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Current Opinion in Investigational... Sep 2000Tezacitabine (MDL-101731, KW-2331, FMdC), an antimetabolite deoxycytidine analog, is an irreversible ribonucleotide reductase inhibitor and DNA chain terminator... (Review)
Review
Tezacitabine (MDL-101731, KW-2331, FMdC), an antimetabolite deoxycytidine analog, is an irreversible ribonucleotide reductase inhibitor and DNA chain terminator discovered by Hoechst Marion Roussel, now Aventis Pharma, and under development by Matrix and Kyowa as a potential treatment for solid tumors [117987,153697]. It is in phase II trials for colorectal and hematological cancer [333949,343071,353481] and was evaluated in a phase II trial for non-small cell lung cancer, for which enrollment was reported to have stopped [342009]; however, tezacitabine continues to be explored for this indication [378351]. In February 1999, the first phase II trial patient was treated with tezacitabine. A total of 30 patients with non-small cell lung cancer were expected to be enrolled by Matrix [316463]; however, in October 1999, Matrix closed enrollment in this trial (after 28 patients were enrolled); preliminary analysis of the evaluable patients did not show meaningful clinical activity with tezacitabine as a stand-alone therapy in this indication at the dose and regimen tested [342009]. In May 1999, Matrix announced it would enroll up to 30 colorectal cancer patients for treatment in a phase II study [326017]. Despite closing enrollment for the NSCLC trial, as of October 1999, the phase II trial of tezacitabine in colorectal cancer was continuing to accrue patients [342009]. In March 2000, a clinical trial was initiated at the University of Pennsylvania to study tezacitabine administered intravenously in combination with cisplatin; a phase I trial studying the drug in combination with 5-FU at the Dana Farber Cancer Institute also commenced at that time [360590]. In May 1999, the results of four phase I trials were presented at the 35th Annual Meeting of the American Society of Clinical Oncology (ASCO). The studies enrolled 70 patients, 97% of whom had had previous chemotherapy and 46% of whom had failed three or more prior regimens. Groups of patients were given i.v. infusions of tezacitabine in schedules ranging from once every 3 weeks to twice a week for 3 weeks at doses ranging from 16 to 630 mg/m2. The dose-escalation studies showed the compound to be well tolerated and indications of efficacy were observed in patients with various advanced solid tumors [325070,327102]. In September 1998, Matrix Pharmaceutical acquired worldwide rights to tezacitabine except in Japan [299373]. Kyowa Hakko Kogyo has a license from HMR to develop tezacitabine in Japan [195494]; in 1995, the company began phase I clinical trials in Japan for tezacitabine administered orally [195494]. In 1996, this product was designated one of HMR's nine top priority products, serving an unmet medical need and addressing a potential market in excess of US $500 million per year [221118].
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Contraindications; Deoxycytidine; Drugs, Investigational; Humans; Structure-Activity Relationship
PubMed: 11249589
DOI: No ID Found -
Biochemical Pharmacology Jan 2007Tezacitabine is a nucleoside analogue characterized by a dual mechanism of action. Following intracellular phosphorylation, the tezacitabine diphosphate irreversibly...
Tezacitabine is a nucleoside analogue characterized by a dual mechanism of action. Following intracellular phosphorylation, the tezacitabine diphosphate irreversibly inhibits ribonucleotide reductase, while the tezacitabine triphosphate can be incorporated into DNA during replication or repair, resulting in DNA chain termination. In the present study we have investigated the effect of the combination of tezacitabine and 5-fluorouracil (5-FU) or 5-fluoro-2'-deoxyuridine (FUdR) on HCT 116 human colon carcinoma cells and xenografts. We used response surface analysis (RSA) and clonogenic assay to evaluate combination effects of tezacitabine and 5-FU. Tezacitabine is antagonistic when combined with 5-FU in the RSA assay and does not effect the clonogenicity of HCT 116 cells when compared with cells treated with 5-FU alone. However, when combined sequentially with FUdR, tezacitabine leads to potentiation of cell killing in the clonogenic assay, additivity in the RSA assay, and increased apoptosis when compared to FUdR alone, suggesting that cytotoxicity of fluoropyrimidines such as FUdR that have more DNA-directed effects can be potentiated by tezacitabine. We also report that oral administration of the fluoropyrimidine capecitabine, an oral prodrug of 5-FU, in combination with tezacitabine shows statistically significant additivity in the HCT 116 xenograft model. This interaction may be explained by the finding that tezacitabine elevates activity of thymidine phosphorylase (TP), the enzyme required for activation of the capecitabine prodrug in tumors. Our results provide evidence that tezacitabine enhances the DNA-directed effects of fluoropyrimidines in human colon cancer cells and may modulate the antitumor activity of fluoropyrimidines.
Topics: Apoptosis; Cell Line, Tumor; Colonic Neoplasms; DNA; DNA Damage; Deoxycytidine; Floxuridine; Fluorouracil; Humans; Thymidine Phosphorylase; Thymidylate Synthase; Transplantation, Heterologous
PubMed: 17046720
DOI: 10.1016/j.bcp.2006.09.009 -
Cancer Apr 2003The authors performed a dose escalation study of cisplatin and the novel deoxycytidine analog, tezacitabine, to determine the maximum tolerated dose of the combination. (Clinical Trial)
Clinical Trial
BACKGROUND
The authors performed a dose escalation study of cisplatin and the novel deoxycytidine analog, tezacitabine, to determine the maximum tolerated dose of the combination.
METHODS
Twenty-three patients with advanced cancer and good performance status were accrued to 3 dose levels of tezacitabine (150-270 mg/m(2)) and cisplatin (50 mg/m(2)). Using a 28-day treatment cycle, both drugs were administered on Days 1 and 15.
RESULTS
Hematologic toxicity was the most frequently observed side effect and was dose limiting. Grade 3 or 4 neutropenia and thrombocytopenia complicated 75% and 31% of all cycles, respectively. Nonhematologic toxicities were mild. Among 18 evaluable patients, 2 with upper gastrointestinal tract tumors achieved partial responses and 4 had stable disease.
CONCLUSIONS
Based on dose-limiting neutropenia and thrombocytopenia at the highest dose level, the recommended Phase II doses are 200 mg/m(2) of tezacitabine and 50 mg/m(2) of cisplatin.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neoplasms; Treatment Outcome
PubMed: 12673728
DOI: 10.1002/cncr.11273 -
Acta Poloniae Pharmaceutica 2005Tezacitabine (FMdC) is a new cytostatic/cytotoxic agent widely investigated in clinical trials and on the cellular level. In a previous paper (3) we worked on human and...
Tezacitabine (FMdC) is a new cytostatic/cytotoxic agent widely investigated in clinical trials and on the cellular level. In a previous paper (3) we worked on human and murine leukemia (L-1210, HL-60, and MOLT-4) cells, and in this paper we investigated the influence of FMdC on the cell cycle and apoptosis in vitro of three other leukemias (CCRF-SB, KG-1, and Jurkat), and human solid tumor (carcinoma) cell lines (COLO-205, MCF-7, and PC-3). We found that FMdC induces the G1 (at concentrations higher than 10 nM). and S-phase (at low concentration) leaky block of the cell cycle. FMdC also effectively induces apoptotic death of cells by the caspase 3/7 pathway. We found also that FMdC induces intensive changes in the protein metabolism. These changes are correlated with the cell death.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Deoxycytidine; G1 Phase; Humans; Jurkat Cells; Mice; S Phase
PubMed: 16193812
DOI: No ID Found -
Acta Biochimica Polonica 2005The aim of the study was to determine the relation between the cytotoxic and cytostatic effects of tezacitabine and cladribine on a HL-60 cell line and the time of...
The aim of the study was to determine the relation between the cytotoxic and cytostatic effects of tezacitabine and cladribine on a HL-60 cell line and the time of exposure of cells to these drugs. Cell viability and induction of apoptosis were assessed using flow cytometry methods. Apoptosis was confirmed by direct microscopic observation. Growth inhibition was examined by cell counting. After 24 h incubation tezacitabine was equally or less toxic compared to cladribine. However, toxicity of tezacitabine strongly rose after 48 h incubation leading to massive cell death at doses much lower than those of cladribine. Assessment of the effect of increased exposure time on the clinical efficacy of tezacitabine is indicated.
Topics: Antineoplastic Agents; Apoptosis; Cell Survival; Cladribine; Deoxycytidine; Flow Cytometry; HL-60 Cells; Humans
PubMed: 15933759
DOI: No ID Found -
Cancer May 2005Tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene) cytidine; FMdC] is a novel nucleoside analog with potent antiproliferative and antitumor activity in preclinical studies.... (Clinical Trial)
Clinical Trial
BACKGROUND
Tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene) cytidine; FMdC] is a novel nucleoside analog with potent antiproliferative and antitumor activity in preclinical studies. A tolerable safety profile and clinical activity have been shown in Phase I and Phase II clinical studies. The purpose of the current open-label, Phase I dose-escalation trial was to evaluate the combination of tezacitabine and 5-fluorouracil (5-FU) in the treatment of patients with advanced solid tumors.
METHODS
Twenty-four patients with a variety of advanced solid tumors for which there was no curative therapy were enrolled. Bolus infusion tezacitabine was administered on Day 1 of a 14-day cycle at escalating doses of 150-350 mg/m(2), with continuous infusion 5-FU (CI 5-FU) given on Days 1-7 at a fixed dose of 200 mg/m(2) per day. Patients underwent objective tumor evaluation by radiologic methods or clinical examination at baseline and after every fourth treatment cycle.
RESULTS
The maximum tolerated dose of the combination therapy was determined to be tezacitabine, 200 mg/m(2), with CI 5-FU, 200 mg/m(2) per day. The toxicities were manageable, the most notable being transient severe (National Cancer Institute Common Toxicity Criteria Grade 3 or 4) neutropenia in 23 patients (96%). Eleven (55%) of the 20 assessable patients had partial responses or stabilization of disease. The highest response rate was in patients with primary tumors of esophageal origin.
CONCLUSIONS
Tezacitabine at a dose of 200 mg/m(2) in combination with CI 5-FU at a dose of 200 mg/m(2) per day was relatively well tolerated and had clinical activity in patients with advanced solid tumors, particularly in patients with esophageal and other gastrointestinal carcinomas.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Treatment Outcome
PubMed: 15772958
DOI: 10.1002/cncr.21002 -
Clinical Cancer Research : An Official... Sep 2002To evaluate safety, tolerability, and pharmacokinetics of a new nucleoside analogue, tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC)] in patients with... (Clinical Trial)
Clinical Trial Comparative Study
PURPOSE
To evaluate safety, tolerability, and pharmacokinetics of a new nucleoside analogue, tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC)] in patients with refractory solid tumors.
EXPERIMENTAL DESIGN
Seventy patients were enrolled in four separate Phase I trials. Patients had metastatic or relapsed cancer of the colon, breast, pancreas, gastrointestinal tract, lung, and other sites. FMdC was administered by i.v. infusion over 30 min in one of four dose schedules--from once every 3 weeks to twice a week for 3 weeks, with dose escalation in each. Maximum doses ranged from 630 to 16 mg/m(2).
RESULTS
Myelotoxicity, especially neutropenia, was the dominant toxicity and was generally dose-related. Grade 3 or 4 neutropenia occurred in 53% of patients but was of relatively short duration (1-8 days) in all of the patients. One patient experienced grade 3 thrombocytopenia and one patient grade 4 (duration 15 and 11 days, respectively). Transient febrile episodes were reported in 82% of patients with drug administration but were easily controlled. Drug-related gastrointestinal events were mild and appeared unrelated to dose. Pharmacokinetics were linear with dose, not appreciably affected by schedules, and not different after single or multiple doses. Terminal half-life was 3-4 h, and 23% of the administered drug was recovered in the urine as unchanged drug. The uridine analogue (FMdU), the deaminated metabolite of FMdC, was the primary metabolite. Objective antitumor activity was observed in eight patients: one exhibited a partial response and seven exhibited stable disease.
CONCLUSIONS
In general, FMdC was well tolerated. On the basis of the time to recovery from neutropenia, the recommended schedule for Phase II studies is one treatment every 2 weeks, at a minimum dose of 270 mg/m(2).
Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Half-Life; Humans; Infections; Infusions, Intravenous; Male; Middle Aged; Molecular Structure; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Neutropenia; Thrombocytopenia
PubMed: 12231523
DOI: No ID Found -
Acta Poloniae Pharmaceutica 2004Physiologic deoxynucleotides are required for an error-proof DNA replication, repair and synthesis. Any inaccuracy in this process results in a block in DNA synthesis... (Review)
Review
Physiologic deoxynucleotides are required for an error-proof DNA replication, repair and synthesis. Any inaccuracy in this process results in a block in DNA synthesis until the error is corrected. If the cell enzymes are unable to correct the error, a signal for apoptosis is generated. This mechanism is the main target for anticancer nucleoside analogs. They also interact with the metabolism of physiological nucleosides, and consequently, have a large number of intracellular targets to induce cytotoxicity. In addition, it is now reported that some analogs may interfere directly with RNA synthesis. A great deal of synthesized nucleoside analogs provide the opportunity to understand the structure-based differences in their metabolism and mechanisms of action as well as to identify the specific intracellular targets and diseases, in which each of these newer nucleoside analogs acts most efficiently. This paper summarizes developments in the area of new nucleoside analogs undergoing clinical evaluation for the treatment of solid tumors, namely tezacitabine, troxacitabine, DMDC, CNDAC, ECyD, clofarabine, and decitabine.
Topics: Adenine Nucleotides; Animals; Antineoplastic Agents; Arabinonucleosides; Azacitidine; Clinical Trials as Topic; Clofarabine; Cytarabine; Cytidine; Cytosine; Decitabine; Deoxycytidine; Dioxolanes; Humans; Neoplasms; Nucleosides
PubMed: 15575597
DOI: No ID Found -
Journal of Cancer Research and Clinical... Aug 2017Ribonucleotide reductase (RR) enzymes (RR1 and RR2) play an important role in the reduction of ribonucleotides to deoxyribonucleotides which is involved in DNA... (Review)
Review
PURPOSE
Ribonucleotide reductase (RR) enzymes (RR1 and RR2) play an important role in the reduction of ribonucleotides to deoxyribonucleotides which is involved in DNA replication and repair. Augmented RR activity has been ascribed to uncontrolled cell growth and tumorigenic transformation.
METHODS
This review mainly focuses on several biological and chemical RR inhibitors (e.g., siRNA, GTI-2040, GTI-2501, triapine, gemcitabine, and clofarabine) that have been evaluated in clinical trials with promising anticancer activity from 1960's till 2016. A summary on whether their monotherapy or combination is still effective for further use is discussed.
RESULTS
Among the RR2 inhibitors evaluated, GTI-2040, siRNA, gallium nitrate and didox were more efficacious as a monotherapy, whereas triapine was found to be more efficacious as combination agent. Hydroxyurea is currently used more in combination therapy, even though it is efficacious as a monotherapy. Gallium nitrate showed mixed results in combination therapy, while the combination activity of didox is yet to be evaluated. RR1 inhibitors that have long been used in chemotherapy such as gemcitabine, cladribine, fludarabine and clofarabine are currently used mostly as a combination therapy, but are equally efficacious as a monotherapy, except tezacitabine which did not progress beyond phase I trials.
CONCLUSIONS
Based on the results of clinical trials, we conclude that RR inhibitors are viable treatment options, either as a monotherapy or as a combination in cancer chemotherapy. With the recent advances made in cancer biology, further development of RR inhibitors with improved efficacy and reduced toxicity is possible for treatment of variety of cancers.
Topics: Carcinogenesis; Cell Proliferation; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Neoplasms; Oligodeoxyribonucleotides; Pharmacology, Clinical; Ribonucleotide Reductases
PubMed: 28624910
DOI: 10.1007/s00432-017-2457-8 -
Best Practice & Research. Clinical... Dec 2004Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders. Therapeutic interventions for MDS other than allogeneic bone marrow... (Review)
Review
Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders. Therapeutic interventions for MDS other than allogeneic bone marrow transplantation have been palliative. Because most of the patients are elderly and may not be candidates for ablative transplant conditioning regimens, treatment has focused on supportive care. Recently, several novel biological and chemotherapeutic agents have demonstrated activity in MDS and are being incorporated into the treatment paradigm. These agents are based on specific mechanisms aimed at angiogenesis in the bone marrow, secretion of growth factors and/or their receptors, and modulators in their intracellular pathways. Several agents are in the initial stages of clinical trial, including anti-vascular endothelial growth factor, bevacizumab, receptor tyrosine kinase inhibitors, farnesyl transferase inhibitors, protein kinase C inhibitors, matrix metalloproteinase inhibitors and other agents such as thalidomide and arsenic trioxide. Novel chemotherapeutic agents include topoisomerase inhibitors such as topotecan and rubitecan, and deoxyadenosine analogues such as troxacitabine, tezacitabine, and clofarabine. Prognostic factors predicting response in MDS patients treated with intensive chemotherapy have been identified and include younger age and favorable cytogenetics.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Humans; Myelodysplastic Syndromes; Nucleosides; Topoisomerase I Inhibitors
PubMed: 15494295
DOI: 10.1016/j.beha.2004.08.009