| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709
Studies on a series of benzoquinazoline folate analogues as inhibitors of human thymidylate synthase led to the selection of 1843U89 for further evaluation. This compound had a Ki of 90 pM versus human thymidylate synthase and was noncompetitive with (6R,S)-5,10-methylenetetrahydrofolate. It was a good substrate for the addition of the second glutamate by hog liver folylpolyglutamate synthetase, having a Vmax/Km value 7.8-fold higher than (6R,S)-tetrahydrofolate. The data indicate that 1843U89 was transported into cells via the reduced folate carrier. The Ki for 1843U89 in MOLT-4 cells was 0.33 µM, which was 3-fold lower than that for methotrexate and 16-fold lower than that for (6S-5-formyltetrahydrofolate. V/K values were 20.3 for 1843U89 versus 1.2 and 1.9 for methotrexate and (6S)-5-formyltetrahydrofolate, respectively. It was a potent inhibitor of the growth of human cells, having 50% inhibitory concentrations below 1 nM for all cell lines tested. Growth inhibition was reversed by thymidine alone, indicating that thymidylate synthase was the only site of action of this compound. Growth inhibition was not affected by (6R,S-5-formyltetrahydrofolate at concentrations below 5 µM. However, the 50% inhibitory concentration increased when the concentration in the medium was increased to 100 µM, presumably due to competition for transport. Relative to the human cell lines used, murine cell lines were 80–1300-fold less sensitive to 1843U89 and the other benzoquinazolines tested. This decreased sensitivity appeared to be due, at least in part, to decreased transport or accumulation in murine cells. Ki values for inhibition of methotrexate transport for the benzoquinazolines were 5–17-fold higher in L1210 cells than in MOLT-4 cells. 1843U89, the benzoquinazoline which was transported most efficiently and which was the most potent inhibitor of the growth of human cells, exhibited the largest difference between binding to the MOLT-4 human and L1210 murine transporter. The V/K for L1210 transport was 80-fold less than that for MOLT-4. Initial antitumor studies, using the human thymidine kinase-deficient line GC3TK- to circumvent problems associated with murine transport as well as the high circulating thymidine levels in mice, indicated that 1843U89 had marked in vivo antitumor activity.
1 To whom requests for reprints should be addressed.
Received 7/20/92. Accepted 12/ 3/92.
This article has been cited by other articles:
|
|
 |
|
  G. Beutel, H. Glen, P. Schoffski, J. Chick, S. Gill, J. Cassidy, and C. Twelves Phase I Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor in Patients with Refractory Solid Tumors Clin. Cancer Res., August 1, 2005; 11(15): 5487 - 5495. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Desjardins, D. L. Emerson, D. B. Colagiovanni, E. Abbott, E. N. Brown, and D. W. Drolet Pharmacokinetics, Safety, and Efficacy of a Liposome Encapsulated Thymidylate Synthase Inhibitor, OSI-7904L [(S)-2-[5-[(1,2-Dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric Acid] in Mice J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 894 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Wells, E. Aboagye, R. N. Gunn, S. Osman, A. V. Boddy, G. A. Taylor, I. Rafi, A. N. Hughes, A. H. Calvert, P. M. Price, et al. 2-[11C]Thymidine Positron Emission Tomography as an Indicator of Thymidylate Synthase Inhibition in Patients Treated With AG337 J Natl Cancer Inst, May 7, 2003; 95(9): 675 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Schwartz, T. R. Johnson, A. Goetz, H. Burris, L. Smetzer, T. Lampkin, J. Sailstad, J. A. Hohneker, D. D. Von Hoff, and E. K. Rowinsky A Phase I and Pharmacokinetic Study of 1843U89, a Noncompetitive Inhibitor of Thymidylate Synthase, in Patients with Advanced Solid Malignancies Clin. Cancer Res., July 1, 2001; 7(7): 1901 - 1911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Smith, H. D. Thomas, H. C. Barlow, R. J. Griffin, B. T. Golding, A. H. Calvert, D. R. Newell, and N. J. Curtin In Vitro and in Vivo Properties of Novel Nucleoside Transport Inhibitors with Improved Pharmacological Properties That Potentiate Antifolate Activity Clin. Cancer Res., July 1, 2001; 7(7): 2105 - 2113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Welsh, J. Titley, L. Brunton, M. Valenti, P. Monaghan, A. L. Jackman, and G. W. Aherne Comparison of Thymidylate Synthase (TS) Protein Up-Regulation after Exposure to TS Inhibitors in Normal and Tumor Cell Lines and Tissues Clin. Cancer Res., June 1, 2000; 6(6): 2538 - 2546. [Abstract] [Full Text]
|
|
|
|
 |
|
 L. Jiang, P.-C. Lee, J. White, and P. K. Rathod Potent and Selective Activity of a Combination of Thymidine and 1843U89, a Folate-Based Thymidylate Synthase Inhibitor, against Plasmodium falciparum Antimicrob. Agents Chemother., April 1, 2000; 44(4): 1047 - 1050. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. J. Peters, E. Smitskamp-Wilms, K. Smid, H. M. Pinedo, and G. Jansen Determinants of Activity of the Antifolate Thymidylate Synthase Inhibitors Tomudex (ZD1694) and GW1843U89 against Mono- and MultilayeredColon Cancer Cell Lines under Folate-restricted Conditions Cancer Res., November 1, 1999; 59(21): 5529 - 5535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Rots, R. Pieters, G. J. Peters, C. H. van Zantwijk, R. Mauritz, P. Noordhuis, J. C. Willey, K. Hahlen, U. Creutzig, G. Janka-Schaub, et al. Circumvention of Methotrexate Resistance in Childhood Leukemia Subtypes by Rationally Designed Antifolates Blood, November 1, 1999; 94(9): 3121 - 3128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Hooijberg, H. J. Broxterman, M. Kool, Y. G. Assaraf, G. J. Peters, P. Noordhuis, R. J. Scheper, P. Borst, H. M. Pinedo, and G. Jansen Antifolate Resistance Mediated by the Multidrug Resistance Proteins MRP1 and MRP2 Cancer Res., June 1, 1999; 59(11): 2532 - 2535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Wong, L. Zhang, T. L. Witt, S. A. Proefke, A. Bhushan, and L. H. Matherly Impaired Membrane Transport in Methotrexate-resistant CCRF-CEM Cells Involves Early Translation Termination and Increased Turnover of a Mutant Reduced Folate Carrier J. Biol. Chem., April 9, 1999; 274(15): 10388 - 10394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Jansen, H. Barr, I. Kathmann, M. A. Bunni, D. G. Priest, P. Noordhuis, G. J. Peters, and Y. G. Assaraf Multiple Mechanisms of Resistance to Polyglutamatable and Lipophilic Antifolates in Mammalian Cells: Role of Increased Folylpolyglutamylation, Expanded Folate Pools, and Intralysosomal Drug Sequestration Mol. Pharmacol., April 1, 1999; 55(4): 761 - 769. [Abstract] [Full Text]
|
|
|
|
|
|
B. van Triest, H. M. Pinedo, Y. van Hensbergen, K. Smid, F. Telleman, P. S. Schoenmakers, C. L. van der Wilt, J. A. M. van Laar, P. Noordhuis, G. Jansen, et al. Thymidylate Synthase Level as the Main Predictive Parameter for Sensitivity to 5-Fluorouracil, but not for Folate-based Thymidylate Synthase Inhibitors, in 13 Nonselected Colon Cancer Cell Lines Clin. Cancer Res., March 1, 1999; 5(3): 643 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tong, X. Liu-Chen, E. A. Ercikan-Abali, S.-C. Zhao, D. Banerjee, F. Maley, and J. R. Bertino Probing the Folate-binding Site of Human Thymidylate Synthase by Site-directed Mutagenesis. GENERATION OF MUTANTS THAT CONFER RESISTANCE TO RALTITREXED, THYMITAQ, AND BW1843U89 J. Biol. Chem., November 20, 1998; 273(47): 31209 - 31214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Jansen, R. Mauritz, S. Drori, H. Sprecher, I. Kathmann, M. Bunni, D. G. Priest, P. Noordhuis, J. H. Schornagel, H. M. Pinedo, et al. A Structurally Altered Human Reduced Folate Carrier with Increased Folic Acid Transport Mediates a Novel Mechanism of Antifolate Resistance J. Biol. Chem., November 13, 1998; 273(46): 30189 - 30198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Laethem, Y. A. Hannun, S. Jayadev, C. J. Sexton, J. C. Strum, R. Sundseth, and G. K. Smith Increases in Neutral, Mg2+-Dependent and Acidic, Mg2+-Independent Sphingomyelinase Activities Precede Commitment to Apoptosis and Are Not a Consequence of Caspase 3-Like Activity in Molt-4 Cells in Response to Thymidylate Synthase Inhibition by GW1843 Blood, June 1, 1998; 91(11): 4350 - 4360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S.A. Longo, R. Gorlick, W. P. Tong, E. Ercikan, and J. R. Bertino Disparate Affinities of Antifolates for Folylpolyglutamate Synthetase From Human Leukemia Cells Blood, August 1, 1997; 90(3): 1241 - 1245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Smith, S. Banks, T. A. Blumenkopf, M. Cory, J. Humphreys, R. M. Laethem, J. Miller, C. P. Moxham, R. Mullin, P. H. Ray, et al. Toward Antibody-directed Enzyme Prodrug Therapy with the T268G Mutant of Human Carboxypeptidase A1 and Novel in Vivo Stable Prodrugs of Methotrexate J. Biol. Chem., June 20, 1997; 272(25): 15804 - 15816. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. H. Takimoto New Antifolates: Pharmacology and Clinical Applications Oncologist, February 1, 1996; 1(1): 68 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Wong, S. A. Proefke, A. Bhushan, and L. H. Matherly Isolation of Human cDNAs That Restore Methotrexate Sensitivity and Reduced Folate Carrier Activity in Methotrexate Transport-defective Chinese Hamster Ovary Cells J. Biol. Chem., July 21, 1995; 270(29): 17468 - 17475. [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 |
