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Clinical Pharmacokinetics 2002Cytarabine (cytosine arabinoside, Ara-C) is an effective chemotherapeutic agent for the treatment of acute myelogenous leukaemia and lymphocytic leukaemias. As... (Review)
Review
Cytarabine (cytosine arabinoside, Ara-C) is an effective chemotherapeutic agent for the treatment of acute myelogenous leukaemia and lymphocytic leukaemias. As cytarabine is an S-phase-specific drug, prolonged exposure of cells to cytotoxic concentrations is critical to achieve maximum cytotoxic activity. However, the activity of cytarabine is decreased by its rapid deamination to the biologically inactive metabolite uracil arabinoside. This rapid deamination is the reason for the ongoing search for effective formulations and derivatives of cytarabine that cannot be deaminated and exhibit better pharmacokinetic parameters. Protection of cytarabine from fast degradation and elimination has been investigated by encapsulating the drug into pharmaceutically acceptable carriers. Cytarabine derivatives have shown promise in vitro and in animal models. For example, ancitabine (cyclocytidine), enocitabine and cytarabine ocfosfate have been used clinically in Japan. Cytarabine encapsulated into multivesicular liposomes has been approved in several countries for the intrathecal treatment of lymphomatous meningitis. Although many compounds have been investigated, few cytarabine derivatives are currently available for clinical use. Further research is needed to improve the efficacy of cytarabine against haematological and solid tumours.
Topics: Animals; Antimetabolites, Antineoplastic; Area Under Curve; Chemistry, Pharmaceutical; Cytarabine; Delayed-Action Preparations; Emulsions; Half-Life; Humans; Liposomes; Metabolic Clearance Rate; Neoplasms
PubMed: 12162758
DOI: 10.2165/00003088-200241100-00002 -
Journal of Pharmaceutical Sciences Jul 1984The kinetics of conversion of the prodrug ancitabine to the anticancer drug cytarabine have been studied in aqueous solutions in the pH range of 1.5-10.7, temperature...
The kinetics of conversion of the prodrug ancitabine to the anticancer drug cytarabine have been studied in aqueous solutions in the pH range of 1.5-10.7, temperature range of 19.5-80.0 degrees C, ionic strength range of 10(-4) to 1.5, and in the presence of several general-base catalysts. Under all conditions ancitabine was quantitatively converted to cytarabine. The pH-rate profiles were linear with slope = 1 in alkaline pH, becoming pH independent in the region of maximum stability at pH less than or equal to 4, where buffer catalysis was found to be insignificant and kobs approximately equal to (1.12 X 10(11) h-1)-exp [-10121 deg/T]. At 30 degrees C, pH less than or equal to 4, it is calculated that an aqueous ancitabine solution will maintain 90% of its initial concentration for 12 d. A novel method for measuring general-base catalysis in competition with predominating specific-base catalysis and in the presence of secondary salt effects at constant ionic strength was developed. Three mechanisms of hydrolytic prodrug conversion are proposed: nucleophilic hydroxide addition, general base-assisted nucleophilic water attack, and spontaneous water attack.
Topics: Ancitabine; Atmosphere; Catalysis; Chemistry, Pharmaceutical; Cytarabine; Drug Stability; Hydrochloric Acid; Hydrogen-Ion Concentration; Kinetics; Sodium Hydroxide; Spectrophotometry, Ultraviolet; Temperature
PubMed: 6206222
DOI: 10.1002/jps.2600730709 -
Gan To Kagaku Ryoho. Cancer &... Oct 1987Cytarabine (ara-C) is the first line agent with its excellent activity for acute myelogenous leukemia. Combination therapy of MFC (mitomycin C, 5-FU, ara-C) has been...
Cytarabine (ara-C) is the first line agent with its excellent activity for acute myelogenous leukemia. Combination therapy of MFC (mitomycin C, 5-FU, ara-C) has been used for GI tract cancer with a synergistic effect on L-1210 mouse leukemia. In the results of research on the administration, a high dose ara-C is an effective agent in the refractory cases to the standard dose ara-C and the combination with daunorubicin is applied to a remission consolidation therapy. A small dose ara-C is used against an atypical leukemia with its mechanism of induction of differenciation. On the other hand, in the development of its derivertive compounds ancitabine or enocitabine (BH-AC) were induced to a treatment of acute myelogenous leukemia. Especially BH-AC is the first choice agent for acute myelogenous leukemia combined with other agents.
Topics: Animals; Antineoplastic Agents; Cytarabine; Humans; Leukemia, Myeloid, Acute; Mice; Myelodysplastic Syndromes; Structure-Activity Relationship
PubMed: 3478003
DOI: No ID Found -
Journal of Pharmaceutical Sciences Jun 1984Conversion rates of the prodrug ancitabine to the antileukemic cytarabine have been measured in vivo (rabbits) and in vitro (in the presence of rabbit blood and human...
Conversion rates of the prodrug ancitabine to the antileukemic cytarabine have been measured in vivo (rabbits) and in vitro (in the presence of rabbit blood and human red blood cells, blood, and plasma) using HPLC analyses for the prodrug, drug, and its inactive metabolite, 1-beta-D-arabinosyluracil. These observed pH-dependent in vitro rate constants were consistent with those for chemical hydrolysis determined from controls using Tris buffers. Hydrolysis of ancitabine to cytarabine is chemically, not enzymatically, mediated. The blood concentration-time course for administered compound was described by a two-compartment open model following a rapid intravenous injection of prodrug, drug, or metabolite in each of three rabbits. The in vivo conversion rate constant (kc) following a rapid intravenous prodrug injection was estimated by simultaneous nonlinear regression of ancitabine and cytarabine blood concentration-time courses using equations for two-compartment prodrug and drug with all possible models describing potential conversion sites. The best fit was obtained for the case allowing simultaneous conversion of the prodrug in both central and peripheral compartments to the drug in the central compartment with a common value for kc. The resulting kc value (0.09 h-1, three rabbits) is similar to that for chemical hydrolysis (0.07 h-1) at 38.8 degrees C. Reasons why this agreement is regarded as fortuitous are discussed.
Topics: Ancitabine; Animals; Biotransformation; Cytarabine; Humans; Hydrogen-Ion Concentration; Hydrolysis; In Vitro Techniques; Injections, Intravenous; Kinetics; Male; Models, Biological; Rabbits; Spectrophotometry, Ultraviolet
PubMed: 6204036
DOI: 10.1002/jps.2600730606 -
Cancer Chemotherapy and Pharmacology 1979The rationale and history of the development of physiologically based pharmacokinetic models are briefly reviewed in this paper. The methods of model construction and... (Review)
Review
The rationale and history of the development of physiologically based pharmacokinetic models are briefly reviewed in this paper. The methods of model construction and the previous application of this type of model to anticancer drugs are discussed. Future research should be focused on the following areas: (1) interspecies scaling, (2) the effects of disease states on the pharmacokinetics of anticancer drugs, and (3) the applications of pharmocokinetics to the studies of growth behavior of cancer cells. The ultimate goal will be to utilize this basic information to design an optimal dosage regimen and treatment schedule for the safe and effective cancer chemotherapy of each individual patient.
Topics: Ancitabine; Animals; Antineoplastic Agents; Blood Proteins; Cisplatin; Cytarabine; Dactinomycin; Doxorubicin; Humans; Kinetics; Methotrexate; Models, Biological; Protein Binding; Species Specificity
PubMed: 93986
DOI: 10.1007/BF00254079 -
Journal of Medical Virology Jun 1990The antiviral activities of antileukemic drugs 1-beta-D-arabinofuranosylcytosine (Cytarabine; Ara-C), 2,2'-anhydro-1-beta-D-arabinofuranosylcytosine (Ancitabine;... (Comparative Study)
Comparative Study
Antiviral effect of antileukemic drugs N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BH-AC) and 2,2'-anhydro-1-beta-D-arabinofuranosylcytosine (cyclo-C) against human cytomegalovirus.
The antiviral activities of antileukemic drugs 1-beta-D-arabinofuranosylcytosine (Cytarabine; Ara-C), 2,2'-anhydro-1-beta-D-arabinofuranosylcytosine (Ancitabine; Cyclo-C), and N4-behenoyl-1-beta-D-arabinofuranosylcytosine (Enocitabine; BH-AC) were evaluated in vitro against human cytomegalovirus (HCMV) in comparison with those of five other antiviral drugs. Both Ara-C and Cyclo-C showed the strongest inhibitory effect to HCMV. BH-AC inhibited the replication of HCMV and depicted almost as the same dose-response curve as Ganciclovir (DHPG). In the presence of Ara-C, Cyclo-C, or BH-AC, triphosphate forms of the nucleoside analogs were detected in the HCMV-infected cells, and synthesis of HCMV DNA was strongly suppressed. Thus, Ara-C, Cyclo-C, and BH-AC were not only antileukemic, but also antiviral in vitro. However, Ara-C and Cyclo-C may not be suitable as anti-HCMV agents, because they are cytotoxic or excreted rapidly in the urine in vivo [Van Voris, 1984; Hirayama et al., 1974]. Because of lower toxicity and longer retention in vivo, BH-AC may be expected as an anti-HCMV agent in patients with leukemia, in addition to serving as an antileukemic drug.
Topics: Ancitabine; Antiviral Agents; Cells, Cultured; Cytarabine; Cytomegalovirus; DNA Replication; DNA, Viral; Fibroblasts; Humans; Nucleotides; Virus Replication
PubMed: 1696958
DOI: 10.1002/jmv.1890310212 -
[Zhonghua Yan Ke Za Zhi] Chinese... Nov 1983
Topics: Adolescent; Adult; Ancitabine; Animals; Child; Child, Preschool; Cytarabine; Delayed-Action Preparations; Female; Humans; Infant; Keratitis, Dendritic; Male; Middle Aged; Rabbits
PubMed: 6202470
DOI: No ID Found -
Cancer Treatment Reviews Mar 1976
Review
Topics: Acrylates; Alkylating Agents; Ancitabine; Animals; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Azacitidine; Chemical Phenomena; Chemistry; Chromomycins; Cisplatin; DNA, Neoplasm; Drug Evaluation, Preclinical; Etoposide; Humans; Ifosfamide; Leukemia L1210; Mice; Mitosis; National Institutes of Health (U.S.); Neoplasms; Neoplasms, Experimental; Razoxane; Tegafur; Teniposide; United States
PubMed: 62615
DOI: 10.1016/s0305-7372(76)80016-3 -
PeerJ 2022Cyclocytidine hydrochloride (HCl) has been reported to inhibit DNA synthesis by affecting DNA polymerase. Here, we tested the antiviral effect of cyclocytidine on...
BACKGROUND
Cyclocytidine hydrochloride (HCl) has been reported to inhibit DNA synthesis by affecting DNA polymerase. Here, we tested the antiviral effect of cyclocytidine on hepatitis B virus (HBV) DNA synthesis, which is reliant on DNA polymerase activity.
MATERIALS AND METHODS
Cyclocytidine HCl was treated to HBV-producing HepAD38 cells or added to an endogenous polymerase reaction, and HBV DNA was detected by Southern blot.
RESULTS
Treatment of 20 µM cyclocytidine HCl significantly decreased the production of relaxed circular (rc) DNA in HepAD38 cells and block rcDNA synthesis in endogenous polymerase reaction (EPR), a cell free assay, possibly by inhibiting the HBV DNA polymerase activity.
CONCLUSION
Cyclocytidine HCl could inhibit the synthesis of HBV rcDNA, the precursor of covalently closed circular DNA, and this result provides a case for the usage of "old" drugs for "new" applications.
Topics: Ancitabine; DNA, Circular; DNA, Viral; DNA-Directed DNA Polymerase; Hepatitis B virus; Virus Replication
PubMed: 35846878
DOI: 10.7717/peerj.13719 -
Gan To Kagaku Ryoho. Cancer &... Aug 1982Ara-C should be converted to ara-CTP to inhibit DNA polymerase in the malignant cells but is rapidly inactivated to uracil arabinoside (ara-U) by cytidine deaminase in... (Review)
Review
Ara-C should be converted to ara-CTP to inhibit DNA polymerase in the malignant cells but is rapidly inactivated to uracil arabinoside (ara-U) by cytidine deaminase in human tissue. Therefore, production as well as maintenance of ara-CTP in the cells is a function of both phosphorylation and deamination of ara-C, but is more dependent on the latter, because the deamination is several times superior to the former in terms of enzymatic activities. In chemotherapy with ara-C, the rate of the inactivation should be estimated for evaluating antitumor effect of the agent. Determination of serum or plasma deaminase activity can be a useful parameter of the inactivation. Attempts have been made to enhance the antitumor activity of ara-C by preventing deamination and a number of ara-C derivatives resistant to the deamination such as cyclocytidine, ara-C-5'-ester and acyl ara-C have been introduced. Cyclo-C gradually receives non-enzymatic hydrolysis to produce ara-C in neutral medium, which is useful for maintaining plasma ara-C level. Acyl ara-C such as behenoyl-ara-C (BHAC) is well incorporated into the cells and is highly distributed to lipophilic components such as membrane, microsome and mitochondria in the cells. The extremely gradual conversion of BHAC to ara-C in the cells is considered to be useful for maintaining effective intracellular concentration. A part of BHAC could be phosphorylated before deacylation. After intravenous administration of BHAC, the plasma drug concentrations are maintained significantly longer than those after the administration of the equivalent dose of ara-C. Therefore, BHAC is more resistant to the deamination than cyclo-C and the antitumor effect of the former is suspected to be milder but prolonged than that of ara-C or cyclo-C.
Topics: Ancitabine; Cytarabine; Humans; Kinetics; Leukemia
PubMed: 6191711
DOI: No ID Found