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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Aitokallio-Tallberg AM, Jung JK, Kim SJ, Viinikka LU, Ylikorkala RO (1991) Urinary excretion of degradation products of prostacyclin and thromboxane is increased in patients with gestational choriocarcoma. Cancer Res 51: 4146–4148
Aitokallio-Tallberg AM, Viinikka LU, Ylikorkala RO (1988) Increased synthesis of prostacyclin and thromboxane in human ovarian malignancy. Cancer Res 48: 2396–2398
Aliño S-F, Unda F-J, Pérez-Yarza G, Caavate M-L (1989) Are laminin binding sites on tumor cell surface involved in the indomethacin-induced sensitivity to natural cytotoxic cells? Biol Cell 66: 255–261
Aliño SF, Unda FJ, Pérez-Yarza G (1990) Laminin surface binding sites and metastatic potential of 3LL tumor cells, increased by indomethacin. Biochem Biophys Res Commun 167: 731–738
Baron JA, Greenberg ER (1991) Could aspirin really prevent colon cancer. N Engl J Med 325: 1644–1646
Baroukh B, Saffar JS (1990) The effect of leukotriene synthesis inhibitors on hamster periodontitis. Arch Oral Biol 35: 189S-192S
Brooks PM, Day RO (1991) Nonsteroidal antiinflammatory drugs — differences and similarities. N Engl J Med 324: 1716–1725
Buckley BJ, Barchowsky A, Dolor RJ, Whorton AR (1991) Regulation of arachidonic acid release in vascular endothelium Ca2+-dependent and-independent pathways. Biochem J 280: 281–287
Castelli MG, Chiabrando C, Fanelli R, Martelli L, Butti G, Gaetani P, Paoletti P (1989) Prostaglandin and thromboxane synthesis by human intracranial tumors. Cancer Res 49: 1505–1508
Castonguary A, Pepin P, Stoner GD (1991) Lung tumorigenicity of NNK given orally to A/J mice: its application to chemoprevention efficacy studies. Exp Lung Res 17: 485–499
Chiabrando C, Brogggini M, Castagnoli MN, Donelli MG, Moseda A, Visintainer M, Farattini S, Fanelli R (1985) Prostaglandin and thromboxane synthesis by Lewis lung carcinoma during growth. Cancer Res 45: 3605–3608
Cowlen MS, Eling TE (1992) Modulation of c-jun andjun-B messenger RNA and inhibition of DNA synthesis by prostaglandin E2 in Syrian hamster embryo cells. Cancer Res 52: 6912–6916
Cucurou JP, Battionie JP, Thang DC, Nam NH, Mansuy D (1991) Mechanisms of inactivation of lipoxygenases by phenidone and BW 755C. Biochemistry 30: 8965–8970
Davis PJ, Guenthner LE (1985) Sulindac oxidation/reduction by microbial cultures; microbial models of mammalian metabolism. Xenobiotica 15: 845–857
Duggan DE, Hooke KF, Noll RM, Hucker HB, Van Arman CG (1978) Comparative disposition of sulindac and metabolites in five species. Biochem Pharmacol 27: 2311–2320
Ellis LM, Copeland EM, Bland K, Sitren HS (1990) Inhibition of tumor growth and metastasis by chronic intravenous infusion of prostaglandin E1. Ann Surg 212: 45–50
Ellis LM, Copeland EM, Bland KI, Sitren HS (1990) Differential role of prostaglandin E1 on tumor metastasis. J Surg Oncol 48: 333–336
Erei E III, Holden SA, Gonin R, Waxman DJ, Teicher BA (1993) Antitumor alkylating agents: in vitro cross-resistance and collateral sensitivity studies. Cancer Chemother Pharmacol (in press)
Friend WG (1990) Sulindac suppression of colorectal polyps in Gardner's syndrome. Am Fam Physician 41:891–894
Fukushima M (1992) Biological activities and mechanisms of action of PGJ2 and related compounds: an update. Prostaglandins Leukotrienes Essential Fatty Acids 47:1–12
Fulton AM, Heppner GH (1985) Relationship of prostaglandin E and natural killer sensitivity to metastatic potential in murine mammary adenocarcinomas. Cancer Res 45:4779–4784
Furuta R, Hall ER, Sanduja S, Barkley TJ, Milas L (1988) Prostaglandin production by murine tumors as a predictor for therapeutic response to indomethacin. Cancer Res 48:3002–3007
Furuta Y, Hunter N, Barkley TJ, Hall E, Milas L (1988) Increase in radioresponse of murine tumors by treatment with indomethacin. Cancer Res 48:3008–3013
Golub LM, McNamara TF, D'Angelo G, Greenwald RA, Ramamurthy NS (1987) A non-antibacterial chemically-modified tetracycline inhibits mammalian collagenase activity. J Dent Res 66:1310–1314
Greenwald RA, Golub LM, Lavietes B, Ramamurthy NS, Bruber B, Laskin RS, McNamara TF (1987) Tetracyclines inhibit human synovial collagenase in vivo and in vitro. J Rheumatol 14:28–32
Griffiths RJ, Li SW, Wood BE, Blackham A (1991) A comparison of the anti-inflammatory activity of selective 5-lipoxygenase inhibitors with dexamethasone and colchicine in a model of zymosan induced inflammation in the rat knee joint and peritoneal cavity. Agents Actions 32:3–4
Grunt TW, Lametschwadtner A, Karrer K, Staindl O (1986) The angioarchitecture of the Lewis lung carcinoma in laboratory mice
Grunt TW, Lametschwadtner A, Kerrer K (1986) The characteristic structural feature of the blood vessels of the Lewis lung carcinoma. Scan Electron Microsc 11:575–589
Gulbenkian AR, Fernandez X, Kreutner W, Minmnicozzi M, Watnick AS, Kung T, Egan RW (1990) Anaphylactic challenge causes eosinophil accumulation in bronchoalveolar lavage fluid of guinea pigs: modulation by betamethasone, phenidone, indomethacin, WEB 2086, and a novel antiallergy agent, SCH 37224. Am Rev Respir Dis 142:680–685
Hla T, Maciag T (1991) Cyclooxygenase gene expression is downregulated by heparin-binding (acidic fibroblast) growth factor-1 in human endothelial cells. J. Biol Chem 266:24059–24063
Honn KV, Busse WD, Sloane BF (1983) Commentary. Prostacyclin and thromboxanes: implications for their role in tumor cell metastasis. Biochem Pharmacol 32:1–11
Hubbard WC, Alley MC, Gray GN, Green KC, McLemore TL, Boyd MR (1989) Evidence for prostanoid biosynthesis as a biochemical feature of certain subclasses of non-small cell carcinomas of the lung as determined in established cell lines derived from human lung tumors. Cancer Res 49:826–832
Hubbard WC, Alley MC, McLemore TL, Boyd MR (1988) Evidence for thromboxane biosynthesis in established cell lines derived from human lung adenocarcinomas. Cancer Res 48: 2674–2677
Hubbard WC, Alley MC, McLemore TL, Boyd MR (1988) Profiles of prostaglandin biosynthesis in sixteen established cell lines derived from human lung, colon, prostate, and ovarian tumors. Cancer Res 48:4770–4775
Hubbard WC, Alley MC, McLemore TL, Boyd MR (1991) Fatty acid cyclooxygenase metabolism of arachidonic acid in human tumor cells. In: Honn KV, Marnett LJ, Nigam S, Walden T Jr (eds) Eicosanoids and other bioactive lipids in cancer and radiation injury. Kluwer, Norwell, Massachusetts, pp 27–32
Klein WA, Miller HH, Anderson M, DeCosse JJ (1987) The use of indomethacin, sulindac, and tamoxifen for the treatment of desmoid tumors associated with familial polyposis. Cancer 60:2863–2868
Laekeman GM, Vergote IB, Keersmaekers GM, Heiremans J, Haensch CF, Roy G de, Uyttenbroeck FL, Herman AG (1986) Prostacyclin and thromboxane in benign and malignant breast tumours. Br J Cancer 54:431–437
Maca RD (1988) Inhibition of the growth of Lewis lung carcinoma by indomethacin in conventional, nude, and beige mice. J Biol Response Modefiers 7:568–580
Marnett LJ (1992) Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 52:5575–5589
McLemore TL, Hubbard WC, Litterst CL, Liu MC, Miller S, McMahon NA, Eggleston JC, Boyd MR (1988) Profiles of prostaglandin biosynthesis in normal lung and tumor tissue from lung cancer patients. Cancer Res 48:3140–3147
Milas L, Furuta Y, Hunter N, Nishiguichi I, Runkel S (1990) Dependence of indomethacin-induced potentiation of murine tumor radioresponse of tumor host immunocompetence. Cancer Res 50:4473
Milas L, Ito H, Nakayama T, Hunter N (1991) Improvement in therapeutic ratio of radiotherapy for a murine sarcoma by indomethacin plus misonidazole. Cancer Res 51:3639–3642
Moorghen M, Ince P, Finney KJ, Sunter JP, Appleton DR, Watson AJ (1988) A protective effect of sulindac against chemically induced primary colonic tumours in mice. J Pathol 156:341–347
Moorghen M, Ince P, Finney KJ, SUnter JP, Watson AJ, Appleton DR (1990) The effect of sulindac on colonic tumour formation in dimethylhydrazine-treated mice. Acta Histochem (Jena) [Suppl] 39:195–199
Nicholls FA, Ahokas JT (1984) Inhibition of purified glutathione S-transferases by indomethacin. Biochim Biophys Res Commun 119:1034–1038
Oates JA, Fitzgerald GA, Branch RA, Jackson EK, Knapp HR, Roberts LJ (1988) Medical progress: clinical implications of prostaglandin and thromboxane A2 formation. N Engl J Med 319:689–698
Petrini B, Wokl G, Wasserman J, Vedin I, Strannegård Ö, Blomgren J, Esposti PL (1991) Indomethacin modulation of monocyte cytokine release following pelvic irradiation for cancer. Eur J Cancer 27:729–733
Reich R, Stratford B, Klein K, Martin GR, Mueller RA, Fuller GC (1988) Inhibitors of collagenase IV and cell adhesion reduce the invasive activity of malignant tumour cells. Metastasis 141:193–210
Rigau J, Piqué JM, Rubio E, Planas R, Tarrech JM, Bordas JM (1991) Effects of long-term sulindac therapy on colonic polyposis. Ann Inter Med 115:952–954
Samuelsson B, Dahlén S-E, Lindgren JÅ, Rouzer CA, Serhan CN (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237:1171–1176
Selawry OS, Hansen HH (1982) Lung cancer. In: Holland JF, Frei E (eds) Cancer medicine. Lea & Febiger, Philadelphia, pp 1735–1739
Shipley WV, Stanley JA, Steel GG (1975) Tumor size dependence in the radiation response of the Lewis lung carcinoma. Cancer Res 35:2488–2493
Skinner SA, Penney AG, O'Brien PE (1991) Sulindac inhibits the rate of growth and appearance of colon tumors in the rat. Arch Surg 126:1094–1096
Skouteris GG, McMenamin M (1992) Transforming growth factor-α-induced DNA synthesis and c-myc expression in primary rat hepatocyte cultures is modulated by indomethacin. Biochem J 281:729–733
Smith WL (1989) The eicosanoids and their biochemical mechanisms of action. Biochem J 259:315–324
Stanley JA, Shipley WV, Steel GA (1977) Influence of tumor size on hypoxic fraction and therapeutic sensitivity of Lewis lung tumor. Br J Cancer 36:105–113
Steel GG, Nill RP, Peckham MJ (1978) Combined radiotherapy-chemotherapy of Lewis lung carcinoma. Int J Radiat Oncol Biol Phys 4:49–52
Tamargo RJ, Bok RA, Brem H (1991) Angiogenesis inhibition by minocycline. Cancer Res 51:672–675
Teicher BA, Holden SA, Ara G, Liu J-TC, Robinson MF, Flodgren P, Dupuis N, Northey D (1993) Cyclooxygenase inhibitors: in vitro and in vivo effects on antitumor alkylating agents in the EMT-6 murine mammary carcinoma. Int J Oncol 2:145–153
Teicher BA, Holden SA, Herman TS, Alvarez Sotomayor E, Khandekar V, Rosbe KW, Brann TW, Korbut TT, Frei E (1991) Characteristics of five human tumor cell lines and sublines resistant tocis-diamminedichloroplatinum(II). Int J Cancer 47: 252–260
Vlodavsky I, Korner G, Ishai-Michaeli R, Bashkin P, Bar-Shavit R, Fuks Z (1990) Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. Cancer Metastasis Rev 9:203–226
Waddell WR, Ganser GF, Cerise EJ, Loughry RW (1990) Sulindac for polyposis of the colon. Am J Surg 41:891–894
Watson J, Chuah SY (1985) Prostaglandins, steroids and human mammary cancer. Eur. J. Cancer Clin Oncol 21:1051–1055
Wu C, Mathews KP (1983) Indomethacin inhibition of glutathione S-transferases. Biochem Biophys Res Commun 112:980–985
Young MR, Hoover CS (1986) Inhibition of spleen cell cytotoxic capacity toward tumor by elevated prostaglandin E2 levels in mice bearing Lewis lung carcinoma. J Natl Cancer Inst 77:425–429
Young MR, Knies S (1984) Prostaglandin E production by Lewis lung carcinoma: mechanism for tumor establishment in vivo. J Natl Cancer Inst 72:919–922
Young MR, Newby M (1986) Differential induction of suppressor macrophages by cloned Lewis lung carcinoma variants in mice. J Natl Cancer Inst 77:1255–1260
Young MR, Newby M, Meunier J (1985) Relationships between morphology, dissemination, migration, and prostaglandin E2 secretion by cloned variants of Lewis lung carcinoma. Cancer Res 45:3918–3923
Young MR, Newby M, Wepsic HT (1987) Hematopoiesis and suppressor bone marrow cells in mice bearing large metastatic Lewis lung carcinoma tumors. Cancer Res 47:100–105
Young MR, Wheeler E, Newby M (1986) Macrophage-mediated suppression of natural killer cell activity in mice bearing Lewis lung carcinoma. J Natl Cancer Inst 76:745–750
Young MR, Young ME, Wepsic HT (1987) Effect of prostaglandin E2-producing nonmetastatic Lewis lung carcinoma cells on the migration of prostagladin E2-responsive metastatic Lewis lung carcinoma cells. Cancer Res 47:3679–3683
Young MRI, Duffie GP, Lozano Y, Young ME, Wright MA (1990) Association of a functional prostaglandin E2-protein kinase A coupling with responsiveness of metastatic Lewis lung carcinoma variants to prostaglandin E2 and to prostaglandin E2-producing nonmetastatic Lewis lung carcinoma variants. Cancer Res 50: 2973–2978
Young MRI, Young ME, Kim K (1988) Regulation of tumor-induced myelopoiesis and the associated immune suppressor cells in mice bearing metastatic Lewis lung carcinoma by prostaglandin E2. Cancer Res 48:6826–6831
Zucker S, Lysik RM, Ramamurthy S, Golub LM, Wieman JM, Wilkie DP (1985) Diversity of melanoma plasma membrane proteinase: inhibition of collagenolytic and cytolytic activities by minocycline. J Natl Cancer Inst 75:517–525
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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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DOI: https://doi.org/10.1007/BF00686511