Abstract
Background: Pancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. Several mechanisms of resistance have been described, though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena. Methods: We examined the ability of cellular arginine depletion through treatment with PEG-ADI to alter in vitro and in vivo cytotoxicity of gemcitabine. The effect on levels of key regulators of gemcitabine efficacy (e.g. RRM2, hENT1, and dCK) were examined. Results: Combination of PEG-ADI and gemcitabine substantially increases growth arrest, leading to increased tumor response in vivo. PEG-ADI is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit M2 (RRM2) levels both in vivo and in vitro, which is associated with gemcitabine resistance. This mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on E2F-1 function, a transcriptional repressor of RRM2. Conclusion: The ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer.
| Original language | English (US) |
|---|---|
| Article number | 102 |
| Journal | Journal of Experimental and Clinical Cancer Research |
| Volume | 33 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2014 |
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Keywords
- Gemcitabine
- Pancreatic cancer
- PEG-ADI
- RRM2
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer. / Daylami, Rouzbeh; Muilenburg, Diego J.; Virudachalam, Subbulakshmi; Bold, Richard J.
In: Journal of Experimental and Clinical Cancer Research, Vol. 33, No. 1, 102, 2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer
AU - Daylami, Rouzbeh
AU - Muilenburg, Diego J.
AU - Virudachalam, Subbulakshmi
AU - Bold, Richard J
PY - 2014
Y1 - 2014
N2 - Background: Pancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. Several mechanisms of resistance have been described, though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena. Methods: We examined the ability of cellular arginine depletion through treatment with PEG-ADI to alter in vitro and in vivo cytotoxicity of gemcitabine. The effect on levels of key regulators of gemcitabine efficacy (e.g. RRM2, hENT1, and dCK) were examined. Results: Combination of PEG-ADI and gemcitabine substantially increases growth arrest, leading to increased tumor response in vivo. PEG-ADI is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit M2 (RRM2) levels both in vivo and in vitro, which is associated with gemcitabine resistance. This mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on E2F-1 function, a transcriptional repressor of RRM2. Conclusion: The ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer.
AB - Background: Pancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. Several mechanisms of resistance have been described, though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena. Methods: We examined the ability of cellular arginine depletion through treatment with PEG-ADI to alter in vitro and in vivo cytotoxicity of gemcitabine. The effect on levels of key regulators of gemcitabine efficacy (e.g. RRM2, hENT1, and dCK) were examined. Results: Combination of PEG-ADI and gemcitabine substantially increases growth arrest, leading to increased tumor response in vivo. PEG-ADI is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit M2 (RRM2) levels both in vivo and in vitro, which is associated with gemcitabine resistance. This mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on E2F-1 function, a transcriptional repressor of RRM2. Conclusion: The ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer.
KW - Gemcitabine
KW - Pancreatic cancer
KW - PEG-ADI
KW - RRM2
UR - http://www.scopus.com/inward/record.url?scp=84965191759&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84965191759&partnerID=8YFLogxK
U2 - 10.1186/s13046-014-0102-9
DO - 10.1186/s13046-014-0102-9
M3 - Article
VL - 33
JO - Journal of Experimental and Clinical Cancer Research
JF - Journal of Experimental and Clinical Cancer Research
SN - 0392-9078
IS - 1
M1 - 102
ER -