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[Cancer Research 51, 6110-6117, November 15, 1991]
© 1991 American Association for Cancer Research
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Action of 2',2'-Difluorodeoxycytidine on DNA Synthesis1

Peng Huang, Sherri Chubb, Larry W. Hertel, Gerald B. Grindey and William Plunkett2

Department of Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [P. H., S. C., W. P.], and Lilly Research Laboratories, Indianapolis IN 46285 [L. W. H., G. B. G.]

The action of the new deoxycytidine analogue 2',2'-difluorodeoxycytidine (dFdC) on DNA synthesis was investigated in whole cells and in vitro assay systems with purified DNA polymerases. DNA synthesis in human lymphoblastoid CEM cells was inhibited by dFdC in a concentration-dependent manner that could not be reversed by exogenous deoxynucleosides. The analogue was incorporated into cellular DNA; most of the incorporated dFdC 5'-monophosphate (dFdCMP) residues were in internucleotide linkage. In vitro DNA primer extension assays demonstrated that dFdC 5'-triphosphate (dFdCTP) competed with deoxycytidine triphosphate for incorporation into the C sites of the growing DNA strand. The ratios of the apparent Km values for the incorporation of dFdCTP and dCTP into a C site of M13mp19 DNA were 21.8 and 22.9 for DNA polymerases {alpha} and {varepsilon}, respectively. The apparent Kl values of dFdCTP were 11.2 µM for DNA polymerase {alpha} and 14.4 µM for polymerase {varepsilon}. After dFdCMP incorporation, the primer was extended by one deoxynucleotide before a major pause in the polymerization process was observed. This was in contrast to the action of arabinosylcytosine 5'-triphosphate, which caused both DNA polymerases {alpha} and {varepsilon} to pause at the site of incorporation. The 3' -> 5' exonuclease activity of DNA polymerase {varepsilon} was essentially unable to excise nucleotides from DNA containing dFdCMP at either the 3'-end or at an internal position, whereas arabinosylcytosine monophosphate was removed from the 3'-terminus at 37% the rate for deoxynucleotides. The cytotoxic activity of dFdC was strongly correlated with the amount of dFdCMP incorporated into cellular DNA. Our results demonstrate qualitative and quantitative differences in the molecular actions of dFdC and arabinosylcytosine on DNA metabolism, but are consistent with an important role for such incorporation in the toxicity of dFdC.

1 Supported in part by Grant CA28596 from the National Cancer Institute, Department of Health and Human Services, and by Grant CH-130 from the American Cancer Society.

2 To whom requests for reprints should be addressed, at Department of Medical Oncology, Box 52, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.

Received 5/23/91. Accepted 9/10/91.




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P. Pourquier, C. Gioffre, G. Kohlhagen, Y. Urasaki, F. Goldwasser, L. W. Hertel, S. Yu, R. T. Pon, W. H. Gmeiner, and Y. Pommier
Gemcitabine (2',2'-Difluoro-2'-Deoxycytidine), an Antimetabolite That Poisons Topoisomerase I
Clin. Cancer Res., August 1, 2002; 8(8): 2499 - 2504.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
L. Leblond, G. Attardo, B. Hamelin, D. Y. Bouffard, N. Nguyen-Ba, and H. Gourdeau
BCH-1868 [(-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-yl-methyl) tetrahydrofuran]: A Cyclic Nucleoside Phosphonate with Antitumor Activity
Mol. Cancer Ther., July 1, 2002; 1(9): 737 - 746.
[Abstract] [Full Text] [PDF]

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M. L. Hensley, R. Maki, E. Venkatraman, G. Geller, M. Lovegren, C. Aghajanian, P. Sabbatini, W. Tong, R. Barakat, and D. R. Spriggs
Gemcitabine and Docetaxel in Patients With Unresectable Leiomyosarcoma: Results of a Phase II Trial
J. Clin. Oncol., June 15, 2002; 20(12): 2824 - 2831.
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C. O. Rodriguez Jr., B. S. Mitchell, M. Ayres, S. Eriksson, and V. Gandhi
Arabinosylguanine Is Phosphorylated by Both Cytoplasmic Deoxycytidine Kinase and Mitochondrial Deoxyguanosine Kinase
Cancer Res., June 1, 2002; 62(11): 3100 - 3105.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
J. R. Kroep, W. J. P. Loves, C. L. van der Wilt, E. Alvarez, I. Talianidis, E. Boven, B. J. M. Braakhuis, C. J. van Groeningen, H. M. Pinedo, and G. J. Peters
Pretreatment Deoxycytidine Kinase Levels Predict in Vivo Gemcitabine Sensitivity
Mol. Cancer Ther., April 1, 2002; 1(6): 371 - 376.
[Abstract] [Full Text] [PDF]

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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]

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V. Gandhi, W. Plunkett, M. Du, M. Ayres, and E. H. Estey
Prolonged Infusion of Gemcitabine: Clinical and Pharmacodynamic Studies During a Phase I Trial in Relapsed Acute Myelogenous Leukemia
J. Clin. Oncol., February 1, 2002; 20(3): 665 - 673.
[Abstract] [Full Text] [PDF]

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D. A. Rizzieri, A. J. Bass, G. L. Rosner, J. P. Gockerman, C. M. DeCastro, W. P. Petros, D. J. Adams, M. J. Laughlin, P. Davis, T. Foster, et al.
Phase I Evaluation of Prolonged-Infusion Gemcitabine With Mitoxantrone for Relapsed or Refractory Acute Leukemia
J. Clin. Oncol., February 1, 2002; 20(3): 674 - 679.
[Abstract] [Full Text] [PDF]

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R. L. Schilsky, D. Bertucci, N. J. Vogelzang, H. L. Kindler, and M. J. Ratain
Dose-Escalating Study of Capecitabine Plus Gemcitabine Combination Therapy in Patients With Advanced Cancer
J. Clin. Oncol., January 15, 2002; 20(2): 582 - 587.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
Y. Zhou, G. Achanta, H. Pelicano, V. Gandhi, W. Plunkett, and P. Huang
Action of (E)-2'-Deoxy-2'-(fluoromethylene)cytidine on DNA Metabolism: Incorporation, Excision, and Cellular Response
Mol. Pharmacol., January 1, 2002; 61(1): 222 - 229.
[Abstract] [Full Text] [PDF]

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G. Achanta, H. Pelicano, L. Feng, W. Plunkett, and P. Huang
Interaction of p53 and DNA-PK in Response to Nucleoside Analogues: Potential Role As a Sensor Complex for DNA Damage
Cancer Res., December 1, 2001; 61(24): 8723 - 8729.
[Abstract] [Full Text] [PDF]

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H. Gourdeau, M. L. Clarke, F. Ouellet, D. Mowles, M. Selner, A. Richard, N. Lee, J. R. Mackey, J. D. Young, J. Jolivet, et al.
Mechanisms of Uptake and Resistance to Troxacitabine, a Novel Deoxycytidine Nucleoside Analogue, in Human Leukemic and Solid Tumor Cell Lines
Cancer Res., October 1, 2001; 61(19): 7217 - 7224.
[Abstract] [Full Text] [PDF]

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A. W. Blackstock, H. Lightfoot, L. D. Case, J. E. Tepper, S. K. Mukherji, B. S. Mitchell, S. G. Swarts, and S. M. Hess
Tumor Uptake and Elimination of 2',2'-Difluoro-2'-deoxycytidine (Gemcitabine) after Deoxycytidine Kinase Gene Transfer: Correlation with in Vivo Tumor Response
Clin. Cancer Res., October 1, 2001; 7(10): 3263 - 3268.
[Abstract] [Full Text] [PDF]

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S. R. Patel, V. Gandhi, J. Jenkins, N. Papadopolous, M. A. Burgess, C. Plager, W. Plunkett, and R. S. Benjamin
Phase II Clinical Investigation of Gemcitabine in Advanced Soft Tissue Sarcomas and Window Evaluation of Dose Rate on Gemcitabine Triphosphate Accumulation
J. Clin. Oncol., August 1, 2001; 19(15): 3483 - 3489.
[Abstract] [Full Text] [PDF]

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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]

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V. Gandhi, W. Plunkett, S. Weller, M. Du, M. Ayres, C. O. Rodriguez Jr, P. Ramakrishna, G. L. Rosner, J. P. Hodge, S. O'Brien, et al.
Evaluation of the Combination of Nelarabine and Fludarabine in Leukemias: Clinical Response, Pharmacokinetics, and Pharmacodynamics in Leukemia Cells
J. Clin. Oncol., April 15, 2001; 19(8): 2142 - 2152.
[Abstract] [Full Text] [PDF]

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A. Azuma, P. Huang, A. Matsuda, and W. Plunkett
2'-C-Cyano-2'-deoxy-1-{beta}-D-arabino-pentofuranosylcytosine: A Novel Anticancer Nucleoside Analog that Causes Both DNA Strand Breaks and G2 Arrest
Mol. Pharmacol., April 1, 2001; 59(4): 725 - 731.
[Abstract] [Full Text]

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E. Rivera, V. Valero, L. Syrewicz, Z. Rahman, F. L. Esteva, R. L. Theriault, M. M. Rosales, D. Booser, J. L. Murray, R. C. Bast Jr, et al.
Phase I Study of Stealth Liposomal Doxorubicin in Combination With Gemcitabine in the Treatment of Patients With Metastatic Breast Cancer
J. Clin. Oncol., March 15, 2001; 19(6): 1716 - 1722.
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Z. Shi, A. Azuma, D. Sampath, Y.-X. Li, P. Huang, and W. Plunkett
S-Phase Arrest by Nucleoside Analogues and Abrogation of Survival without Cell Cycle Progression by 7-Hydroxystaurosporine
Cancer Res., February 1, 2001; 61(3): 1065 - 1072.
[Abstract] [Full Text]

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T. H. Doyle, F. Mornex, and W. G. McKenna
The Clinical Implications of Gemcitabine Radiosensitization
Clin. Cancer Res., February 1, 2001; 7(2): 226 - 228.
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S. C. H. Chen, M.-C. Lin, J. W. C. Chang, S.-W. Wang, C.-H. Lee, and T. C. Y. Tsao
Phase II Study of Regimen of Gemcitabine and Cisplatin in Advanced Non-small Cell Lung Cancer
Jpn. J. Clin. Oncol., November 1, 2000; 30(11): 494 - 498.
[Abstract] [Full Text] [PDF]

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L. J. Ostruszka and D. S. Shewach
The Role of Cell Cycle Progression in Radiosensitization by 2',2'-Difluoro-2'-deoxycytidine
Cancer Res., November 1, 2000; 60(21): 6080 - 6088.
[Abstract] [Full Text]

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R. A. Nagourney, J. S. Link, J. B. Blitzer, C. Forsthoff, and S. S. Evans
Gemcitabine Plus Cisplatin Repeating Doublet Therapy in Previously Treated, Relapsed Breast Cancer Patients
J. Clin. Oncol., June 11, 2000; 18(11): 2245 - 2249.
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M. Haq, A. Shafii, E. E. Zervos, and A. S. Rosemurgy
Addition of Matrix Metalloproteinase Inhibition to Conventional Cytotoxic Therapy Reduces Tumor Implantation and Prolongs Survival in a Murine Model of Human Pancreatic Cancer
Cancer Res., June 1, 2000; 60(12): 3207 - 3211.
[Abstract] [Full Text]

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W. Voigt, A. Bulankin, T. Muller, C. Schoeber, A. Grothey, C. Hoang-Vu, and H-J. Schmoll
Schedule-dependent Antagonism of Gemcitabine and Cisplatin in Human Anaplastic Thyroid Cancer Cell Lines
Clin. Cancer Res., May 1, 2000; 6(5): 2087 - 2093.
[Abstract] [Full Text] [PDF]

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L.-Y. Yang, L. Li, H. Jiang, Y. Shen, and W. Plunkett
Expression of ERCC1 Antisense RNA Abrogates Gemcitabine-mediated Cytotoxic Synergism with Cisplatin in Human Colon Tumor Cells Defective in Mismatch Repair but Proficient in Nucleotide Excision Repair
Clin. Cancer Res., March 1, 2000; 6(3): 773 - 781.
[Abstract] [Full Text]

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P. Kramata and K. M. Downey
9-(2-Phosphonylmethoxyethyl) Derivatives of Purine Nucleotide Analogs: A Comparison of Their Metabolism and Interaction with Cellular DNA Synthesis
Mol. Pharmacol., December 1, 1999; 56(6): 1262 - 1270.
[Abstract] [Full Text]

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C. O. Rodriguez Jr. and V. Gandhi
Arabinosylguanine-induced Apoptosis of T-Lymphoblastic Cells: Incorporation into DNA Is a Necessary Step
Cancer Res., October 1, 1999; 59(19): 4937 - 4943.
[Abstract] [Full Text] [PDF]

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P. A. Coucke, L. A. Decosterd, Y.-X. Li, E. Cottin, X. Chen, L.-Q. Sun, S. Stern, N. Paschoud, and J. Denekamp
The Ribonucleoside Diphosphate Reductase Inhibitor (E)-2'-Deoxy-(fluoromethylene)cytidine as a Cytotoxic Radiosensitizer in Vitro
Cancer Res., October 1, 1999; 59(20): 5219 - 5226.
[Abstract] [Full Text] [PDF]

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J. L. Tonkinson, J. F. Worzalla, C.-H. Teng, and L. G. Mendelsohn
Cell Cycle Modulation by a Multitargeted Antifolate, LY231514, Increases the Cytotoxicity and Antitumor Activity of Gemcitabine in HT29 Colon Carcinoma
Cancer Res., August 1, 1999; 59(15): 3671 - 3676.
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D. J. Mazur and F. W. Perrino
Identification and Expression of the TREX1 and TREX2 cDNA Sequences Encoding Mammalian 3'right-arrow5' Exonucleases
J. Biol. Chem., July 9, 1999; 274(28): 19655 - 19660.
[Abstract] [Full Text] [PDF]

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J. R. Kroep, G. Giaccone, D. A. Voorn, E. F. Smit, J. H. Beijnen, H. Rosing, C. J.A. van Moorsel, C. J. van Groeningen, P. E. Postmus, H. M. Pinedo, et al.
Gemcitabine and Paclitaxel: Pharmacokinetic and Pharmacodynamic Interactions in Patients With Non-Small-Cell Lung Cancer
J. Clin. Oncol., July 1, 1999; 17(7): 2190 - 2190.
[Abstract] [Full Text] [PDF]

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M. Hidalgo, D. Castellano, L. Paz-Ares, C. Gravalos, M. Diaz-Puente, R. Hitt, S. Alonso, and H. Cortes-Funes
Phase I-II Study of Gemcitabine and Fluorouracil as a Continuous Infusion in Patients With Pancreatic Cancer
J. Clin. Oncol., February 1, 1999; 17(2): 585 - 585.
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P. Kramata, K. M. Downey, and L. R. Paborsky
Incorporation and Excision of 9-(2-Phosphonylmethoxyethyl)guanine (PMEG) by DNA Polymerase delta  and epsilon  in Vitro
J. Biol. Chem., August 21, 1998; 273(34): 21966 - 21971.
[Abstract] [Full Text] [PDF]

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 BloodHome page
H. Iwasaki, P. Huang, M. J. Keating, and W. Plunkett
Differential Incorporation of Ara-C, Gemcitabine, and Fludarabine Into Replicating and Repairing DNA in Proliferating Human Leukemia Cells
Blood, July 1, 1997; 90(1): 270 - 278.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
C. J.A. van Moorsel, G. J. Peters, and H. M. Pinedo
Gemcitabine: Future Prospects of Single-Agent and Combination Studies
Oncologist, June 1, 1997; 2(3): 127 - 134.
[Abstract] [Full Text] [PDF]

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K.-i. Kamiya, P. Huang, and W. Plunkett
Inhibition of the 3' right-arrow 5' Exonuclease of Human DNA Polymerase epsilon by Fludarabine-terminated DNA
J. Biol. Chem., August 9, 1996; 271(32): 19428 - 19435.
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Y.-Z. Xu, P. Huang, and W. Plunkett
Functional Compartmentation of dCTP Pools
J. Biol. Chem., January 13, 1995; 270(2): 631 - 637.
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V. Skalski, K. R. Brown, B. Y. Choi, Z.-Y. Lin, and S. Chen
A 3'-5' Exonuclease in Human Leukemia Cells. IMPLICATIONS FOR RESISTANCE TO 1-beta -D-ARABINOFURANOSYLCYTOSINE AND 9-beta -D-ARABINOFURANOSYL-2-FLUOROADENINE 5'-MONOPHOSPHATE
J. Biol. Chem., August 11, 2000; 275(33): 25814 - 25819.
[Abstract] [Full Text] [PDF]


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