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The synthesis of dTDP is unique because of a requirement for thymidylate kinase ( TMPK). All other dNDPs including dUDP are directly produced by ribonucleotide reductase (RNR). In tumor cells.TMPK intervention leads to dUTP incorporation during repair.Disrupting RNR recruitment to damage sites or reducing the expression of the R2 subunit of RNR prevents the impairment of DNA repair by TMPK intervention,indicating that RNR contributes to dUTP incorporation during DSB repair.Normal cycling cells express low levels of R2 after DNA damage,thereby dispensing with the requirement for TMPK during repair.We further identified a novel cell-permeable non-toxic inhibitor of TMPK that sensitizes tumor cells to doxorubicin in vitro and in vivo while having little effect on growth and survival of normal cycling cells.This study offers a new strategy by which TMPK is targeted as an adjunctive therapy that aims to minimizing side effects by discriminating between tumor and rapidly-dividing cells in normal tissues.