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Ribonucleoside- diphosphate reductase subunit M2 Ribonucleoside- diphosphate reductase subunit M2 B Equilibrative nucleoside transporter 1 Sodium/nucleoside cotransporter 2 Equilibrative nucleoside transporter 2 Deoxycytidine kinase Adenylate kinase 9 Nucleoside diphosphate kinase 3 Clofarabine 5'-triphosphate Clofarabine 5'-triphosphate Clofarabine Clofarabine an oxidized thioredoxin dADP H2O ADP reduced thioredoxin clofarabine-5´-monophosphate Clofarabine 5'-diphosphate Na+ Na+ ATP ADP ATP ADP DNA polymerase catalytic subunit Fe2+ DNA synthesis Cytosol Clofarabine is converted to its monophosphate, diphosphate and, finally, its triphosphate forms in the nucleoside salvage pathway. T or B Cell Blood vessel T or B Cell Apoptosis The apoptosis of the T and B cells results in the death of the cancerous white blood cells but also ini the mmunosuppression of the patient by the death of the B and T cells and, also, by the arrest of antibodies production. Due to the inhibition of the DNA synthesis, the inhibition of the DNA polymerase, and the inhibition of the ribonucleoside reductase, the T and B cells will go through apoptosis.This drug cause cells to accumulate at the G1/S phase junction. Clofarabine 5'-triphosphate accumulates and is incorporated in the DNA due to its structure. Through competitive inhibition, this drug also inhibits the DNA polymerase. Nucleus The accumulation of the triphosphate metabolite is due to the fact that the 2-chloro moiety of the molecule makes it a relatively poor substrate for the monophosphate kinase. The incorporation in the DNA results in DNA breaks and the inhibition of DNA synthesis and repair. During the replication of the DNA, this will cause the apoptosis of the T or B cells. The accumulation of clofarabine 5'-triphosphate inhibits the ribonuclotide reductase. This leads to an imbalance in dNTP. This will impact the DNA synthesis because the dNTP pool will be changed. The imbalanced dNTP pool leads to DNA strand breaks and to the inhibition of the DNA synthesis. Through depletion of the dNTP pool, clofarabine self-potentiates the incorporation of clofarabine triphosphates into DNA.
Nucleus RRM2 RRM2B SLC29A1 SLC28A2 SLC29A2 DCK AK9 NME3 Clofarabine 5'-triphosphate Clofarabine 5'-triphosphate Clofarabine Clofarabine an oxidized thioredoxin dADP Water Adenosine diphosphate reduced thioredoxin clofarabine- 5´- monophosphate Clofarabine 5'-diphosphate Sodium Sodium Adenosine triphosphate Adenosine diphosphate Adenosine triphosphate Adenosine diphosphate UL30 DNA synthesis
RRM2 RRM2B SLC29A1 SLC28A2 SLC29A2 DCK AK9 NME3 Cl 5'-t Cl 5'-t Cafda Cafda AOT dADP H2O ADP RT cl-5´-m Cl 5'-d Na+ Na+ ATP ADP ATP ADP UL30 Fe2+ DNA syn Cytosol Clofarabine is converted to its monophosphate, diphosphate and, finally, its triphosphate forms in the nucleoside salvage pathway. T or B Cell Blood vessel T or B Cell Apoptosis The apoptosis of the T and B cells results in the death of the cancerous white blood cells but also ini the mmunosuppression of the patient by the death of the B and T cells and, also, by the arrest of antibodies production. Due to the inhibition of the DNA synthesis, the inhibition of the DNA polymerase, and the inhibition of the ribonucleoside reductase, the T and B cells will go through apoptosis.This drug cause cells to accumulate at the G1/S phase junction. Clofarabine 5'-triphosphate accumulates and is incorporated in the DNA due to its structure. Through competitive inhibition, this drug also inhibits the DNA polymerase. Nucleus The accumulation of the triphosphate metabolite is due to the fact that the 2-chloro moiety of the molecule makes it a relatively poor substrate for the monophosphate kinase. The incorporation in the DNA results in DNA breaks and the inhibition of DNA synthesis and repair. During the replication of the DNA, this will cause the apoptosis of the T or B cells. The accumulation of clofarabine 5'-triphosphate inhibits the ribonuclotide reductase. This leads to an imbalance in dNTP. This will impact the DNA synthesis because the dNTP pool will be changed. The imbalanced dNTP pool leads to DNA strand breaks and to the inhibition of the DNA synthesis. Through depletion of the dNTP pool, clofarabine self-potentiates the incorporation of clofarabine triphosphates into DNA.
Nucleus RRM2 RRM2B SLC29A1 SLC28A2 SLC29A2 DCK AK9 NME3 Cl 5'-t Cl 5'-t Cafda Cafda AOT dADP H2O ADP RT cl-5´-m Cl 5'-d Na+ Na+ ATP ADP ATP ADP UL30 DNA syn