| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510 [K. G., X. G., S-H. L., Y-C. C.], and the Department of Medicinal Chemistry, School of Pharmacy, University of Georgia, Athens, Georgia 30602 [Z. G., C. C.]
Naturally occurring nucleosides and all anticancer nucleoside analogue drugs are in the ß-D configuration. L-(-)-dioxolane-cytidine [(-)-OddC] is the first L-nucleoside analogue ever shown to have anticancer activity. This compound was converted within cells to its mono-, di-, and triphosphate metabolites and was incorporated into DNA. As with cytosine arabinoside, conversion to the monophosphate was catalyzed by cellular deoxycytidine kinase, which was essential for cytotoxicity. However, unlike cytosine arabinoside, (-)-OddC was not susceptible to degradation by deoxycytidine deaminase. Because (-)-OddC inhibited the growth of hepatocellular and prostate tumors that are generally difficult to treat, it is a promising candidate for additional testing. Our results indicate that there is a great deal of variability in the chiral specificities of cellular enzymes and demonstrate how these differences can be exploited in the design of better anti-viral and anticancer drugs.
1 Supported by USPHS Grants CA 44358 and AI 33655.
2 To whom requests for reprints should be addressed, at Department of Pharmacology, Yale University School of Medicine, SHM B-313, 333 Cedar Street, New Haven, CT 06510-8066.
Received 4/17/95. Accepted 6/ 1/95.
This article has been cited by other articles:
|
|
 |
|
  W. Lam, S. Bussom, and Y.-C. Cheng Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma Mol. Cancer Ther., February 1, 2009; 8(2): 415 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Lam, C.-H. Leung, S. Bussom, and Y.-C. Cheng The Impact of Hypoxic Treatment on the Expression of Phosphoglycerate Kinase and the Cytotoxicity of Troxacitabine and Gemcitabine Mol. Pharmacol., September 1, 2007; 72(3): 536 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Sabini, S. Hazra, M. Konrad, S. K. Burley, and A. Lavie Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase Nucleic Acids Res., January 12, 2007; 35(1): 186 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Lam, S.-Y. Park, C.-H. Leung, and Y.-C. Cheng Apurinic/Apyrimidinic Endonuclease-1 Protein Level Is Associated with the Cytotoxicity of L-Configuration Deoxycytidine Analogs (Troxacitabine and beta-L-2',3'-Dideoxy-2',3'-didehydro-5-fluorocytidine) but Not D-Configuration Deoxycytidine Analogs (Gemcitabine and beta-D-Arabinofuranosylcytosine) Mol. Pharmacol., May 1, 2006; 69(5): 1607 - 1614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. K. K. Lee, E. K. Rowinsky, J. Li, F. Giles, M. J. Moore, M. Hidalgo, E. Capparelli, J. Jolivet, and S. D. Baker Population pharmacokinetics of troxacitabine, a novel dioxolane nucleoside analogue. Clin. Cancer Res., April 1, 2006; 12(7): 2158 - 2165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Hsu, J.-Y. Liou, G. E. Dutschman, and Y.-C. Cheng Phosphorylation of Cytidine, Deoxycytidine, and Their Analog Monophosphates by Human UMP/CMP Kinase Is Differentially Regulated by ATP and Magnesium Mol. Pharmacol., March 1, 2005; 67(3): 806 - 814. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Lapointe, R. Letourneau, W. Steward, R. E. Hawkins, G. Batist, M. Vincent, R. Whittom, M. Eatock, J. Jolivet, and M. Moore Phase II study of troxacitabine in chemotherapy-naive patients with advanced cancer of the pancreas: Gastrointestinal tumors Ann. Onc., February 1, 2005; 16(2): 289 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Gourdeau, L. Leblond, B. Hamelin, K. Dong, F. Ouellet, C. Boudreau, D. Custeau, A. Richard, M.-J. Gilbert, and J. Jolivet Species Differences in Troxacitabine Pharmacokinetics and Pharmacodynamics: Implications for Clinical Development Clin. Cancer Res., November 15, 2004; 10(22): 7692 - 7702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. Kim, S.-Y. Park, C.-H. Hsu, G. E. Dutschman, and Y.-C. Cheng Synergistic Antitumor Activity of Troxacitabine and Camptothecin in Selected Human Cancer Cell Lines Mol. Pharmacol., August 1, 2004; 66(2): 285 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Krishnan, E. A. Gullen, W. Lam, G. E. Dutschman, S. P. Grill, and Y.-c. Cheng Novel Role of 3-Phosphoglycerate Kinase, a Glycolytic Enzyme, in the Activation of L-Nucleoside Analogs, a New Class of Anticancer and Antiviral Agents J. Biol. Chem., September 19, 2003; 278(38): 36726 - 36732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Chen, S. B. Pai, S. J. Hurwitz, C. K. Chu, Y. Glazkova, H. M. McClure, M. Feitelson, and R. F. Schinazi Antiviral Activity and Pharmacokinetics of 1-(2,3-Dideoxy-2-Fluoro-{beta}-L-Glyceropent-2-Enofuranosyl)Cytosine Antimicrob. Agents Chemother., June 1, 2003; 47(6): 1922 - 1928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-m. Chou and Y.-c. Cheng The Exonuclease Activity of Human Apurinic/Apyrimidinic Endonuclease (APE1). BIOCHEMICAL PROPERTIES AND INHIBITION BY THE NATURAL DINUCLEOTIDE Gp4G J. Biol. Chem., May 9, 2003; 278(20): 18289 - 18296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. J. Giles, H. M. Kantarjian, J. E. Cortes, G. Garcia-Manero, S. Verstovsek, S. Faderl, D. A. Thomas, A. Ferrajoli, S. O'Brien, J. K. Wathen, et al. Adaptive Randomized Study of Idarubicin and Cytarabine Versus Troxacitabine and Cytarabine Versus Troxacitabine and Idarubicin in Untreated Patients 50 Years or Older With Adverse Karyotype Acute Myeloid Leukemia J. Clin. Oncol., May 1, 2003; 21(9): 1722 - 1727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.A. Townsley, K. Chi, D.S. Ernst, K. Belanger, I. Tannock, G.A. Bjarnason, D. Stewart, R. Goel, J.D. Ruether, L.L. Siu, et al. Phase II Study of Troxacitabine (BCH-4556) in Patients With Advanced and/or Metastatic Renal Cell Carcinoma: A Trial of the National Cancer Institute of Canada-Clinical Trials Group J. Clin. Oncol., April 15, 2003; 21(8): 1524 - 1529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Giles, S. Faderl, D. A. Thomas, J. E. Cortes, G. Garcia-Manero, D. Douer, A. M. Levine, C. A. Koller, S. S. Jeha, S. M. O'Brien, et al. Randomized Phase I/II Study of Troxacitabine Combined With Cytarabine, Idarubicin, or Topotecan in Patients With Refractory Myeloid Leukemias J. Clin. Oncol., March 15, 2003; 21(6): 1050 - 1056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Liou, P. Krishnan, C.-C. Hsieh, G. E. Dutschman, and Y.-c. Cheng Assessment of the Effect of Phosphorylated Metabolites of Anti-Human Immunodeficiency Virus and Anti-Hepatitis B Virus Pyrimidine Analogs on the Behavior of Human Deoxycytidylate Deaminase Mol. Pharmacol., January 1, 2003; 63(1): 105 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Krishnan, J.-Y. Liou, and Y.-C. Cheng Phosphorylation of Pyrimidine L-Deoxynucleoside Analog Diphosphates. KINETICS OF PHOSPHORYLATION AND DEPHOSPHORYLATION OF NUCLEOSIDE ANALOG DIPHOSPHATES AND TRIPHOSPHATES BY 3-PHOSPHOGLYCERATE KINASE J. Biol. Chem., August 23, 2002; 277(35): 31593 - 31600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Belanger, M. Moore, S. D. Baker, J. Dionne, M. Maclean, J. Jolivet, L. Siu, D. Soulieres, N. Wainman, and L. Seymour Phase I and Pharmacokinetic Study of Novel L-Nucleoside Analog Troxacitabine Given as a 30-Minute Infusion Every 21 Days J. Clin. Oncol., May 15, 2002; 20(10): 2567 - 2574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Y. Liou, G. E. Dutschman, W. Lam, Z. Jiang, and Y.-C. Cheng Characterization of Human UMP/CMP Kinase and Its Phosphorylation of D- and L-Form Deoxycytidine Analogue Monophosphates Cancer Res., March 1, 2002; 62(6): 1624 - 1631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Krishnan, Q. Fu, W. Lam, J.-Y. Liou, G. Dutschman, and Y.-C. Cheng Phosphorylation of Pyrimidine Deoxynucleoside Analog Diphosphates. SELECTIVE PHOSPHORYLATION OF L-NUCLEOSIDE ANALOG DIPHOSPHATES BY 3-PHOSPHOGLYCERATE KINASE J. Biol. Chem., February 8, 2002; 277(7): 5453 - 5459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Giles, G. Garcia-Manero, J. E. Cortes, S. D. Baker, C. B. Miller, S. M. O'Brien, D. A. Thomas, M. Andreeff, C. Bivins, J. Jolivet, et al. Phase II Study of Troxacitabine, a Novel Dioxolane Nucleoside Analog, in Patients With Refractory Leukemia J. Clin. Oncol., February 1, 2002; 20(3): 656 - 664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. de Bono, J. Stephenson Jr, S. D. Baker, M. Hidalgo, A. Patnaik, L. A. Hammond, G. Weiss, A. Goetz, L. Siu, C. Simmons, et al. Troxacitabine, an L-Stereoisomeric Nucleoside Analog, on a Five-Times-Daily Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies J. Clin. Oncol., January 1, 2002; 20(1): 96 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Druker, S. G. O'Brien, J. Cortes, and J. Radich Chronic Myelogenous Leukemia Hematology, January 1, 2002; 2002(1): 111 - 135. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
|
|
F. J. Giles, J. E. Cortes, S. D. Baker, D. A. Thomas, S. O'Brien, T. L. Smith, M. Beran, C. Bivins, J. Jolivet, and H. M. Kantarjian Troxacitabine, A Novel Dioxolane Nucleoside Analog, Has Activity in Patients With Advanced Leukemia J. Clin. Oncol., February 1, 2001; 19(3): 762 - 771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kira, S. P. Grill, G. E. Dutschman, J.-S. Lin, F. Qu, Y. Choi, C. K. Chu, and Y.-C. Cheng Anti-Epstein-Barr Virus (EBV) Activity of beta -L-5-Iododioxolane Uracil Is Dependent on EBV Thymidine Kinase Antimicrob. Agents Chemother., December 1, 2000; 44(12): 3278 - 3284. [Abstract] [Full Text]
|
|
|
|
|
|
L. Li, G. E. Dutschman, E. A. Gullen, E. Tsujii, S. P. Grill, Y. Choi, C. K. Chu, and Y.-c. Cheng Metabolism and Mode of Inhibition of Varicella-Zoster Virus by L-beta -5-Bromovinyl-(2-hydroxymethyl)-(1,3-dioxolanyl)uracil Is Dependent on Viral Thymidine Kinase Mol. Pharmacol., November 1, 2000; 58(5): 1109 - 1114. [Abstract] [Full Text]
|
|
|
|
|
|
S. Weitman, J. Marty, J. Jolivet, C. Locas, and D. D. Von Hoff The New Dioxolane, (-)-2'-Deoxy-3'-oxacytidine (BCH-4556, Troxacitabine), Has Activity against Pancreatic Human Tumor Xenografts Clin. Cancer Res., April 1, 2000; 6(4): 1574 - 1578. [Abstract] [Full Text]
|
|
|
|
|
|
G. E. Dutschman, E. G. Bridges, S.-H. Liu, E. Gullen, X. Guo, M. Kukhanova, and Y.-C. Cheng Metabolism of 2',3'-Dideoxy-2',3'-Didehydro-beta -L(-)-5-Fluorocytidine and Its Activity in Combination with Clinically Approved Anti-Human Immunodeficiency Virus beta -D(+) Nucleoside Analogs In Vitro Antimicrob. Agents Chemother., July 1, 1998; 42(7): 1799 - 1804. [Abstract] [Full Text]
|
|
|
|
|
|
L. L. Bennett Jr., P. W. Allan, G. Arnett, Y. F. Shealy, D. S. Shewach, W. S. Mason, I. Fourel, and W. B. Parker Metabolism in Human Cells of the D and L Enantiomers of the Carbocyclic Analog of 2'-Deoxyguanosine: Substrate Activity with Deoxycytidine Kinase, Mitochondrial Deoxyguanosine Kinase, and 5'-Nucleotidase Antimicrob. Agents Chemother., May 1, 1998; 42(5): 1045 - 1051. [Abstract] [Full Text]
|
|
|
|
|
|
M. Kukhanova, S.-H. Liu, D. Mozzherin, T.-S. Lin, C. K. Chu, and Y.-C. Cheng L- and D-Enantiomers of 2`,3`-Dideoxycytidine 5`-Triphosphate Analogs as Substrates for Human DNA Polymerases J. Biol. Chem., September 29, 1995; 270(39): 23055 - 23059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-M. Chou, M. Kukhanova, and Y.-C. Cheng A Novel Action of Human Apurinic/Apyrimidinic Endonuclease. EXCISION OF L-CONFIGURATION DEOXYRIBONUCLEOSIDE ANALOGS FROM THE 3' TERMINI OF DNA J. Biol. Chem., September 29, 2000; 275(40): 31009 - 31015. [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 |
