Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer

Farrell, James J.; Elsaleh, Hany; García, Miguel López; Lai, Raymond; Ammar, Ali; Regine, William F.; Abrams, Ross A.; Benson, Al B.; Macdonald, John S.; Cass, Carol E.; Dicker, Adam P.; Mackey, John R.

doi:10.1053/j.gastro.2008.09.067

Cited by 407 publications

(355 citation statements)

References 25 publications

Supporting

Mentioning

340

Contrasting

Unclassified

Order By: Relevance

“…Gemcitabine is taken up into cells primarily by human concentrative nucleoside transporter 1 and 3 (hCNT1 and hCNT3) and by human equilibrative nucleoside transporter (hENT1) [18]. The expression of these nucleoside transporters is correlated with chemosensitivity and patient survival [19][20][21][22][23]. After being taken into the cells, gemcitabine is activated by deoxycytidine (dCK) [24,25].…”

Section: Discussionmentioning

confidence: 99%

Vasohibin 2 reduces chemosensitivity to gemcitabine in pancreatic cancer cells via JUN proto-oncogene dependent transactivation of ribonucleotide reductase regulatory subunit M2

et al. 2017

Pancreatology

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Vasohibin 2 reduces chemosensitivity to gemcitabine in pancreatic cancer cells via JUN proto-oncogene dependent transactivation of ribonucleotide reductase regulatory subunit M2

et al. 2017

Pancreatology

View full text Add to dashboard Cite

“…The expression of ENT1 of this tumor was elevated compared with the other 2 tumors. ENT1 is a key transporter responsible for the uptake of gemcitabine but not LY2334737, and is a biomarker for the response of patients with pancreatic cancer to Gemzar treatment (44)(45)(46). Low-dose LY2334737 treatment provided only approximately 10% of the total gemcitabine dose delivered by the gemcitabine.HCl therapy; however, elevated tumor expression of the high-affinity ENT1 transporter would enhance gemcitabine uptake, thereby arresting more cells progressing through S-phase due to prolonged systemic gemcitabine exposure.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Pratt

Durland-Busbice

Shepard

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

LY2334737, an oral prodrug of gemcitabine, is cleaved in vivo, releasing gemcitabine and valproic acid. Oral dosing of mice results in absorption of intact prodrug with slow systemic hydrolysis yielding higher plasma levels of LY2334737 than gemcitabine and prolonged gemcitabine exposure. Antitumor activity was evaluated in human colon and lung tumor xenograft models. The dose response for efficacy was examined using 3 metronomic schedules, once-a-day dosing for 14 doses, every other day for 7 doses, and once a day for 7 doses, 7 days rest, followed by an additional 7 days of once-a-day dosing. These schedules gave significant antitumor activity and were well tolerated. Oral gavage of 6 mg/kg LY2334737 daily for 21 days gave equivalent activity to i.v. 240 mg/kg gemcitabine. HCl administered once a week for 3 weeks to mice bearing a patient mesothelioma tumor PXF 1118 or a non-small cell lung cancer tumor LXFE 937. The LXFE 397 tumor possessed elevated expression of the equilibrative nucleoside transporter-1 (ENT1) important for gemcitabine uptake but not prodrug uptake and responded significantly better to treatment with LY2334737 than gemcitabine (P 0.001). In 3 colon xenografts, antitumor activity of LY2334737 plus a maximally tolerated dose of capecitabine, an oral prodrug of 5-fluorouracil, was significantly greater than either monotherapy. During treatment, the expression of carboxylesterase 2 (CES2) and concentrative nucleoside transporter-3 was induced in HCT-116 tumors; both are needed for the activity of the prodrugs. Thus, metronomic oral low-dose LY2334737 is efficacious, well tolerated, and easily combined with capecitabine for improved efficacy. Elevated CES2 or ENT1 expression may enhance LY2334737 tumor response.

show abstract

“…5,30 Many studies have shown that the hENT1 but also hCNT3 expression determination can be used as a prognostic marker to provide prospective evaluations for patients receiving gemcitabine-based adjuvant therapy. 6,31,32 In L1210 murine leukaemia cells made resistant to ara-C and cross-resistant to gemcitabine, altered action of dCK can be observed, due to genomic recombination. 27 These results suggest that a partial deletion of the dCK gene observed after selection in the presence of gemcitabine is involved with resistance to this agent both in vitro and in vivo.…”

Section: Resistancementioning

confidence: 99%

Gemcitabine versus Modified Gemcitabine: A Review of Several Promising Chemical Modifications

2012

View full text Add to dashboard Cite

Gemcitabine, an anticancer agent which acts against a wide range of solid tumors, is known to be rapidly deaminated in blood to the inactive metabolite 2',2'-difluorodeoxyuridine and to be rapidly excreted by the urine. Moreover, many cancers develop resistance against this drug, such as loss of transporters and kinases responsible for the first phosphorylation step. To increase its therapeutic levels, gemcitabine is administered at high dose (1000mg/m²) causing sides effects (neutropenia, nausea…).To improve its metabolic stability, its cytotoxic activity and to

show abstract

Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer

Cited by 407 publications

References 25 publications

Vasohibin 2 reduces chemosensitivity to gemcitabine in pancreatic cancer cells via JUN proto-oncogene dependent transactivation of ribonucleotide reductase regulatory subunit M2

Vasohibin 2 reduces chemosensitivity to gemcitabine in pancreatic cancer cells via JUN proto-oncogene dependent transactivation of ribonucleotide reductase regulatory subunit M2

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Gemcitabine versus Modified Gemcitabine: A Review of Several Promising Chemical Modifications

Contact Info

Product

Resources

About