Radiosensitization of pancreatic cancer cells by 2′,2′-difluoro-2′-deoxycytidine

Lawrence, Theodore S.; Chang, Eun-Ha; Hahn, Tina M.; Hertel, Larry W.; Shewach, Donna S.

doi:10.1016/0360-3016(95)02134-5

Cited by 282 publications

(146 citation statements)

References 20 publications

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“…In this study, both dFdCTP accumulation and dATP depletion paralleled DNA synthesis inhibition. Similar data were reported in BxPC-3 and Panc-1 pancreatic carcinoma cell lines (Lawrence et al, 1996). However, it has been shown recently that dFdC has no effect on the radiation response of a human D54 glioblastoma cell line, although intracellular dATP depletion was decreased by more than 90% (Ostruszka, 1997).…”

supporting

confidence: 75%

“…In various cell lines, radiosensitization for cell lethality has been reported, with dose modification factors ranging from 1.2 to 3.0 depending on the cell lines, drug concentration and timing of administration (Rockwell, 1992;Mullen et al, 1994;Shewach et al, 1994;Lawrence et al, 1995Lawrence et al, , 1996Gregoire et al, 1996;Rosier et al 1997]. In vivo radiosensitization has also been reported in a murine sarcoma with regrowth delay enhancements in the range of 1.1-2.0, depending on the schedule of drug administration in relation to irradiation (Hittelman et al, 1996).…”

mentioning

confidence: 99%

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Kinetics of mouse jejunum radiosensitization by 2',2'-difluorodeoxycytidine (gemcitabine) and its relationship with pharmacodynamics of DNA synthesis inhibition and cell cycle redistribution in crypt cells

Grégoire

Beauduin²,

Rosier³

et al. 1997

Br J Cancer

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Summary Gemcitabine (dFdC), a deoxycitidine nucleoside analogue, inhibits DNA synthesis and repair of radiation-induced chromosome breaks in vitro, radiosensitizes various human and mouse cells in vitro and shows clinical activity in several tumours. Limited data are however available on the effect of dFdC on normal tissue radiotolerance and on factors associated with dFdC's radiosensitization in vivo. The purpose of this study was to determine the effect of dFdC on mouse jejunum radiosensitization and to investigate the kinetics of DNA synthesis inhibition and cell cycle redistribution in the jejunal crypts as surrogates of radiosensitization in vivo. For assessment of jejunum tolerance, the mice were irradiated on the whole body with 6OCo gamma rays (3.5-18 Gy single dose) with or without prior administration of dFdC (150 mg kg-'). Jejunum tolerance was evaluated by the number of regenerated crypts per circumference at 86 h after irradiation. For pharmacodynamic studies, dFdC (150 or 600 mg kg-') was given i.p. and jejunum was harvested at various times (0-48 h), preceded by a pulse BrdUrd labelling. Labelled cells were detected by immunohistochemistry on paraffin-embedded sections. DNA synthesis was inhibited within 3 h after dFdC administration. After an early wave of apoptosis (3-6 h), DNA synthesis recovered by 6 h, and crypt cells became synchronized. At 48 h, the labelling index returned almost to background level. At a level of 40 regenerated crypts, radiosensitization was observed for a 3 h time interval (dose modification factor of 1.3) and was associated with DNA synthesis inhibition, whereas a slight radioprotection was observed for a 48-h time interval (dose modification factor of 0.9) when DNA synthesis has reinitiated. In conclusion, dFdC altered the radioresponse of the mouse jejunum in a schedule-dependent fashion. Our data tend to support the hypothesis that DNA synthesis inhibition and cell cycle redistribution are surrogates for radiosensitization. More data points are however required before a definite conclusion can be drawn.

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supporting

confidence: 75%

mentioning

confidence: 99%

Kinetics of mouse jejunum radiosensitization by 2',2'-difluorodeoxycytidine (gemcitabine) and its relationship with pharmacodynamics of DNA synthesis inhibition and cell cycle redistribution in crypt cells

Grégoire

Beauduin²,

Rosier³

et al. 1997

Br J Cancer

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“…Based on these results, gemcitabine is generally accepted as a standard chemotherapy agent. In addition, it reportedly radiosensitizes human tumor cells in culture, particularly cells derived from carcinomas of the pancreas, breast, and head and neck 28,29 and there have been studies of gemcitabine chemoradiotherapy. 30 -32 In Phase I trials of dose escalation of gemcitabine with concurrent radiotherapy, gemcitabine was administered at doses of only 40 -90 mg/m 2 twice weekly and 300 -500 mg/m 2 weekly because of GI and hematologic toxicity.…”

Section: Figurementioning

confidence: 99%

Intraoperative and conformal external‐beam radiation therapy with protracted 5‐fluorouracil infusion in patients with locally advanced pancreatic carcinoma

Furuse

Kinoshita

Kawashima

et al. 2003

Cancer

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“…The clinical primacy of gemcitabine [31] in APC has led to preclinical studies with human pancreatic and colon cancer cell lines that have shown its potency as a powerful radiosensitizer [32,33]. Phase I trials of gemcitabine with 50.4 Gy of radiation given in 1.8-Gy fractions established dose-limiting hematologic and gastrointestinal toxicities at a dose of 700 mg/m 2 weekly.…”

Section: Combining Chemotherapy With Radiotherapymentioning

confidence: 99%

Chemoradiation in Pancreatic Adenocarcinoma: A Literature Review

Roy

Maraveyas

2010

The Oncologist

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Adenocarcinoma of the exocrine pancreas has an annual incidence of 7,400 cases in the U.K. In comparison with other common cancers of solid organs, namely, breast, colorectal, and prostate cancer, pancreatic cancer has a high morbidity and mortality. Radical resection is possible in only 15%-20% of patients, and only 3%-4% of all patients presenting with this condition achieve long-term control and cure. Various strategies in the form of neoadjuvant and adjuvant treatment have been employed over the years to improve outcome, with limited success. Systemic chemotherapy remains the gold standard in the metastatic setting in good performance status patients, and adjuvant chemotherapy after resection of localized and locally advanced cancer has been found to improve outcome. The role of radiotherapy, however, remains controversial and is an area that merits further investigation in well-conducted multicenter trials at various stages of the disease in combination with systemic agents and exploiting recent advances in the delivery of radiotherapy. In this article, we review the published literature on the use of chemoradiation as a modality in various stages of pancreatic adenocarcinoma and highlight areas that future trials in this field should target for a way forward in this malignancy. The Oncologist 2010;15:259 -269

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Radiosensitization of pancreatic cancer cells by 2′,2′-difluoro-2′-deoxycytidine

Cited by 282 publications

References 20 publications

Kinetics of mouse jejunum radiosensitization by 2',2'-difluorodeoxycytidine (gemcitabine) and its relationship with pharmacodynamics of DNA synthesis inhibition and cell cycle redistribution in crypt cells

Kinetics of mouse jejunum radiosensitization by 2',2'-difluorodeoxycytidine (gemcitabine) and its relationship with pharmacodynamics of DNA synthesis inhibition and cell cycle redistribution in crypt cells

Intraoperative and conformal external‐beam radiation therapy with protracted 5‐fluorouracil infusion in patients with locally advanced pancreatic carcinoma

Chemoradiation in Pancreatic Adenocarcinoma: A Literature Review

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