Cell cycle effect of gemcitabine and its role in the radiosensitizing mechanism in vitro

Pauwels, Bea; Korst, A.E.C.; Pattyn, G; Lambrechts, Hilde; Bockstaele, Dirk R. Van; Vermeulen, Katrien; Lenjou, Marc; Pooter, Christel M J De; Vermorken, Jan B.; Lardon, Filip

doi:10.1016/s0360-3016(03)01443-3

Cited by 66 publications

(56 citation statements)

References 28 publications

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“…Mechanisms of gemcitabine radiosensitization included dATP depletion (39,40), accumulation of cells in the S phase of the cell cycle (41), and increased DNA residual damage. It is unknown whether nucleoside transporters are related to the ability of gemcitabine to radiosensitize pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma

Maréchal¹,

Mackey²,

Lai

et al. 2009

Clinical Cancer Research

197

159

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Purpose: Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic adenocarcinoma and its use in combination with radiotherapy is under exploration. Human equilibrative nucleoside transporter 1(hENT1) and human concentrative nucleoside transporter (hCNT) 1and 3 are the major transporters responsible for 2 ¶,2 ¶-difluoro-2-deoxycytidine (gemcitabine) uptake into cells. The aim of this study was to determine patients' outcome according to the expression of hENT1 and hCNT3 in tumoral cells after postoperative gemcitabine-based chemoradiation regimen. Experimental Design: We studied tumor blocks from 45 pancreatic adenocarcinoma patients treated with gemcitabine-based chemoradiation after curative resection and assessed hENT1and hCNT3 expression using immunohistochemistry. Results: When adjusted for the effects of lymph node ratio and tumor diameter, patients with high hENT1 expression had significantly longer disease-free survival and overall survival (OS) than patients with low expression, whereas high hCNT3 expression was only associated with longer OS. In a combined analysis, patients with two favorable prognostic factors (hENT1 high / hCNT3 high expression) had a longer survival (median OS, 94.8 months) than those having one (median OS, 18.7 months) or no (median OS, 12.2 months) favorable prognostic factor. Conclusions: Pancreatic adenocarcinoma patients with a high expression of hENT1and hCNT3 immunostaining have a significantly longer survival after adjuvant gemcitabine-based chemoradiation. These biomarkers deserve prospective evaluation in patients receiving gemcitabinebased adjuvant therapy.Pancreatic head adenocarcinoma has a very poor prognosis.Even after curative surgery, which concerns only 10% to 15% of patients at the time of the diagnosis, 5-year survival is only 10% to 20% and median survival is 20 to 24 months (1, 2). This poor survival rate is attributed to a high rate of local recurrence and development of distant metastases even after complete resection of the tumor (R0 surgery). Several multimodal adjuvant and neoadjuvant therapies have been developed to reduce both local and systemic recurrence of the disease and improve survival. Nevertheless, the value of such adjuvant radiotherapy and/or chemotherapy regimens remains questionable because several trials have failed to draw any firm conclusions. Most of these adjuvant treatments were based on the combination of radiation and 5-fluorouracil (2 -5).Gemcitabine is a 2 ¶,2 ¶-difluoro-2-deoxycytidine analogue that inhibits DNA replication and repair. Gemcitabine monotherapy has clinically important activity in advanced and metastatic pancreatic adenocarcinoma and for which it is now the standard of care (6). In the adjuvant setting, it was enhanced disease-free survival (DFS) and survival compared with surgery alone (7, 8) and significantly increased DFS, but not overall survival (OS), when added to 5-fluorouracil-based chemoradiotherapy in a recent RTOG trial (9).As gemcitabine possesses radiosensitizing prope...

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Section: Discussionmentioning

confidence: 99%

Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma

Maréchal¹,

Mackey²,

Lai

et al. 2009

Clinical Cancer Research

197

159

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“…(40). The clinically relevant nucleoside analogue gemcitabine (2V,2V-difluoro-2V-deoxycytidine) neither increases doublestrand breaks nor decreases the rate of their repair (41,42) but gemcitabine-mediated decrease in the dATP pool is relevant for S-phase-dependent radiosensitization (43,44). Further genetic elements which activate an S-phase checkpoint, like enhanced expression of the transcription factor E2F-1, also enhance the cytotoxic effect of IR (45).…”

Section: Discussionmentioning

confidence: 99%

Patupilone Acts as Radiosensitizing Agent in Multidrug-Resistant Cancer Cells In vitro and In vivo

Hofstetter

Vuong²,

Broggini-Tenzer³

et al. 2005

Clinical Cancer Research

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Interference with microtubule function is a promising antitumoral concept. Paclitaxel is a clinically validated tubulin-targeting agent; however, treatment with paclitaxel is often limited by taxane-related toxicities and is ineffective in tumors with multidrug-resistant cells. Patupilone (EPO906, epothilone B) is a novel non-taxane-related microtubule-stabilizing natural compound that retains full activity in multidrug-resistant tumors and is clinically less toxic than paclitaxel. Here we have investigated the effect of combined treatment with ionizing radiation and patupilone or paclitaxel in the P-glycoprotein-overexpressing, p53-mutated human colon adenocarcinoma cell line SW480 and in murine, genetically defined E1A/ras-transformed paclitaxel-sensitive embryo fibroblasts. Patupilone and paclitaxel alone and in combination with ionizing radiation reduced the proliferative activity of the E1A/ras-transformed cell line with similar potency in the sub and low nanomolar range. SW480 cells were only sensitive to patupilone, and combined treatment with low-dose patupilone (0.1 nmol/L) followed by clinically relevant doses of ionizing radiation (2 and 5 Gy) resulted in a supra-additive cytotoxic effect. Inhibition of the drug efflux protein P-glycoprotein with verapamil resensitized SW480 cells to treatment with low doses of paclitaxel alone and in combination with IR. In tumor xenografts derived from SW480 cells a minimal treatment regimen with patupilone and fractionated irradiation (1 Â 2 mg/kg plus 4 Â 3 Gy) resulted in an at least additive tumor response with extended tumor growth arrest. Analysis by flow cytometry in vitro revealed an apoptosis-and G 2 -M-independent mode of radiosensitization by patupilone. Interestingly though, a transient accumulation of cells in S phase was observed on combined treatment. Overall, patupilone might be a promising alternative in paclitaxel-resistant, P-glycoproteinoverexpressing tumors for a combined treatment regimen using ionizing radiation and a microtubule inhibitor.

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“…This causes cells to redistribute into the early S-phase of the cell cycle. Correlative studies have suggested that simultaneous depletion of dATP pools (through ribonucleotide reductase inhibition) and accumulation in the S-phase of the cell cycle are required to achieve radiosensitization by gemcitabine (1,4,5).…”

Section: Introductionmentioning

confidence: 99%

Role of Checkpoint Kinase 1 in Preventing Premature Mitosis in Response to Gemcitabine

Morgan

Parsels

et al. 2005

Cancer Research

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The deoxycytidine analogue 2V,2V -difluoro-2V -deoxycytidine (gemcitabine) is a potent radiation sensitizer in a variety of solid tumors and tumor cell lines. Previous studies have shown that radiosensitization by gemcitabine is accompanied by simultaneous depletion of dATP pools (through ribonucleotide reductase inhibition) and accumulation in the S-phase of the cell cycle. Because of the importance of cell cycle redistribution in gemcitabine-mediated radiosensitization, we investigated the role of checkpoint kinase (Chk) 1 and Chk2 in gemcitabine-induced cell cycle arrest. We hypothesized that gemcitabine might induce Chk1 or Chk2 signal transduction pathways that mediate S-phase arrest. We found that radiosensitizing concentrations of gemcitabine induced accumulation of phosphorylated Chk1 and Chk2 and downregulation of Cdc25A in BxPC-3 (10 nmol/L), Panc-1 (100 nmol/L), A549 (30 nmol/L), RKO (30 nmol/L), and SW620 (30 nmol/L) cells. Depletion of Chk1 from Panc-1 cells prevented the down-regulation of Cdc25A in response to gemcitabine. Furthermore, Chk1 depletion permitted Panc-1 and SW620 cells treated with gemcitabine to enter mitosis despite incomplete DNA synthesis. However, depletion of neither Chk1 nor Chk2 abrogated the inhibition of DNA synthesis in response to gemcitabine. These results provide evidence that Chk1 negatively regulates entry into mitosis in response to gemcitabine. Furthermore, these data imply that Chk1 acts to coordinate the cell cycle with DNA synthesis, thus preventing premature mitotic entry in gemcitabine-treated cells. (Cancer Res 2005; 65(15): 6835-42)

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Cell cycle effect of gemcitabine and its role in the radiosensitizing mechanism in vitro

Cited by 66 publications

References 28 publications

Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma

Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma

Patupilone Acts as Radiosensitizing Agent in Multidrug-Resistant Cancer Cells In vitro and In vivo

Role of Checkpoint Kinase 1 in Preventing Premature Mitosis in Response to Gemcitabine

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