2′,2′-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines

Haperen, V. W. T. Ruiz Van; Veerman, G.; Vermorken, Jan B.; Peters, Godefridus J.

doi:10.1016/0006-2952(93)90566-f

Cited by 221 publications

(137 citation statements)

References 11 publications

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“…Resistance to antimetabolic drugs such as gemcitabine can be achieved by various genomic alterations. 29 A major cause of resistance can be attributed to alterations in the transporter. The development of resistance to gemcitabine correlates strongly with a deficiency of hENT1 expression in human breast and pancreatic cancer cells.…”

Section: Resistancementioning

confidence: 99%

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

2012

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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

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Section: Resistancementioning

confidence: 99%

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

2012

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“…48 Gemcitabine is not only incorporated into DNA, but also into RNA. 49 The spectrum of activity of gemcitabine in solid tumors may be due to different characteristics. Compared with ara-C, gemcitabine serves as a better transport substrate for membrane pumps, is phosphorylated more efficiently, and is eliminated more slowly, favoring a longer retention time of the active metabolite in tumor cells.…”

Section: Figurementioning

confidence: 99%

Nucleoside analogues: mechanisms of drug resistance and reversal strategies

2001

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“…Gemcitabine undergoes intracellular phosphorylation to the active metabolites gemcitabine diphosphate and gemcitabine triphosphate, leading to inhibition of ribonucleotide reductase and incorporation of gemcitabine triphosphate into DNA and RNA (Xu and Plunkett, 1992;Ruiz van Haperen et al, 1993). It is active against non-small-cell lung cancer, pancreatic cancer, breast cancer and ovarian cancer (Abratt et al, 1994;Lund et al, 1994;Carmichael et al, 1995Carmichael et al, , 1996.…”

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confidence: 99%

Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

Tanaka

Sun

et al. 2005

Br J Cancer

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The relevance of gemcitabine timing for chronotherapeutic optimisation was investigated. Healthy mice received multiple doses of gemcitabine (120, 160 or 200 mg kg À1 injection (inj) À1 ) at one of six circadian times (3, 7, 11, 15, 19 or 23 h after light onset -HALO) on days 1, 4, 7 and 10 or a single dose of gemcitabine (400 mg kg À1 ) at 11 or 23 HALO7cisplatin (5 mg kg À1 at 1 min, 4 or 8 h later). Mice bearing Glasgow osteosarcoma received multiple doses of gemcitabine (200 mg kg À1 inj À1 ) at 11 or 23 HALO7cisplatin (5 mg kg À1 inj À1 at 1 min or 4 h later) on days of 10, 13, 16 and 19 following tumour inoculation. A circadian rhythm in body weight loss was statistically validated, with 1030 HALO corresponding to the least toxic time (95% CL, 0800 to 1300). Gemcitabine dosing produced least body weight loss and least neutropenia after injection at 11 vs 23 HALO, whether the drug was given alone or with cisplatin (P ¼ 0.001). Gemcitabine -cisplatin tolerability was improved by dosing gemcitabine at 11 HALO and CDDP at 15 HALO (Po0.001). The administration of this schedule to tumour-bearing mice increased median survival three-fold as compared to treatments where both drugs were given simultaneously at 11 or 23 HALO (P ¼ 0.02). The optimal schedule would correspond to the delivery of gemcitabine upon awakening and cisplatin near mid-activity in cancer patients.

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2′,2′-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines

Cited by 221 publications

References 11 publications

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

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

Nucleoside analogues: mechanisms of drug resistance and reversal strategies

Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

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