| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics |
Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0504
Gemcitabine (2', 2'-difluoro-2'-deoxycytidine; dFdCyd) has been shown to
be a potent radiosensitizer in tumor cells both in vitro
and in vivo. We evaluated the ability of dFdCyd to
enhance the radiosensitivity of two human glioblastoma cell lines. The
results demonstrated that U251 cells were more sensitive to the
cytotoxicity of dFdCyd, and that dFdCyd was able to radiosensitize
these cells. In contrast, D54 cells were more resistant to the
cytotoxic effect of dFdCyd, and no radiosensitization occurred at any concentration of dFdCyd tested. Because radiosensitization by
dFdCyd has been correlated with its ability to deplete dATP pools
through inhibition of ribonucleotide reductase by dFdCyd diphosphate,
we evaluated the metabolism of dFdCyd in both cell lines. At equitoxic
concentrations of dFdCyd, both cell lines accumulated similar levels of
the cytotoxic metabolite, dFdCyd triphosphate, as well as similar
levels of dFdCyd monophosphate in DNA. In U251 cells,
radiosensitizing concentrations of dFdCyd (10 or 25 nM;
IC10 or IC50) depleted dATP by 
80% within
4 h. In contrast, 80 nM (IC50) was unable
to deplete dATP by >30% within 4 h in D54 cells. Higher
concentrations of dFdCyd or hydroxyurea, an inhibitor of ribonucleotide
reductase that depleted dATP >90%, also did not produce
radiosensitization in D54 cells. D54 cells were not resistant to
radiosensitization because bromodeoxyuridine was able to induce
radiosensitization. Because D54 cells express wild-type p53, whereas
U251 cells express a mutant p53, the effect of dFdCyd and ionizing
radiation on cell cycle progression was evaluated. Radiation alone
produced a G1 block in D54 cells and a transient
G2-M block in U251 cells. After a 24 h incubation with
dFdCyd alone or in combination with ionizing radiation, U251 cells
readily accumulated in S-phase, which remained elevated for at least
72 h, consistent with previous results in other mutant p53 cell
lines. In addition, radiation enhanced the ability of dFdCyd to induce
S-phase-specific cell death in U251 cells. In contrast, D54 cells
showed a G1 block after dFdCyd and radiation exposure, with
fewer cells in S-phase for at least 48 h after drug
washout/irradiation. Furthermore, treatment with dFdCyd and/or
radiation did not increase the amount of S-phase-specific cell death in
D54 cells compared with control cells. These results suggest that the
G1 block in D54 cells resulting from wild-type p53
induction prevented radiosensitization by dFdCyd.
This article has been cited by other articles:
|
|
 |
|
  M. A. Morgan, L. A. Parsels, J. Maybaum, and T. S. Lawrence Improving Gemcitabine-Mediated Radiosensitization Using Molecularly Targeted Therapy: A Review Clin. Cancer Res., November 1, 2008; 14(21): 6744 - 6750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Flanagan, C. M. Krokosky, S. Mannava, M. A. Nikiforov, and D. S. Shewach MLH1 Deficiency Enhances Radiosensitization with 5-Fluorodeoxyuridine by Increasing DNA Mismatches Mol. Pharmacol., September 1, 2008; 74(3): 863 - 871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Okazaki, L. Jiao, P. Chang, D. B. Evans, J. L. Abbruzzese, and D. Li Single-Nucleotide Polymorphisms of DNA Damage Response Genes Are Associated with Overall Survival in Patients with Pancreatic Cancer Clin. Cancer Res., April 1, 2008; 14(7): 2042 - 2048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Flanagan, B. W. Robinson, C. M. Krokosky, and D. S. Shewach Mismatched nucleotides as the lesions responsible for radiosensitization with gemcitabine: a new paradigm for antimetabolite radiosensitizers Mol. Cancer Ther., June 1, 2007; 6(6): 1858 - 1868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Milenic, K. Garmestani, E. D. Brady, P. S. Albert, A. Abdulla, J. Flynn, and M. W. Brechbiel Potentiation of High-LET Radiation by Gemcitabine: Targeting HER2 with Trastuzumab to Treat Disseminated Peritoneal Disease Clin. Cancer Res., March 15, 2007; 13(6): 1926 - 1935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bianco, E. Giovannetti, F. Ciardiello, V. Mey, S. Nannizzi, G. Tortora, T. Troiani, F. Pasqualetti, G. Eckhardt, M. de Liguoro, et al. Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer Clin. Cancer Res., December 1, 2006; 12(23): 7099 - 7107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Morgan, L. A. Parsels, J. D. Parsels, A. K. Mesiwala, J. Maybaum, and T. S. Lawrence Role of Checkpoint Kinase 1 in Preventing Premature Mitosis in Response to Gemcitabine Cancer Res., August 1, 2005; 65(15): 6835 - 6842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Hofstetter, V. Vuong, A. Broggini-Tenzer, S. Bodis, I. F. Ciernik, D. Fabbro, M. Wartmann, G. Folkers, and M. Pruschy Patupilone Acts as Radiosensitizing Agent in Multidrug-Resistant Cancer Cells In vitro and In vivo Clin. Cancer Res., February 15, 2005; 11(4): 1588 - 1596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Pauwels, A. E.C. Korst, F. Lardon, and J. B. Vermorken Combined Modality Therapy of Gemcitabine and Radiation Oncologist, January 1, 2005; 10(1): 34 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Kvols Radiation Sensitizers: A Selective Review of Molecules Targeting DNA and non-DNA Targets J. Nucl. Med., January 1, 2005; 46(1_suppl): 187S - 190S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. W. Robinson, M. M. Im, M. Ljungman, F. Praz, and D. S. Shewach Enhanced Radiosensitization with Gemcitabine in Mismatch Repair-Deficient HCT116 Cells Cancer Res., October 15, 2003; 63(20): 6935 - 6941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sun, R. Urrabaz, S. Kelly, M. Nguyen, and S. Weitman Enhancement of DNA Ligase I Level by Gemcitabine in Human Cancer Cells Clin. Cancer Res., April 1, 2002; 8(4): 1189 - 1195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. W. Robinson and D. S. Shewach Radiosensitization by Gemcitabine in p53 Wild-Type and Mutant MCF-7 Breast Carcinoma Cell Lines Clin. Cancer Res., August 1, 2001; 7(8): 2581 - 2589. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
