Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer.

Fossella, Frank V.; Lippman, S. M.; Shin, Dong M.; Tarassoff, Peter G.; Calayag-Jung, M.; Pérez-Soler, Román; Lee, Jin Soo; Murphy, William K.; Glisson, Bonnie S.; Rivera, Edgardo; Hong, Waun Ki

doi:10.1200/jco.1997.15.1.310

Cited by 120 publications

(57 citation statements)

References 6 publications

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“…For instance, the clinical effectiveness for the treatment of lung or breast cancer with cytosine nucleoside analogues, such as Ara-C 15 and the new promising agents, dFdC 16 and 5-AZACdR 17 is limited by their hematopoietic toxicity. The efficacy of chemotherapy with these analogues would be improved if their dose-dependent myelotoxicity could be circumvented.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 Myelosuppression constitutes a major limiting factor for the utilization of high doses of these analogues in cancer therapy. [14][15][16][17] In previous studies, we purified, cloned and expressed the human CD cDNA. 18 We demonstrated increased resistance to Ara-C, 19,20 dFdC and 5-AZA-CdR 21,22 in murine fibroblasts following retroviral gene transfer of CD.…”

Section: Introductionmentioning

confidence: 99%

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Retroviral transfer and long-term expression of human cytidine deaminase cDNA in hematopoietic cells following transplantation in mice

Eliopoulos

Bovenzi

et al. 1998

Gene Ther

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Retroviral transfer and long-term expression of human cytidine deaminase cDNA in hematopoietic cells following transplantation in mice

Eliopoulos

Bovenzi

et al. 1998

Gene Ther

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“…The effect of gemcitabine on transaminases is well described and is a dose limiting toxicity at higher doses of gemcitabine (Fossella et al, 1997). Liver enzymes returned to normal by 6 months post-chemotherapy in all bar one EC-T patient with an abnormal AST and four patients (2 EC-T, 2EC-GT) with abnormal ALT levels.…”

Section: Discussionmentioning

confidence: 85%

tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast cancer: a prospective pulmonary, cardiac and hepatic function evaluation

et al. 2008

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tAnGo is a large randomised trial assessing the addition of gemcitabine(G) to paclitaxel(T), following epirubicin(E) and cyclophosphamide(C) in women with invasive higher risk early breast cancer. To assess the safety and tolerability of adding G, a detailed safety substudy was undertaken. A total of 135 patients had cardiac, pulmonary and hepatic function assessed at (i) randomisation, (ii) mid-chemotherapy, (iii) immediately post-chemotherapy and (iv) 6 months post-chemotherapy. Skin toxicity was assessed during radiotherapy. No differences were detected in FEV 1 or FVC levels between treatment arms or time points. Diffusion capacity (TL CO ) reduced during treatment (Po0.0001), with a significantly lower drop in EC-GT patients (P ¼ 0.02). Most of the reduction occurred during EC and recovered by 6-months post treatment. There was no difference in cardiac function between treatment arms. Only 11 patients had echocardiography/MUGA results change from normal to abnormal during treatment, with only five having LVEFo50%. Transient transaminitis occurred in both treatment arms with significantly more in EC-GT patients postchemotherapy (AST P ¼ 0.03, ALT P ¼ 0.003), although the majority was low grade. There was no correlation between transaminitis and other toxicities. Both treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis levels. Despite these being greater with EC-GT, both regimens appear well tolerated.

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“…A randomized phase II study by Tempero et al [81] in 92 patients with pancreatic cancer compared standard infusion (2,200 mg/m 2 in 30 minutes) with an FDR infusion (1,500 mg/m 2 in 150 minutes) of gemcitabine. The dose levels for each dosing regimen were based on the established MTD for gemcitabine in previous studies [61,82,83], which permitted comparison of clinical responses at equitoxic gemcitabine doses between the two dosing schedules. They found that the concentration of dFdCTP in PBMCs increased linearly with the infusion time up to 188 M at the end of the 150-minute infusion, while infusion of the higher dose in 30 minutes resulted in a plateau in the dFdCTP concentration of 103 M at 1 hour after the end of the infusion.…”

Section: Phase Ii/iii Randomized Trials Comparing Fdr With Standard Dmentioning

confidence: 99%

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

2008

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After completing this course, the reader will be able to:1. Describe the molecular pharmacology of nucleoside analogues.2. Explain transport, metabolism, and elimination in relation to the activity of gemcitabine.3. Describe the clinical pharmacology of gemcitabine in relation to its rate of administration.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTGemcitabine is frequently used in the treatment of patients with solid tumors. Gemcitabine is taken up into the cell via human nucleoside transporters (hNTs) and is intracellularly phosphorylated by deoxycytidine kinase (dCK) to its monophosphate and subsequently into its main active triphosphate metabolite 2,2-difluorodeoxycytidine triphosphate (dFdCTP), which is incorporated into DNA and inhibits DNA synthesis. In addition, gemcitabine is extensively deaminated to 2,2-difluorodeoxyuridine, which is largely excreted into the urine. High expression levels of human equilibrative nucleoside transporter type 1 were associated with a significantly longer overall survival duration after gemcitabine treatment in patients with pancreatic cancer.Clinical studies in blood mononuclear and leukemic cells demonstrated that a lower infusion rate of gemcitabine was associated with higher intracellular dFdCTP levels. Prolonged infusion of gemcitabine at a fixed dose rate (FDR) of 10 mg/m 2 per minute was associated with a higher intracellular accumulation of dFdCTP, greater toxicity, and a higher response rate than with the standard 30-minute infusion of gemcitabine in patients with pancreatic cancer.In the current review, we discuss the molecular pharmacology of nucleoside analogues and the influence of hNTs and dCK on the activity and toxicity of gemcitabine, which is the basis for clinical studies on

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Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer.

Cited by 120 publications

References 6 publications

Retroviral transfer and long-term expression of human cytidine deaminase cDNA in hematopoietic cells following transplantation in mice

Retroviral transfer and long-term expression of human cytidine deaminase cDNA in hematopoietic cells following transplantation in mice

tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast cancer: a prospective pulmonary, cardiac and hepatic function evaluation

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

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