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Cyclooxygenase and lipoxygenase inhibitors as modulators of cancer therapies

  • Original Articles
  • Cyclooxygenase Inhibitors, Lipoxygenase Inhibitor, Cancer Therapy
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Abstract

Like many clinical non-small-cell lung cancers, the Lewis lung carcinoma produces prostaglandins. The Lewis lung carcinoma was used as a model of both primary and metastatic disease to assess the ability of cyclooxygenase inhibitors (mefenamic acid, diflunisal, sulindac, and indomethacin), the collagenase inhibitor minocycline, and the lipoxygenase inhibitor phenidone to act as modulators of cytotoxic cancer therapies. Although none of the single modulators given i.p. daily on days 4–18 altered tumor growth or the number of metastases found on day 20, modulator combinations consisting of minocycline/a cyclooxygenase inhibitor and, especially, of phenidone/a cyclooxygenase inhibitor resulted in modest tumor growth delay and a decreased number of lung metastases on day 20. The most effective modulators of cisplatin (CDDP) were phenidone/sulindac and phenidone/indomethacin, which led to 2.4- to 2.5-fold increases in the tumor growth delay produced by CDDP. The most effective modulations of cyclophosphamide resulted from administration of minocycline, minocycline/sulindac, or phenidone/sulindac and led to 2.0- to 2.1-fold increases in tumor growth delay by cyclophosphamide. The most effective modulators of melphalan produced 4.5- to 4.7-fold increases in tumor growth delay by the drug and were minocycline/sulindac, minocycline/mefenamic acid, and phenidone/sulindac. The most effective modulation of carmustine (BCNU) was obtained with minocycline/sulindac and minocycline/diflunisal leading to 2.8- to 3.1-fold increases in tumor growth delay by BCNU. Finally, the most effective modulation of radiation was obtained with minocycline/sulindac and phenidone/sulindac and resulted in 2.8- to 3.3-fold increases in tumor growth delay by radiation. The modulator combination that along with the cytotoxic therapies was most effective against metastatic disease was phenidone/mefenamic acid. There was no clear relationship between effective modulation of the cancer therapies and the degree of reduction in serum levels of prostaglandin E2 and leukotriene B4 by the agents in Lewis lung tumor bearing mice.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, 44 Binney Street, 02115, Boston, MA, USA

    Beverly A. Teicher, Timothy T. Korbut, Krishna Menon, Sylvia A. Holden & Gulshan Ara

  2. Joint Center for Radiation Therapy, 44 Binney Street, 02115, Boston, MA, USA

    Beverly A. Teicher

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  1. Beverly A. Teicher
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  3. Krishna Menon
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This work was supported by NIH grants PO1-CA19589, PO1-CA38493, by a grant from the Mathers Foundation, and by a grant from Bristol-Myers-Squibb, Wallingford, Connecticut

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Teicher, B.A., Korbut, T.T., Menon, K. et al. Cyclooxygenase and lipoxygenase inhibitors as modulators of cancer therapies. Cancer Chemother. Pharmacol. 33, 515–522 (1994). https://doi.org/10.1007/BF00686511

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