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A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus
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  • Published: 12 March 1999

A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus

  • L A Skelton1,
  • M G Ormerod1,
  • J Titley1,
  • R Kimbell1,
  • L A Brunton1 &
  • …
  • A L Jackman1 

British Journal of Cancer volume 79, pages 1692–1701 (1999)Cite this article

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Summary

Three lipophilic quinazoline-based aminomethyl pyridine compounds, which differ only in the position of the nitrogen in their pyridine ring, are described. CB300179 (2-pyridine), CB300189 (4-pyridine) and CB30865 (3-pyridine) all inhibited isolated mammalian TS with IC50 values of 508, 250 and 156 nM respectively. CB30865 was the most potent growth inhibitory agent (IC50 values in the range 1– 100 nM for several mouse and human cell types). CB300179 and CB300189 were active in the micromolar range. Against W1L2 cells, CB300179 and CB300189 demonstrated reduced potency in the presence of exogenous thymidine (dThd), and against a W1L2:C1 TS overproducing cell line. In contrast, CB30865 retained activity in these systems. Furthermore, combinations of precursors and end products of folate metabolism, e.g. dThd/hypoxanthine (HX) or leucovorin (LV), did not prevent activity. CB30865 did not interfere with the incorporation of tritiated dThd, uridine or leucine after 4 h. A cell line was raised with acquired resistance to CB30865 (W1L2:R865; > 200-fold), which was not cross-resistant to CB300179 or CB300189. In addition, W1L2:R865 cells were as sensitive as parental cells to agents from all the major chemotherapeutic drug classes. CB300179 and CB300189 induced an S phase accumulation (preventable by co-administration of dThd). No cell cycle redistribution was observed following exposure (4–48 h) to an equitoxic concentration of CB30865. In the NCI anticancer drug-discovery screen, CB30865 displayed a pattern of activity which was not consistent with known anti-tumour agents. These data suggest that CB30865 represents a class of potent potential anti-tumour agents with a novel mechanism of action.

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  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

References

  • Bavetsias, V., Marriott, J. H., Melin, C., Kimbell, R., Boyle, F. T. & Jackman, A. L. (1997). Synthesis and antitumour activity of cyclopenta[g]quinazoline-based antifolates, a novel class of thymidylate synthase (TS) inhibitors. Br J Cancer 75(Suppl 1): 24

    Google Scholar 

  • Boyd, M. R. (1989). Status of the NCI preclinical antitumor drug discovery screen: implications for selection of new agents for clinical trial. In Cancer: Principles and Practice of Oncology Updates, Vol. 3, De Vita VT, Hellman S and Rosenberg SA (eds), pp. 1–12. Lippincott: Philadelphia

  • Boyd, M. R., Paull, K. D. & Rubinstein, L. R. (1992). Data display and analysis strategies for the NCI disease-orientated in vitro antitumour drug screen. In Cytotoxic Anticancer Drugs: Models and Concepts for Drug Discovery and Development, Valeriote FA, Corbett T and Baker L (eds), pp. 11–34. Kluwer Academic Publishers: Amsterdam

  • Calvert, A. H., Jones, T. R., Jackman, A. L., Brown, S. J. & Harrap, K. R. (1980). An approach to the design of antimetabolites active against cells resistant to conventional agents illustrated by quinazoline antifolates with N10-substitutions. In Advances in Tumor Prevention, Detection and Characterisation, Vol. 5, Davis W, Harrap KR and Stathopoulos G (eds), pp. 272–283. Excepta Medica: Amsterdam

  • Charcosset, J. Y. (1986). Effects of antineoplastic agents on the cell cycle progression. Biol Cell 58: 135–138.

    Article  CAS  Google Scholar 

  • Hook, K. E., Nelson, J. M., Roberts, B. J., Griswold, D. P. & Leopold, W. R. (1986). Cell cycle effects of trimetrexate (CI-898). Cancer Chemother Pharmacol 16: 116–120.

    Article  CAS  Google Scholar 

  • Jackman, A. L., Calvert, A. H., Hart, L. I. & Harrap, K. R. (1984). Inhibition of thymidylate synthetase by the new quinazoline antifolate CB3717; enzyme purification and kinetics. In Purine Metabolism in Man IV, Part B: Biochemical, Immunological and Cancer Research, de Bruyn C, Simmonds H and Miller M (eds), pp. 375–378. Plenum Press: New York

  • Jackman, A. L., Alison, D. L., Calvert, A. H. & Harrap, K. R. (1986). Increased thymidylate synthase in L1210 cells possessing acquired resistance to N10-propargyl-5,8-dideazafolic acid (CB 3717): development, characterisation, and cross-resistance studies. Cancer Res 46: 2810–2815.

    CAS  PubMed  Google Scholar 

  • Jackman, A. L., Taylor, G. A., O’Connor, B. M., Bishop, J. A., Moran, R. G. & Calvert, A. H. (1990). Activity of the thymidylate synthase inhibitor 2-desamino-N10-propargyl-5,8-dideazafolic acid and related compounds in murine (L1210) and human (W1L2) systems in vitro and in L1210 in vivo. Cancer Res 50: 5212–5218.

    CAS  PubMed  Google Scholar 

  • Jackman, A. L., Newell, D. R., Gibson, W., Jodrell, D. I., Taylor, G. A., Bishop, J. A., Hughes, L. R. & Calvert, A. H. (1991). The biochemical pharmacology of the thymidylate synthase inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583). Biochem Pharmacol 42: 1885–1895.

    Article  CAS  Google Scholar 

  • Jackman, A. L., Kelland, L. R., Kimbell, R., Brown, M., Gibson, W., Aherne, G. W. & Hardcastle, A., Boyle-FT (1995a). Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines. Br J Cancer 71: 914–924.

    Article  CAS  Google Scholar 

  • Jackman, A. L., Kimbell, R., Brown, M., Brunton, L. & Boyle, F. T. (1995b). Quinazoline thymidylate synthase inhibitors: methods for assessing the contribution of polyglutamation to their in vitro activity. Anti-Cancer Drug Design 10: 555–572.

    CAS  PubMed  Google Scholar 

  • Jackman, A. L., Kimbell, R., Brown, M., Brunton, L., Harrap, K. R., Wardleworth, J. M. & Boyle, F. T. (1995c). The antitumour activity of ZD9331, a non-polyglutamatable quinazoline thymidylate synthase inhibitor. In Purine and Pyrimidine Metabolism in Man. Advances in Experimental Medicine and Biology, Vol. 370, Sahota A and Taylor M (eds), pp. 185–188. Plenum Press: New York

  • Jackman, A. L., Boyle, F. T. & Harrap, K. R. (1996a). TomudexTM (ZD1694): from concept to care, a programme in rational drug discovery. Invest New Drugs 14: 305–316.

    Article  CAS  Google Scholar 

  • Jackman, A. L., Skelton, L. A., Kimbell, R., Hughes, L. R. & Boyle, F. T. (1996b). Lipophilic quinazoline analogues of folic acid with 3-pyridylamide replacing the glutamate: evidence for a non-folate locus. Proc Amer Assoc Cancer Res 37: 394

    Google Scholar 

  • Jackman, A. L., Kimbell, R., Aherne, G. W., Brunton, L., Jansen, G., Stephens, T. C., Smith, M. N., Wardleworth, J. M. & Boyle, F. T. (1997a). Cellular pharmacology and in vivo activity of a new anticancer agent, ZD9331: a water-soluble, nonpolyglutamatable, quinazoline-based inhibitor of thymidylate synthase. Clinical Cancer Res 3: 911–921.

    CAS  Google Scholar 

  • Jackman, A. L., Kimbell, R., Melin, C., Boyle, F. T., Marriott, J. & Bavetsias, V. (1997b). Folate-based (acidic) thymidylate synthase (TS) inhibitors with activity independent of the reduced-folate carrier (RFC) and folylpolyglutamate synthetase (FPGS). Proc Amer Assoc Cancer Res 38: 162

    Google Scholar 

  • Kobayashi, H., Takemura, Y., Miyachi, H., Skelton, L. A. & Jackman, A. L. (1995). Effect of hammerhead ribozyme against thymidylate synthase on the cytotoxicity of thymidylate synthase inhibitors. Jpn J Cancer Res 86: 1014–1018.

    Article  CAS  Google Scholar 

  • Lorico, A., Toffoli, G., Boiocchi, M., Erba, E., Broggini, M., Rappa, G. & D’Incalci, M. (1988). Accumulation of DNA strand breaks in cells exposed to methotrexate or N10-propargyl-5,8-dideazafolic acid. Cancer Res 48: 2036–2041.

    CAS  PubMed  Google Scholar 

  • Melin, C., Kimbell, R., Bavetsias, V., Marriott, J. H., Boyle, F. T. & Jackman, A. L. (1997). In vitro activity of the cyclopenta[g]quinazolines, a novel class of thymidylate synthase (TS) inhibitors. Br J Cancer 75(Suppl 1): 24

    Google Scholar 

  • Monks, A., Scudiero, D., Skehan, P., Shoemaker, R., Paull, K., Vistica, D., Hose, C., Langley, J., Cronise, P., Vaigro-Wolff, A., Gray-Goodrich, M., Campbell, H., Mayo, J. & Boyd, M. (1991). Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumour cell lines. J Natl Cancer Inst 11: 757–776.

    Article  Google Scholar 

  • O’Connor, B. M., Jackman, A. L., Crossley, P. H., Freemantle, S. E. & Calvert, A. H. (1992). Human lymphoblastoid cells with acquired resistance to C2-desamino-C2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583); a novel folate-based TS inhibitor. Cancer Res 52: 1137–1143.

    PubMed  Google Scholar 

  • Ormerod, M. G. (1994). Analysis of DNA-general methods. In Flow Cytometry: A Practical Approach, 2nd edn, Ormerod MG (ed), pp. 118–135. Oxford University Press: New York

  • Paull, K. D., Shoemaker, R. H., Hodes, L., Monks, A., Scudiero, D. A., Rubinstein, L., Plowman, J. & Boyd, M. R. (1989). Display and analysis of patterns of differential activity of drugs against human tumour cell lines: development of mean graph and COMPARE algorithm. J Natl Cancer Inst 81: 1088–1092.

    Article  CAS  Google Scholar 

  • Skelton, L. A., Kimbell, R., Brunton, L., Boyle, F. T. & Jackman, A. L. (1994a). Lipophilic inhibitors of thymidylate synthase: 2-pyridyl quinazolines. Br J Cancer 69(Suppl XXI): 41

    Google Scholar 

  • Skelton, L. A., Kimbell, R., Brunton, L. A., Boyle, F. T. & Jackman, A. L. (1994b). 2-Pyridyl quinazolines as inhibitors of thymidylate synthase. Proc Amer Assoc Cancer Res 35: 301

    Google Scholar 

  • Skelton, L. A., Kimbell, R., Boyle, F. T. & Jackman, A. L. (1997). Aminomethyl pyridine analogues of the quinazoline antifolate ICI 198583 with a folate-independent locus of action. In Chemistry and Biology of Pteridines and Folates, Pfleiderer W and Rokos H (eds), pp. 209–212. Blackwell Science: Berlin

  • Skelton, L. A., Ormerod, M. G., Titley, J. & Jackman, A. L. (1998). Cell cycle effects of CB30865 – a lipophilic quinazoline-based analogue of the antifolate TS inhibitor, ICI 198583, with an undefined mechanism of action. Cytometry 33: 56–66.

    Article  CAS  Google Scholar 

  • Stephens, T. C., Smith, M. N., Waterman, S. E., McCloskey, M. L., Jackman, A. L. & Boyle, F. T. (1993). Use of murine L5178Y lymphoma thymidine kinase mutants for in vitro and in vivo antitumour efficacy evaluation of novel thymidylate synthase inhibitors. In Chemistry and Biology of Pteridines and Folates, Ayling J, Nair MG and Baugh CM (eds), pp. 589–582. Plenum Press: New York

  • Taylor, G. A., Jackman, A. L., Balmanno, K., Hughes, L. R. & Calvert, A. H. (1989). Estimation of the in vitro and in vivo inhibitory effect of antifolates upon thymidylate synthase (TS) in whole cells. In Purine and Pyrimidine Metabolism in Man VI, Part B, Mikanagi K, Nishioka K and Kelley WN (eds), pp. 383–388. Plenum: New York

  • Taylor, I. W. & Tattersall, M. N. H. (1981). Methotrexate cytotoxicity in cultured human leukaemic cells studied by flow cytometry. Cancer Res 51: 1549–1558.

    Google Scholar 

  • Twentyman, P. R. & Luscombe, M. (1987). A study of some variables in a tetrazolium dye (MTT) based assay for cell growth and chemosensitivity. Br J Cancer 56: 279–285.

    Article  CAS  Google Scholar 

  • Ward, W. H. J., Kimbell, R. & Jackman, A. L. (1992). Kinetic characteristics of ICI D1694: a quinazoline antifolate which inhibits thymidylate synthase. Biochem Pharmacol 43: 2029–2031.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. The CRC Centre for Cancer Therapeutics at The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, SM2 5NG, Surrey, UK

    L A Skelton, M G Ormerod, J Titley, R Kimbell, L A Brunton & A L Jackman

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From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

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Skelton, L., Ormerod, M., Titley, J. et al. A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus. Br J Cancer 79, 1692–1701 (1999). https://doi.org/10.1038/sj.bjc.6690270

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  • Received: 09 May 1998

  • Revised: 01 September 1998

  • Accepted: 02 September 1998

  • Published: 12 March 1999

  • Issue date: 01 April 1999

  • DOI: https://doi.org/10.1038/sj.bjc.6690270

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Keywords

  • ZM198583
  • CB30865
  • TS
  • cell cycle
  • cross-resistance
  • folate-independent

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