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Comparison of Ara-C and Tezacitabine :. Similarities and Reasons of Different Therapeutic Applications. By: Mohammed M. Abbas. Abstract
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Comparison of Ara-C and Tezacitabine: Similarities and Reasons of Different Therapeutic Applications By: Mohammed M. Abbas
Abstract The aim of this paper is to discuss the chemical features of both,ara-Candtezacitabine, showing the differences in their characteristics with focusing on the similarities and differences in their mechanism of action, therapeutic applications including their administration, pharmacokinetics, toxicities, adverse effects and their drug interactions. In addition, this paper shows the main mechanisms of resistance in both agents and describes ways of following up the resistance/no-resistance to these compounds the reason of the different therapeutic applications. Also, it discusses the therapeutic applications of those two drugs and finally summarizes the main similarities and differences between them.
Ara-C • Antimetabolite Synthesized in late 1950s from the sponge Cryptothethya crypta. • Also known as cytosine arabinoside or cytarabine. • One of the most widely used anticancer agents. Tezacitabine • Synthesized in 1998 by McCarthy at Marrion Marrrel Dow at the Hoechst Marion Roussel research institute. • Known as (E)-2`-deoxy-2`-(fluromethylene)-cytidine. • Novel deoxycytidine analogue with a structural similarity to ara-C.
Chemical composition (Nitrogen group) Site of deamination (Hydroxyl group) Responsible site for phosphorylation Groups in a trans position Fluorine containing group responsible for the increased lipophilicity
Metabolism Ara-C • Convertion to the active form, arabinosyl-cytidine triphosphate through phosphorylation reactions. • Degradation by cytidine deaminase to form the inactive product uracil arabinoside. Tezacitabine • Converted to monophosphate followed by further phosphorylation reactions produce diphosphate triphosphatemetabolites. • Poor deamination resulting fluoromethylene deoxyuridine (FMdU).
Mechanism of Action Ara-C • Inhibition of DNA template function and chain elongation. • Unusual replication of DNA segments • Inhibition of ara-CDP-choline formation. Tezacitabine • Inhibition of ribonucleotide reductase. • Angiogenic effect.
Indication Ara-C • Hematological malignancies (mainly leukemia). • Hodgkin's Non-Hodgkin's lymphoma. • Glioma, prophylaxis of CNS metastases. • Antiviral activity. Tezacitabine • Solid tumors (such as lung, prostate, overy, cervix and hematopoietic tissues). • CNS tumors. • Multi-drug resistant cancer cells.
Administration Adverse Reactions
Resistance Ara-C • Activating enzyme deficiency or upregulated deactivating enzyme (most frequent). • Defects in nucleoside transport into the cell. • Inhibition of nucleoside analogues. • Decreased the inhibitory effect of nucleoside analogues for DNA polymerases. • Defects in the induction of apoptosis. Tezacitabine • Safer and well tolerable • Minimal conversion to (E)-2'-deoxy-2'-(fluromethylene) uridine. • Not known.
Follow up Ara-C • Liquid scintillation using a radioactive ara-C. • Using ara-C-sensitive strain of streptococcus faecalis. • Inhibition of DNA synthesis in bone marrow cells from nude mouse xenografts. • Measuring ara-C-ovalbumin conjugate with highly sensitive radioimmunoassay technique. • Cation-exchange HPLC in measuring triphosphate nucleotide levels in cells. • Gas chromatography-mass spectroscopy method. Tezacitabine • Not fully developed. • Magnetic resonance imagining technique for measuring tumor volume.
Summery (2) • Ara-C resistance occurs through different mechanisms. The most frequent mechanism for resistance is due to decreased activity of deoxycytidine kinase. Different assay methods are used to measure plasma ara-C concentration. • The mechanisms of resistance to tezacitabine are not fully elucidated and following up techniques are not develop and/or reported in scientific literature yet. • The information regarding tezacitabine properties is limited, probably because of the early stages of its development and also because possible commercial aspects. Researches and trials should be done to determine many features in the structure activity relationship, mechanism of action, drug interactions, mechanisms of resistance and follow-up.
Latest Issue: Tezacitabine Phase II Trial Halted Friday, March 19 2004 @ 02:27 PM EST Contributed by: tberberabe Chiron Corporation, the company that acquired tezacitabine in January 2002 with the purchase of Matrix Pharmaceutical, today announced that the company has decided to discontinue further development of tezacitabine based on an analysis of the data from a Phase II trial in patients with gastroesophageal cancer. The compound did not demonstrate sufficient antitumor activity in the trial to satisfy Chiron's predetermined criteria to advance the program. Source: http://www.biotechnologyhealthcare.com/article.php?story=20040319142720105&query=tezacitabine