Gemcitabine and Oxaliplatin in Patients With Pancreatic Adenocarcinoma

Airoldi, Mario; Cattel, Luigi; Passera, Roberto; Pedani, Fulvia; Milla, Paola; Zanon, Claudio

doi:10.1097/01.mpa.0000191649.47667.06

Cited by 11 publications

(10 citation statements)

References 18 publications

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“…Encouraging results were obtained in some phase II trials using different schedules with an overall TTP from 3.6 to 5.7 and an OS from 5.6 to 9.5 months (37)(38)(39)(40)(41)(42)(43)(44)47). In particular, a preliminary trial assessed the combination of gemcitabine (1000 mg/m 2 as a 10 mg/m 2 /min infusion on day 1) plus oxaliplatin (100 mg/m 2 as a 2-h infusion on day 2 every two Table II.…”

Section: Gemcitabine and Capecitabinementioning

confidence: 99%

Metastatic pancreatic cancer: Is gemcitabine still the best standard treatment? (Review)

Marco¹

2010

Oncol Rep

118

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Abstract. Pancreatic ductal adenocarcinoma is the fourth cause of death in the Western world. Surgery remains the only treatment offering an advantage in terms of overall survival (5-year survival range, 15-25%), but unfortunately only 10-20% of patients present resectable disease at the time of diagnosis. Hence chemotherapy, possibly combined with radiation therapy, remains the only treatment option aimed at palliation of symptoms and ensuring a better quality of life. Notwithstanding the efforts to find more effective therapies for the treatment of pancreatic cancer, significant results have not yet been achieved. Increasing interest has focused on integrated treatments, i.e. chemotherapy combined with targeted therapies, and a better selection of patients. This study examines the principal clinical trials that will help give clinicians an overview of the progress made in the systemic therapy for advanced pancreatic cancer patients in recent years.

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Section: Gemcitabine and Capecitabinementioning

confidence: 99%

Metastatic pancreatic cancer: Is gemcitabine still the best standard treatment? (Review)

Marco¹

2010

Oncol Rep

118

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“…It has also shown promising efficacy for the treatment of other solid tumors and hematological malignancies (5)(6)(7)(8)(9)(10)(11)(12) suggesting more widespread use in the future. In addition to its use as a monotherapy, gemcitabine is often most effective when used as part of a combination therapy, frequently with platinum-based and topoisomerase-targeted chemotherapeutic agents (13)(14)(15).…”

mentioning

confidence: 99%

Kinetic Investigation of the Inhibitory Effect of Gemcitabine on DNA Polymerization Catalyzed by Human Mitochondrial DNA Polymerase

Fowler

Brown

Johnson

et al. 2008

Journal of Biological Chemistry

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Gemcitabine, 2-deoxy-2,2-difluorocytidine (dFdC), is a drug approved for use against various solid tumors. Clinically, this moderately toxic nucleoside analog causes peripheral neuropathy, hematological dysfunction, and pulmonary toxicity in cancer patients. Although these side effects closely mimic symptoms of mitochondrial dysfunction, there is no direct evidence to show gemcitabine interferes with mitochondrial DNA replication catalyzed by human DNA polymerase ␥. Here we employed presteady state kinetic methods to directly investigate the incorporation of the 5-triphosphorylated form of gemcitabine (dFdCTP), the excision of the incorporated monophosphorylated form (dFdCMP), and the bypass of template base dFdC catalyzed by human DNA polymerase ␥. Opposite template base dG, dFdCTP was incorporated with a 432-fold lower efficiency than dCTP. Although dFdC is not a chain terminator, the incorporated dFdCMP decreased the incorporation efficiency of the next 2 correct nucleotides by 214-and 7-fold, respectively. Moreover, the primer 3-dFdCMP was excised with a 50-fold slower rate than the matched 3-dCMP. When dFdC was encountered as a template base, DNA polymerase ␥ paused at the lesion and one downstream position but eventually elongated the primer to full-length product. These pauses were because of a 1,000-fold decrease in nucleotide incorporation efficiency. Interestingly, the polymerase fidelity at these pause sites decreased by 2 orders of magnitude. Thus, our pre-steady state kinetic studies provide direct evidence demonstrating the inhibitory effect of gemcitabine on the activity of human mitochondrial DNA polymerase.Many nucleoside analogs are potent anti-cancer and antiviral drug compounds. Among 15 Food and Drug Administration-approved nucleoside analogs, gemcitabine or 2Ј-deoxy-2Ј,2Ј-difluorocytidine (dFdC, 4 supplemental Fig. 1) is an anticancer drug that is clinically used for the treatment of nonsmall cell lung cancer (1), pancreatic cancer (2), metastatic breast cancer (3), and ovarian cancer (4). It has also shown promising efficacy for the treatment of other solid tumors and hematological malignancies (5-12) suggesting more widespread use in the future. In addition to its use as a monotherapy, gemcitabine is often most effective when used as part of a combination therapy, frequently with platinum-based and topoisomerase-targeted chemotherapeutic agents (13-15).Gemcitabine is administered in the form of a biologically inactive prodrug that first permeates the cellular membrane by facilitated diffusion (16, 17) almost exclusively via the human equilibrative nucleoside transporter number 1 (17, 18). Following transport, dFdC is metabolized to the biologically active monophosphorylated form (dFdCMP) by deoxycytidine kinase, which is the rate-limiting step during the activation of gemcitabine (19). Subsequently, dFdCMP is further phosphorylated to form the cytotoxic metabolites gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP) by cellular kinases. It has been shown that dFdCTP com...

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“…So far, all the published data on the possible PK interaction between gemcitabine and oxaliplatin were incomplete because of the absence of any internal control for the gemcitabine monotherapy in the same patients [9,12,13,16]. This study was designed to directly assess the effect of oxaliplatin on gemcitabine PKs in patients with advanced solid tumors by comparing PK parameters of gemcitabine between the combination day (day 8) and the monotherapy day (day 1).…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of the different mechanisms of action of the two drugs, the in-vitro evidence of synergy when combined [8] and the broad spectrum of antineoplastic activity with nonoverlapping toxicity, phase I-II studies of the combination have already been conducted in various tumor types [9][10][11][12][13][14][15][16][17]. In a dose-escalation study, we have previously reported that tolerability was excellent and full doses of both drugs, e.g.…”

Section: Introductionmentioning

confidence: 99%

“…gemcitabine 1200-1400 mg/m 2 on days 1 and 8 and oxaliplatin 130 mg/m 2 on day 8, can be utilized for further phase II studies [16]. Moreover, other phase I-II studies with different schedules and dosages have reported lack of any PK interaction between gemcitabine and oxaliplatin when the obtained PK measurements were indirectly compared with previous PK studies of each drug given as monotherapy [9,12,13]. No PK data were, however, collected from day 1 when gemcitabine was given alone, and therefore direct comparisons for the same patients between gemcitabine monotherapy and gemcitabine-oxaliplatin coadministration were not possible.…”

Section: Introductionmentioning

confidence: 99%

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Coadministration of oxaliplatin does not influence the pharmacokinetics of gemcitabine

Pappas

Mavroudis²,

Nikolaidou³

et al. 2006

Anti-Cancer Drugs

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We investigated the possible pharmacokinetic interactions of gemcitabine and oxaliplatin in patients with advanced solid tumors. Ten patients with advanced stage solid tumors were treated with gemcitabine (1500 mg/m) as a 30-min intravenous infusion on days 1 and 8, followed by oxaliplatin (130 mg/m) as a 4-h intravenous infusion, on day 8 every 21 days. Pharmacokinetic data for 24 h after dosing were obtained for both day 1 (gemcitabine without oxaliplatin coadministration) and day 8 (gemcitabine with oxaliplatin) during the first cycle of treatment. Gemcitabine levels in plasma were quantified using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection, and total and ultrafiltrated platinum levels by flameless atomic absorption spectrophotometry with deuterium correction. All pharmacokinetic parameters of gemcitabine seemed to be unchanged when coadministered with oxaliplatin (day 8) compared with pharmacokinetic data of gemcitabine given as a single agent (day 1). The mean (maximum) concentration of gemcitabine on days 1 and 8 was 13.57 (+/-7.42) and 10.23 (+/-5.21) mg/l, respectively (P=0.28), and the mean half-life was 0.32 and 0.44 h, respectively (P=0.40). Similarly, the P-values for AUC0-24 and the observed clearance were 0.61 and 0.30, respectively. Plasma total and free platinum levels were in agreement with other published data. Gemcitabine disposition appeared to be unaffected by oxaliplatin coadministration because no significant changes in pharmacokinetics between day 1 (gemcitabine without oxaliplatin coadministration) and day 8 (gemcitabine with oxaliplatin) were observed.

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Gemcitabine and Oxaliplatin in Patients With Pancreatic Adenocarcinoma

Abstract: The combination of GEM and OXA was well tolerated and showed a promising activity in patients with advanced pancreatic adenocarcinoma; no sequence-dependent pharmacokinetic interaction occurred when comparing the GEM-OXA versus the OXA-GEM sequence, with a 24-hour interval.

Cited by 11 publications

References 18 publications

Metastatic pancreatic cancer: Is gemcitabine still the best standard treatment? (Review)

Metastatic pancreatic cancer: Is gemcitabine still the best standard treatment? (Review)

Kinetic Investigation of the Inhibitory Effect of Gemcitabine on DNA Polymerization Catalyzed by Human Mitochondrial DNA Polymerase

Coadministration of oxaliplatin does not influence the pharmacokinetics of gemcitabine

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