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


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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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2 2 difluoro 2 deoxycytidine dfdcyd gemcitabine gemzar

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


2 2 difluoro 2 deoxycytidine dfdcyd gemcitabine gemzar

Radiosensitization Corresponds to dATP Depletion


Hypothesis for radiosensitization by gemcitabine

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


Ribonucleotide reductase

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


Sirna protocol

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


Conclusions and future directions

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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