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[Cancer Research 57, 1116-1123, March 15, 1997]
© 1997 American Association for Cancer Research
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LY231514, a Pyrrolo[2,3-d]pyrimidine-based Antifolate That Inhibits Multiple Folate-requiring Enzymes

Chuan Shih1, Victor J. Chen, Lynn S. Gossett, Susan B. Gates, Warren C. MacKellar, Lillian L. Habeck, Katherine A. Shackelford, Lurane G. Mendelsohn, Daniel J. Soose, Vinod F. Patel, Sherri L. Andis, Jesse R. Bewley, Elizabeth A. Rayl, Barbara A. Moroson, G. Peter Beardsley, William Kohler, Manshan Ratnam and Richard M. Schultz

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285 [C. S., V. J. C., L. S. G., S. B. G., W. C. M., L. L. H., K. A. S., L. G. M., D. J. S., V. F. P., S. L. A., J. R. B., R. M. S.]; Department of Pediatrics, Yale University, New Haven, Connecticut 06510 [E. A. R., B. A. M., G. P. B.]; and Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43699 [W. K., M. R.]

N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-benzoyl]-L-glutamic acid (LY231514) is a novel pyrrolo[2,3-d]pyrimidine-based antifolate currently undergoing extensive Phase II clinical trials. Previous studies have established that LY231514 and its synthetic {gamma}-polyglutamates (glu3 and glu5) exert potent inhibition against thymidylate synthase (TS). We now report that LY231514 and its polyglutamates also markedly inhibit other key folate-requiring enzymes, including dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT). For example, the Ki values of the pentaglutamate of LY231514 are 1.3, 7.2, and 65 nM for inhibition against TS, DHFR, and GARFT, respectively. In contrast, although a similar high level of inhibitory potency was observed for the parent monoglutamate against DHFR (7.0 nM), the inhibition constants (Ki) for the parent monoglutamate are significantly weaker for TS (109 nM) and GARFT (9,300 nM). The effects of LY231514 and its polyglutamates on aminoimidazole carboxamide ribonucleotide formyltransferase, 5,10-methylenetetrahydrofolate dehydrogenase, and 10-formyltetrahydrofolate synthetase were also evaluated. The end product reversal studies conducted in human cell lines further support the concept that multiple enzyme-inhibitory mechanisms are involved in cytotoxicity. The reversal pattern of LY231514 suggests that although TS may be a major site of action for LY231514 at concentrations near the IC50, higher concentrations can lead to inhibition of DHFR and/or other enzymes along the purine de novo pathway. Studies with mutant cell lines demonstrated that LY231514 requires polyglutamation and transport via the reduced folate carrier for cytotoxic potency. Therefore, our data suggest that LY231514 is a novel classical antifolate, the antitumor activity of which may result from simultaneous and multiple inhibition of several key folate-requiring enzymes via its polyglutamated metabolites.

1 To whom requests for reprints should be addressed, at Cancer Research Division, Lilly Research Laboratories, Drop 0540, Eli Lilly and Company, 307 E. McCarty St., Indianapolis, IN 46285. Phone: (317) 276-3520; Fax: (317) 277-3652.

Received 8/21/96. Accepted 1/17/97.




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C. J. Allegra, A. L. Parr, L. E. Wold, M. R. Mahoney, D. J. Sargent, P. Johnston, P. Klein, K. Behan, M. J. O'Connell, R. Levitt, et al.
Investigation of the Prognostic and Predictive Value of Thymidylate Synthase, p53, and Ki-67 in Patients With Locally Advanced Colon Cancer
J. Clin. Oncol., April 1, 2002; 20(7): 1735 - 1743.
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A. Tesei, L. Ricotti, F. D. Paola, D. Amadori, G. L. Frassineti, and W. Zoli
In Vitro Schedule-dependent Interactions between the Multitargeted Antifolate LY231514 and Gemcitabine in Human Colon Adenocarcinoma Cell Lines
Clin. Cancer Res., January 1, 2002; 8(1): 233 - 239.
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D. B. Longley, P. R. Ferguson, J. Boyer, T. Latif, M. Lynch, P. Maxwell, D. P. Harkin, and P. G. Johnston
Characterization of a Thymidylate Synthase (TS)-inducible Cell Line: A Model System for Studying Sensitivity to TS- and non-TS-targeted Chemotherapies
Clin. Cancer Res., November 1, 2001; 7(11): 3533 - 3539.
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 The OncologistHome page
A.-R. Hanauske, V. Chen, P. Paoletti, and C. Niyikiza
Pemetrexed Disodium: A Novel Antifolate Clinically Active Against Multiple Solid Tumors
Oncologist, August 1, 2001; 6(4): 363 - 373.
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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.
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X. Lu, J. Errington, N. J. Curtin, J. Lunec, and D. R. Newell
The Impact of p53 Status on Cellular Sensitivity to Antifolate Drugs
Clin. Cancer Res., July 1, 2001; 7(7): 2114 - 2123.
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 Cancer Res.Home page
C. L. van der Wilt, H. H. J. Backus, K. Smid, L. Comijn, G. Veerman, D. Wouters, D. A. Voorn, D. G. Priest, M. A. Bunni, F. Mitchell, et al.
Modulation of Both Endogenous Folates and Thymidine Enhance the Therapeutic Efficacy of Thymidylate Synthase Inhibitors
Cancer Res., May 1, 2001; 61(9): 3675 - 3681.
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 Clin. Cancer Res.Home page
R. Zhao, S. Babani, F. Gao, L. Liu, and I. D. Goldman
The Mechanism of Transport of the Multitargeted Antifolate (MTA) and Its Cross-resistance Pattern in Cells with Markedly Impaired Transport of Methotrexate
Clin. Cancer Res., September 1, 2000; 6(9): 3687 - 3695.
[Abstract] [Full Text]

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 Clin. Cancer Res.Home page
R. Zhao, F. Gao, S. Babani, and I. D. Goldman
Sensitivity to 5,10-Dideazatetrahydrofolate Is Fully Conserved in a Murine Leukemia Cell Line Highly Resistant to Methotrexate Due to Impaired Transport Mediated by the Reduced Folate Carrier
Clin. Cancer Res., August 1, 2000; 6(8): 3304 - 3311.
[Abstract] [Full Text]

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 BloodHome page
D. H. Patel, J. A. Allay, J. A. Belt, and B. P. Sorrentino
Retroviral transfer of the hENT2 nucleoside transporter cDNA confers broad-spectrum antifolate resistance in murine bone marrow cells
Blood, April 1, 2000; 95(7): 2356 - 2363.
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B. A. Teicher, V. Chen, C. Shih, K. Menon, P. A. Forler, V. G. Phares, and T. Amsrud
Treatment Regimens Including the Multitargeted Antifolate LY231514 in Human Tumor Xenografts
Clin. Cancer Res., March 1, 2000; 6(3): 1016 - 1023.
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 JNCI J Natl Cancer InstHome page
M. Aghi, C. M. Kramm, and X. O. Breakefield
RESPONSE: Re: Folylpolyglutamyl Synthetase Gene Transfer and Glioma Antifolate Sensitivity in Culture and In Vivo
J Natl Cancer Inst, December 1, 1999; 91(23): 2048 - 2049.
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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.
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 JCOHome page
R. Thodtmann, H. Depenbrock, H. Dumez, J. Blatter, R. D. Johnson, A. van Oosterom, and A.-R. Hanauske
Clinical and Pharmacokinetic Phase I Study of Multitargeted Antifolate (LY231514) in Combination With Cisplatin
J. Clin. Oncol., October 1, 1999; 17(10): 3009 - 3016.
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 Cancer Res.Home page
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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J. J. Rusthoven, E. Eisenhauer, C. Butts, R. Gregg, J. Dancey, B. Fisher, and J. Iglesias
Multitargeted Antifolate LY231514 as First-Line Chemotherapy for Patients With Advanced Non-Small-Cell Lung Cancer: A Phase II Study
J. Clin. Oncol., April 1, 1999; 17(4): 1194 - 1194.
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 Mol. Pharmacol.Home page
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.
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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.
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J. L. Tonkinson, L. L. Habeck, J. E. Toth, L. G. Mendelsohn, J. Bewley, K. A. Shackelford, S. B. Gates, J. Ray, and V. J. Chen
The Antiproliferative and Cell Cycle Effects of 5,6,7,8-Tetrahydro-N5,N10-Carbonylfolic Acid, an Inhibitor of Methylenetetrahydrofolate Dehydrogenase, Are Potentiated by Hypoxanthine
J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 315 - 321.
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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.
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 J. Biol. Chem.Home page
R. Zhao, S. Titus, F. Gao, R. G. Moran, and I. D. Goldman
Molecular Analysis of Murine Leukemia Cell Lines Resistant to 5,10-Dideazatetrahydrofolate Identifies Several Amino Acids Critical to the Function of Folylpolyglutamate Synthetase
J. Biol. Chem., August 18, 2000; 275(34): 26599 - 26606.
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 J. Biol. Chem.Home page
C. S. Mintz-Weber and J. P. Johnson
Identification of the Elements Regulating the Expression of the Cell Adhesion Molecule MCAM/MUC18. LOSS OF AP-2 IS NOT REQUIRED FOR MCAM EXPRESSION IN MELANOMA CELL LINES
J. Biol. Chem., October 27, 2000; 275(44): 34672 - 34680.
[Abstract] [Full Text] [PDF]

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S. Drori, G. Jansen, R. Mauritz, G. J. Peters, and Y. G. Assaraf
Clustering of Mutations in the First Transmembrane Domain of the Human Reduced Folate Carrier in GW1843U89-resistant Leukemia Cells with Impaired Antifolate Transport and Augmented Folate Uptake
J. Biol. Chem., September 29, 2000; 275(40): 30855 - 30863.
[Abstract] [Full Text] [PDF]


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