A phase I and pharmacologic study of weekly gemcitabine in combination with infusional 5-fluorodeoxyuridine and oral calcium leucovorin

Grem, Jean L.; Quinn, Mary; Keith, Bruce; Monahan, Brian P.; Hamilton, J. Michael; Xu, Yan; Harold, Nancy; Nguyen, Dat; Takimoto, Chris H.; Rowedder, A; Pang, Janet; Morrison, Geraldine; Chen, Alice

doi:10.1007/s00280-003-0698-5

Cited by 6 publications

(4 citation statements)

References 23 publications

(21 reference statements)

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“…2'-deoxy-2',2'-difluorocytidine (commonly named gemcitabine), the pro-drug of F 2 dNDP, is a very promising anticancer agent already approved for clinical use in some therapeutic indications, such as non-small cell lung and bladder cancers and adenocarcinoma of the pancreas [151][152][153]. Interestingly F 2 dNDP inhibition mechanism over RNR is different from the suicide inhibitors already mentioned above since the presence of reducing agents does not preclude the inhibition, which explains its effectiveness in vivo [154].…”

Section: Ii) Allosteric Inhibitorsmentioning

confidence: 99%

Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

Cerqueira¹,

Pereira²,

Fernandes³

et al. 2005

CMC

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This review provides up-to-date information on the inhibition of ribonucleotide reductase (RNR), the enzyme that catalyses the reduction of ribonucleotides into deoxyribonucleotides. Taking in account that DNA replication and repair are essential mechanisms for cell integrity and are dependent on the availability of deoxyribonucleotides, many researchers are giving special attention to this enzyme, since it is an attractive target to treat several diseases of our time specially cancer. This investment has already given some benefits since some of these inhibitors show potent chemotherapeutic efficacy against a wide range of tumours such as non-small cell lung cancer, adenocarcinoma of pancreas, bladder cancer, leukaemia and some solid tumours. In fact a few of them have already been approved for the clinical treatment of some kinds of cancer. All aspects of RNR inhibition and corresponding inhibitors are the subjects of this review. The inhibitors are divided in three main groups: translation inhibitors, which unable the formation of the enzyme; dimerization inhibitors that prevent the complexation of the two RNR subunits (R1 and R2); and catalytic inhibitors that inactivate subunit R1 and/or subunit R2, leading to RNR inactivity. In this last group special focus will be addressed to substrate analogues.

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Section: Ii) Allosteric Inhibitorsmentioning

confidence: 99%

Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

Cerqueira¹,

Pereira²,

Fernandes³

et al. 2005

CMC

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“…GEM in plasma was analyzed using a validated high-performance liquid chromatography method (24). Briefly, control drug -free plasma containing known concentrations of GEM and difluoro-deoxyuridine were used to prepare the standard curve.…”

Section: Methodsmentioning

confidence: 99%

Phase I and Pharmacokinetic Study of Imatinib Mesylate (Gleevec) and Gemcitabine in Patients with Refractory Solid Tumors

Ali

Lin

Gharibo

et al. 2007

Clinical Cancer Research

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Purpose: Preclinical data shows improvements in response for the combination of imatinib mesylate (IM, Gleevec) and gemcitabine (GEM) therapy compared with GEM alone. Our goals were to determine the maximum tolerated dose of GEM and IM in combination, the pharmacokinetics of GEM in the absence and in the presence of IM, and IM pharmacokinetics in this combination. Patients and Methods: Patients with refractory malignancy, intact intestinal absorption, measurable/evaluable disease, adequate organ function, Eastern Cooperative Oncology Group PS 0-2, and signed informed consent were eligible. Initially, treatment consisted of 600 mg/m 2 of GEM (10 mg/m 2 /min) on days 1, 8, and 15, and 300 mg of IM daily every 28 days. Due to excessive toxicity, the schedule was altered to IM on days 1to 5 and 8 to 12, and GEM on days 3 and 10 every 21days. Two final cohorts received IM on days 1to 5, 8 to 12, and 15 to 19. Results: Fifty-four patients were treated. IM and GEM given daily at 500 to 600 mg/m 2 on days 1, 8, and 15 produced frequent dose-limiting toxicities.With the modified scheduling, GEM given at 1,500 mg/m 2 /150 min was deliverable, along with 400 mg of IM, without dose-limiting toxicities.Three partial (laryngeal, renal, and mesothelioma) and two minor (renal and pancreatic) responses were noted at GEM doses of 450 to 1,500 mg/m 2 . Stable disease >24 weeks was seen in 17 patients. CA19-9 in 7 of 10 patients with pancreatic cancer was reduced by f90%. IM did not significantly alter GEM pharmacokinetics. Conclusion: The addition of intermittently dosed IM to GEM at low to full dose was associated with broad antitumor activity and little increase in toxicity.

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“…Efforts to maximize the clinical efficacy of 5-FU focus on biochemical modulation by co-treatment with the folate analog Leucovorin [ 44 ], which promotes TS ternary complex formation despite the relatively low plasma folate levels of humans [ 45 ]. Continuous intra-venous infusion of 5-FU [ 46 ] is also used to maximize exposure to malignant cells while they are in S-phase when high TS levels occur. Therapeutic drug monitoring (TDM) is being implemented to optimize 5-FU plasma levels and account for high inter-patient variability in drug metabolism [ 47 ].…”

Section: Ts Inhibition and Dna-directed Effects Of Fpsmentioning

confidence: 99%

Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine

Gmeiner

2020

Molecules

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We review developments in fluorine chemistry contributing to the more precise use of fluorinated pyrimidines (FPs) to treat cancer. 5-Fluorouracil (5-FU) is the most widely used FP and is used to treat > 2 million cancer patients each year. We review methods for 5-FU synthesis, including the incorporation of radioactive and stable isotopes to study 5-FU metabolism and biodistribution. We also review methods for preparing RNA and DNA substituted with FPs for biophysical and mechanistic studies. New insights into how FPs perturb nucleic acid structure and dynamics has resulted from both computational and experimental studies, and we summarize recent results. Beyond the well-established role for inhibiting thymidylate synthase (TS) by the 5-FU metabolite 5-fluoro-2′-deoxyuridine-5′-O-monophosphate (FdUMP), recent studies have implicated new roles for RNA modifying enzymes that are inhibited by 5-FU substitution including tRNA methyltransferase 2 homolog A (TRMT2A) and pseudouridylate synthase in 5-FU cytotoxicity. Furthermore, enzymes not previously implicated in FP activity, including DNA topoisomerase 1 (Top1), were established as mediating FP anti-tumor activity. We review recent literature summarizing the mechanisms by which 5-FU inhibits RNA- and DNA-modifying enzymes and describe the use of polymeric FPs that may enable the more precise use of FPs for cancer treatment in the era of personalized medicine.

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A phase I and pharmacologic study of weekly gemcitabine in combination with infusional 5-fluorodeoxyuridine and oral calcium leucovorin

Abstract: Gemcitabine 100-150 mg/m2 over 24 h was poorly tolerated, whereas toxicity was acceptable with 800-1000 mg/m2 over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses.

Cited by 6 publications

References 23 publications

Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

Phase I and Pharmacokinetic Study of Imatinib Mesylate (Gleevec) and Gemcitabine in Patients with Refractory Solid Tumors

Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine

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