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Cytarabine
- 2. CYTARABINE • Used in the treatment of WBC cancers (AML/ALL) and Lymphoma • Antimetabolite • S-Phase-specific Chemotherapy drug
- 3. CYTARABINE • Ara-C / Cytosine Arabinoside
- 4. CYTIDINE • Cytosine normally combines with Ribose / Deoxyribose sugar
- 6. CYTARABINE (Mechanism of Action) Nucleoside Transporter dCK Deoxycytidylate Kinase NDK Nucleotidase 1
- 7. CYTARABINE (Mechanism of Action) MDR (P-glycoprotein)
- 8. CYTARABINE (Mechanism of Action) Cytidine Deaminase Deoxycytidylate Deaminase
- 10. ACTION MODE OF araCTP
- 11. CYTARABINE Cytarabine is converted to its activated Triphosphate form Upon incorporation into DNA, the Cytidine analog interferes with chain elongation and promotes abnormal fragment ligation of newly synthesized DNA If araCTP ends up being incorporated into DNA, it leads to Apoptosis
- 12. CONCLUSION Parameters in araC Sensitivity Conversion to Triphosphate activated form by Kinases Inactivation via Deamination Overexpression of MDR transporters Half-life of active form araCTP Increased expression of MDR such as P-glycoprotein and enzymes (Deaminases) that counteract the activation of araC to its activated araCTP cause cancer tumor cell resistance.
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Notas del editor
- It is used in the treatment of WBC cancers such as AML & ALL as well as Lymphoma.It acts as an ANTIMETABOLITE. Meaning it mimics or competes for normal metabolites needed by cells. In the case of Cytarabine, it competes with normal Cytosine base incorporated within the DNA.Cytarabine exerts its chemotherapeutic action during the S PHASE of the Cell cycle where DNA Replication happens.
- Cytarabine is otherwise known as Ara-Cor Cytosine Arabinoside. Its components include a Cytosine Base + Arabinose Sugar
- Cytosine normally binds to Ribose (in RNA) orDeoxyribose (in DNA) forming normal Nucleosides.
- Cytidine with Ribose sugar is usually incorporated in RNA.Deoxycytidine with Deoxyribose sugar is usually incorporated in DNA.Arabinose sugar moiety is epimeric at 2’ position with Ribose.
- Nucleoside Transporter facilitates entry of Cytarabine into the cell.Phosphorylation is needed to convert Cytarabine to its activated Triphosphate form in order to become a substrate for DNA Polymerase. The enzymes needed for Phosphorylation include the kinases.The first Phosphorylation is catalyzed by DEOXYCYTOSINE KINASE forming Cytarabine Monophosphate.Note that Enzyme NUCLEOTIDASE 1 can dephosphorylate Cytarabine Monophosphate reverting back Cytarabine to its inactive form.Additional two Phosphorylation steps are catalyzed by DEOXYCYTIDYLATE KINASE and NUCLEOSIDE DIPHOSPHATE KINASE forming Cytarabine Triphosphate, the Active form of Cytarabine.
- The activation of araC to araCTP can be intercepted at several stages. The extrusion of araC is mediated by multi-drug resistance transporters (MDRs) such as P-GLYCOPROTEIN which belongs to the family of ATP-Binding Cassette transporters.
- Deamination reactions can promote conversion of Cytarabine to other species, an effect that reduces araCTP concentrations, thereby potentially limiting its apoptosis-promoting action.CYTIDINE DEAMINASE may deaminateCytarabine forming Uridine.And DEOXYCYTIDYLATE DEAMINASE may deaminateCytarabine Monophosphate forming Uridine monophosphate.
- After entering the cells via Hent1, araC is phosphorylated in a stepwise fashion at the 5’ position of Arabinose.Phosphorylation is needed to convert Cytarabine to its activated Triphosphate form in order to become a substrate for DNA Polymerase. The enzymes needed for Phosphorylation include the kinases.The first Phosphorylation is catalyzed by DEOXYCYTOSINE KINASE forming Cytarabine Monophosphate.Note that Enzyme NUCLEOTIDASE 1 can dephosphorylate Cytarabine Monophosphate reverting back araCMP to its inactive form.Additional two Phosphorylation steps are catalyzed by DEOXYCYTIDYLATE KINASE and NUCLEOSIDE DIPHOSPHATE KINASE forming Cytarabine Triphosphate, the Active form of Cytarabine.
- araCTP is accepted as a substrate by DNA Polymaerase and becomes incorporated into a growing DNA strand.Due to incorrect araC nucleotide base incorporation, Abortion of Polymerization happens activating DNA repair and causes delay in DNA replication and constitutes a proapoptotic signal.Topoisomerase II which checks any errors after Polymerization, cleaves the DNA double strand. Resealing of the double strand by Ligase may fail and lead to Chromosome breaks.