IC20 dose for MDA-MB-468 after 6 days of treatment with trastuzumab were 0.25, 1 and 170 µg/ml, respectively. FDG incorporation by SKBr3 and MDA-MB-453 cells was found to be decreased using IC50 doses of trastuzumab for 6 days. At the IC50 doses, FDG incorporation was also decreased at 4 days and, in the case of MDA-MB-453, even after 4 h of treatment. Decreased FDG incorporation corresponded with decreased HK activity in these cells. Lactate production, previously suggested to be a potential measure of response, was found to be significantly decreased by SKBr3 and MDA-MB-453 cells responding to trastuzumab. Conclusion: FDG incorporation at the tumor cell level is modulated by treatment with growth-inhibitory doses of trastuzumab due to modulation of HK activity. Changes in lactate production may also be a useful determinant of response to trastuzumab. © 2010 Elsevier Inc. All rights reserved.

KW - Trastuzumab

KW - FDG

KW - PET

KW - Hexokinase

KW - Lactate

U2 - 10.1016/j.nucmedbio.2010.09.005

DO - 10.1016/j.nucmedbio.2010.09.005

M3 - Article

VL - 38

SP - 339

EP - 346

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

SN - 0969-8051

IS - 3

ER -