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2’,2’-Difluoro-2’-Deoxycytidine (dFdCyd, Gemcitabine, Gemzar®)

2’,2’-Difluoro-2’-Deoxycytidine (dFdCyd, Gemcitabine, Gemzar®). Metabolism of Gemcitabine. deoxycytidine kinase. Transport. dFdCDP. dFdCyd. dFdCMP. dFdCyd. dFdCTP. DNA. dFdUrd. dFdUMP. DNA polymerases. dNTP. rNDP. dNDP. ribonucleotide reductase.

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2’,2’-Difluoro-2’-Deoxycytidine (dFdCyd, Gemcitabine, Gemzar®)

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  1. 2’,2’-Difluoro-2’-Deoxycytidine(dFdCyd, Gemcitabine, Gemzar®)

  2. Metabolism of Gemcitabine deoxycytidine kinase Transport dFdCDP dFdCyd dFdCMP dFdCyd dFdCTP DNA dFdUrd dFdUMP DNA polymerases dNTP rNDP dNDP ribonucleotide reductase

  3. Radiosensitization Corresponds to dATP Depletion

  4. X X X X X X X X X X X X Hypothesis for Radiosensitization by Gemcitabine Mismatched Nucleotides Most lesions repaired correctly No further damage + Gemcitabine dATP Mismatches become mutations DNA + g-ray Mismatches not repaired

  5. Ribonucleotide Reductase R1 • Composed of 2 homodimeric subunits • R1- 86 kDa Regulatory subunit • R2- 43 kDa Catalytic subunit R2 Eklund et al, Progress in Biophysics & Molecular Biology 77 (2001) 177–268

  6. siRNA Protocol Exposed to Transfection Mixture for 24 h Allowed to grow 0-72 h Split into T25 24 h prior to treatment Wash, replete media Grow 24 h + ionizing radiation Western blot Cytotoxicity Radiosensitization Add Drug 24 h

  7. Conclusions and Future Directions • p53 status on dFdCyd efficacy • Solid tumors expressing wt or mt p53 should be sensitive to radiosensitization with dFdCyd • Manipulation of p53R2 to increase cytotoxicity • Differential sensitivities of R1/p53R2 pairing compared to R1/R2 to anticancer agents • p53R2 suppression increased 5-FU cytotoxicity • p53R2 silencing and radiosensitization • In some tumors, p53R2 silencing may enhance radiosensitization • Are the two cell lines inherently different, or are the differences due to incomplete silencing?

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