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BMC Cancer Jul 2007Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer... (Comparative Study)
Comparative Study
BACKGROUND
Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials.
METHODS
The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1) tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired t test using GraphPad prism software.
RESULTS
Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth). The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of troxacitabine when cells were exposed at equal drug concentrations, there was no effect on phosphorylated pools at drug combinations that were synergistic. The amount of troxacitabine incorporated into DNA was also not affected by the presence of gemcitabine. In vivo testing against a human pancreatic (AsPC-1) xenograft mouse tumor model indicated that both drugs were more than additive at well-tolerated doses and schedule. The biological basis for this synergy is unclear as we did not observe changes in apoptosis, DNA repair, troxacitabine incorporation into DNA or troxacitabine metabolism in the presence of gemcitabine.
CONCLUSION
These data, together with phase I clinical data showing tolerability of both agents when combined, suggest combination therapy with troxacitabine and gemcitabine warrants further evaluation in advanced pancreatic cancer patients.
Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Cytosine; Deoxycytidine; Dioxolanes; Drug Synergism; Female; Humans; Mice; Mice, Nude; Mice, SCID; Pancreatic Neoplasms; Treatment Outcome; Tritium; Tumor Cells, Cultured; Uridine; Xenograft Model Antitumor Assays; Gemcitabine
PubMed: 17608948
DOI: 10.1186/1471-2407-7-121 -
Bulletin Du Cancer Mar 2004Nucleoside analogues are commonly used in the treatment of hematological malignancies and solid tumors. As antimetabolites, these drugs act by disrupting DNA synthesis... (Review)
Review
Nucleoside analogues are commonly used in the treatment of hematological malignancies and solid tumors. As antimetabolites, these drugs act by disrupting DNA synthesis and inducing apoptosis following their incorporation into DNA. Troxacitabine (Troxatyl) is the first nucleoside analogue with anticancer activity that has an unnatural stereochemical configuration. Its broad preclinical antineoplastic spectrum led to its clinical development. Summaries of the preclinical data and of the initial phase I and II clinical trials are presented.
Topics: Acute Disease; Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cytosine; Dioxolanes; Drug Screening Assays, Antitumor; Humans; Leukemia; Neoplasms
PubMed: 15171046
DOI: No ID Found -
SpringerPlus 2014We aimed to determine whether the multidrug-resistance-proteins MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the antimetabolites cytarabine (Ara-C), gemcitabine...
UNLABELLED
We aimed to determine whether the multidrug-resistance-proteins MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the antimetabolites cytarabine (Ara-C), gemcitabine (GEM), and the L-nucleoside analog troxacitabine. For this purpose we used HEK293 and the transfected HEK/MRP4 (59-fold increased MRP4) or HEK/MRP5i (991-fold increased MRP5) as model systems and tested the cells for drug sensitivity using a proliferation test. Drug accumulation was performed by using radioactive Ara-C, and for GEM and troxacitabine with HPLC with tandem-MS or UV detection. At 4-hr exposure HEK/MRP4 cells were 2-4-fold resistant to troxacitabine, ara-C and 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and HEK/MRP5i to ara-C and PMEA, but none to GEM. The inhibitors probenecid and indomethacin reversed resistance. After 4-hr exposure ara-C-nucleotides were 2-3-fold lower in MRP4/5 cells, in which they decreased more rapidly after washing with drug-free medium (DFM). Trocacitabine accumulation was similar in the 3 cell lines, but after the DFM period troxacitabine decreased 2-4-fold faster in MRP4/5 cells. Troxacitabine-nucleotides were about 25% lower in MRP4/5 cells and decreased rapidly in MRP4, but not in MRP5 cells. Accumulation of GEM-nucleotides was higher in the MRP4/5 cells.
IN CONCLUSION
MRP4 and MRP5 overexpression confer resistance to troxacitabine and ara-C, but not to GEM, which was associated with a rapid decline of the ara-C and troxacitabine-nucleotides in HEK/MRP4-5 cells.
PubMed: 25674464
DOI: 10.1186/2193-1801-3-732 -
British Journal of Haematology Mar 2004The in vitro and in vivo activity of a deoxycytidine analogue, troxacitabine, alone or in combination with imatinib mesylate (IM), was evaluated against human chronic...
The in vitro and in vivo activity of a deoxycytidine analogue, troxacitabine, alone or in combination with imatinib mesylate (IM), was evaluated against human chronic myeloid leukaemia (CML) cell lines both sensitive (KBM5 and KBM7) and resistant (KBM5-R and KBM7-R) to IM. These cell lines differ in their sensitivity to IM but all showed similar sensitivity to treatment with troxacitabine (IC50 = 0.5-1 micromol/l). Combined treatment with troxacitabine and IM revealed additive or synergistic effects. Greater apoptotic response was seen with combined treatment than with either agent alone in KBM7-R cells. In clonogenic assays, troxacitabine showed activity against mononuclear cells from CML patients (IC50 = 0.01 micromol/l) with either IM-sensitive or resistant disease. In vivo efficacy studies were carried out in severe combined immunodeficient mice bearing KBM5 or KBM5-R cells. Troxacitabine was administered i.p. daily for 5 d starting on day 20, at doses of 5, 10, 20, or 25 mg/kg. IM was administered i.p. twice a day for 10 d at a dose of 50 mg/kg starting on day 25. In this setting of late stage disease, troxacitabine led to a significant increase in life span, while IM did not. When IM was combined with troxacitabine at 10 and 25 mg/kg in the KBM5 xenograft model, a further increase in life span was observed and some mice achieved long-term survival. These data indicate that the combination of troxacitabine and IM has significant preclinical activity in advanced CML and that clinical evaluation of this combination is warranted.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Survival; Cytosine; Dioxolanes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Inbred ICR; Mice, SCID; Neoplasm Transplantation; Piperazines; Pyrimidines; Survival Analysis; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 15009060
DOI: 10.1111/j.1365-2141.2004.04831.x -
Cancer Feb 2004Over the past several decades, improvements in chemotherapeutic agents and supportive care have resulted in significant progress in treating patients with acute myeloid... (Comparative Study)
Comparative Study Review
Over the past several decades, improvements in chemotherapeutic agents and supportive care have resulted in significant progress in treating patients with acute myeloid leukemia (AML). More recently, advances in understanding the biology of AML have resulted in the identification of new therapeutic targets. The success of all-trans-retinoic acid in acute promyelocytic leukemia and of imatinib mesylate in chronic myeloid leukemia have demonstrated that targeted therapy may be more effective and less toxic when well defined targets are available. At the same time, understanding mechanisms of drug resistance and means to overcome them has led to modification of some of the existing cytotoxic agents. Rational design and conduct of clinical trials is necessary to ensure that the full potential of these new agents is realized.
Topics: Antineoplastic Agents; Cyclosporine; Cytosine; Deoxycytidine; Dioxolanes; Female; Humans; Immunosuppressive Agents; Immunotherapy; Leukemia, Myeloid, Acute; Male; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Survival Analysis; Treatment Outcome; Gemcitabine
PubMed: 14745859
DOI: 10.1002/cncr.11935 -
Annals of Oncology : Official Journal... Feb 2008Troxacitabine is a novel L-nucleoside analogue. Preclinical studies showed improved activity with infusions of at least 3 days compared with bolus regimens, especially...
BACKGROUND
Troxacitabine is a novel L-nucleoside analogue. Preclinical studies showed improved activity with infusions of at least 3 days compared with bolus regimens, especially at concentrations >20 ng/ml. This phase I study tested the feasibility of achieving a troxacitabine steady-state concentration of 20 ng/ml for at least 72 h in patients with solid tumors.
PATIENTS AND METHODS
Patients with solid tumors received troxacitabine as a progressively longer infusion on days 1-4 of a 28-day cycle. The initial length of infusion and infusion rate were 48 h and 3 mg/m(2)/day.
RESULTS
Twenty-one patients were treated at infusion lengths that increased from 48 to 72 h and then 96 h. The infusion rate was decreased from 3 to 1.88 mg/m(2)/day due to toxicity. Dose-limiting toxicities consisted of grade 4 neutropenia (three) and grade 3 constipation (one). The maximum tolerated dose of continuous infusion troxacitabine in patients with solid tumors is 7.5 mg/m(2) administered over 96 h. This dose level resulted in steady-state drug concentration of at least 20 ng/ml for 72 h.
CONCLUSIONS
Administration of troxacitabine by continuous infusion achieved the prospectively defined target plasma concentration. Pharmacokinetics (PK) modeling coupled with real-time PK assessment was an efficient approach to conduct hypothesis-driven phase I trials.
Topics: Adult; Aged; Cytosine; Dioxolanes; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Feasibility Studies; Female; Follow-Up Studies; Humans; Immunohistochemistry; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms; Predictive Value of Tests; Probability; Risk Assessment; Survival Analysis; Time Factors; Treatment Outcome
PubMed: 18245131
DOI: 10.1093/annonc/mdm572 -
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 -
Acta Poloniae Pharmaceutica 2004Cytotoxic nucleoside analogs have a broad clinical use. They were among the first chemotherapeutic agents used in the treatment of malignant diseases. The anticancer... (Review)
Review
Cytotoxic nucleoside analogs have a broad clinical use. They were among the first chemotherapeutic agents used in the treatment of malignant diseases. The anticancer nucleosides include analogs of physiologic pyrimidine and purine nucleosides. They are used in oncology in the treatment of both, solid tumors and hematological malignancies. These agents have many intracellular targets, e.g. they act as antimetabolites, competing with natural nucleosides during DNA or RNA synthesis and as inhibitors of key cell enzymes. Understanding of the mechanisms of action of these compounds and synthesis of new analogs provides the possibility to further expand the spectrum of their clinical use and enhance their antitumor activity. In this paper we describe mechanisms of action and possible clinical use in the treatment of hematological malignancies of these nucleoside analogs, which are now in different stages of clinical trials, namely tezacitabine, troxacitabine, clofarabine, nelarabine, decitabine, CNDAC and ECyD.
Topics: Adenine Nucleotides; Animals; Antineoplastic Agents; Arabinonucleosides; Clinical Trials as Topic; Clofarabine; Cytarabine; Cytosine; Deoxycytidine; Dioxolanes; Half-Life; Hematologic Neoplasms; Humans; Purine Nucleosides; Pyrimidine Nucleosides; Stereoisomerism
PubMed: 15481249
DOI: No ID Found -
Nucleic Acids Research 2007L-nucleoside analogs represent an important class of small molecules for treating both viral infections and cancers. These pro-drugs achieve pharmacological activity...
L-nucleoside analogs represent an important class of small molecules for treating both viral infections and cancers. These pro-drugs achieve pharmacological activity only after enzyme-catalyzed conversion to their tri-phosphorylated forms. Herein, we report the crystal structures of human deoxycytidine kinase (dCK) in complex with the L-nucleosides (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC)--an approved anti-human immunodeficiency virus (HIV) agent--and troxacitabine (TRO)--an experimental anti-neoplastic agent. The first step in activating these agents is catalyzed by dCK. Our studies reveal how dCK, which normally catalyzes phosphorylation of the natural D-nucleosides, can efficiently phosphorylate substrates with non-physiologic chirality. The capability of dCK to phosphorylate both D- and L-nucleosides and nucleoside analogs derives from structural properties of both the enzyme and the substrates themselves. First, the nucleoside-binding site tolerates substrates with different chiral configurations by maintaining virtually all of the protein-ligand interactions responsible for productive substrate positioning. Second, the pseudo-symmetry of nucleosides and nucleoside analogs in combination with their conformational flexibility allows the L- and D-enantiomeric forms to adopt similar shapes when bound to the enzyme. This is the first analysis of the structural basis for activation of L-nucleoside analogs, providing further impetus for discovery and clinical development of new agents in this molecular class.
Topics: Anti-HIV Agents; Antineoplastic Agents; Crystallography, X-Ray; Cytosine; Deoxycytidine Kinase; Dioxolanes; Humans; Lamivudine; Models, Molecular; Prodrugs; Stereoisomerism; Substrate Specificity
PubMed: 17158155
DOI: 10.1093/nar/gkl1038 -
Annals of Oncology : Official Journal... Feb 2005Troxacitabine (Troxatyl) is a novel L-enantiomer nucleoside analog with activity in pancreatic cancer xenograft models. (Clinical Trial)
Clinical Trial
BACKGROUND
Troxacitabine (Troxatyl) is a novel L-enantiomer nucleoside analog with activity in pancreatic cancer xenograft models.
PATIENTS AND METHODS
Troxacitabine 1.5 mg/m(2) was administered by 30-min infusions daily x5 every 4 weeks to 54 patients with advanced pancreatic cancer. Patients were evaluated for objective tumor response, time to tumor progression (TTP), changes in tumor marker CA 19-9, survival, safety, pain, analgesic consumption, Karnofsky performance status and weight change.
RESULTS
Median TTP was 3.5 months (95% CI 2.0-3.8), median survival 5.6 months (95% CI 4.9-7.4), and the 1 year survival rate 19%. Best responses were stable disease in 24 patients with eight patients having stable disease for at least 6 months (15%). A 50% or greater decrease in CA 19-9 was seen in seven of 44 assessed patients (16%). Grade 3 and 4 neutropenia were observed in 37% and 30% of patients with one episode of febrile neutropenia. The most common drug-related non-hematological toxic effects reported were cutaneous, with 22% and 6% of patients reporting grade 2 and 3 skin rash, respectively and 4% grade 2 hand-foot syndrome.
CONCLUSION
Troxacitabine administered by a bolus daily x5 monthly regimen has modest activity in advanced pancreatic adenocarcinoma.
Topics: Adult; Aged; Antineoplastic Agents; Body Weight; Cytosine; Dioxolanes; Disease Progression; Female; Health Status; Humans; Infusions, Intravenous; Male; Middle Aged; Pain; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome
PubMed: 15668286
DOI: 10.1093/annonc/mdi061