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Br J Cancer. 1999 Jan; 79(1): 114–118.
Published online 1999 Sep 24. doi:  10.1038/sj.bjc.6690020
PMCID: PMC2362163

Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits


Neovascularization facilitates tumour growth and metastasis formation. In our laboratory, we attempt to identify clinically available oral efficacious drugs for antiangiogenic activity. Here, we report which non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit corneal neovascularization, induced by basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF). This antiangiogenic activity may contribute to the known effects of NSAIDs on gastric ulcers, polyps and tumours. We found that sulindac was one of the most potent antiangiogenic NSAIDs, inhibiting bFGF-induced neovascularization by 50% and VEGF-induced neovascularization by 55%. Previously, we reported that thalidomide inhibited growth factor-induced corneal neovascularization. When we combined sulindac with thalidomide, we found a significantly increased inhibition of bFGF- or VEGF-induced corneal neovascularization (by 63% or 74% respectively) compared with either agent alone (P< 0.01). Because of this strong antiangiogenic effect, we tested the oral combination of thalidomide and sulindac for its ability to inhibit the growth of V2 carcinoma in rabbits. Oral treatment of thalidomide or sulindac alone inhibited tumour growth by 55% and 35% respectively. When given together, the growth of the V2 carcinoma was inhibited by 75%. Our results indicated that oral antiangiogenic combination therapy with thalidomide and sulindac may be a useful non-toxic treatment for cancer. © 1999 Cancer Research Campaign

Keywords: basic fibroblast growth factor, vascular endothelial growth factor, corneal neovascularization, non-steroidal anti-inflammatory drug, cyclo-oxygenase

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  • Bossi P, Viale G, Lee AK, Alfano R, Coggi G, Bosari S. Angiogenesis in colorectal tumors: microvessel quantitation in adenomas and carcinomas with clinicopathological correlations. Cancer Res. 1995 Nov 1;55(21):5049–5053. [PubMed]
  • Chiu CH, McEntee MF, Whelan J. Sulindac causes rapid regression of preexisting tumors in Min/+ mice independent of prostaglandin biosynthesis. Cancer Res. 1997 Oct 1;57(19):4267–4273. [PubMed]
  • D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4082–4085. [PMC free article] [PubMed]
  • Duggan DE, Hooke KF, Risley EA, Shen TY, Arman CG. Identification of the biologically active form of sulindac. J Pharmacol Exp Ther. 1977 Apr;201(1):8–13. [PubMed]
  • Folkman J. Tumor angiogenesis: a possible control point in tumor growth. Ann Intern Med. 1975 Jan;82(1):96–100. [PubMed]
  • Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990 Jan 3;82(1):4–6. [PubMed]
  • Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995 Jan;1(1):27–31. [PubMed]
  • Folkman J, Ingber DE. Angiostatic steroids. Method of discovery and mechanism of action. Ann Surg. 1987 Sep;206(3):374–383. [PMC free article] [PubMed]
  • Fulton AM. In vivo effects of indomethacin on the growth of murine mammary tumors. Cancer Res. 1984 Jun;44(6):2416–2420. [PubMed]
  • Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, Booker SV, Robinson CR, Offerhaus GJ. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993 May 6;328(18):1313–1316. [PubMed]
  • Gross J, Azizkhan RG, Biswas C, Bruns RR, Hsieh DS, Folkman J. Inhibition of tumor growth, vascularization, and collagenolysis in the rabbit cornea by medroxyprogesterone. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1176–1180. [PMC free article] [PubMed]
  • Gutman M, Szold A, Ravid A, Lazauskas T, Merimsky O, Klausner JM. Failure of thalidomide to inhibit tumor growth and angiogenesis in vivo. Anticancer Res. 1996 Nov-Dec;16(6B):3673–3677. [PubMed]
  • Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L, Shiff SI, Rigas B. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol. 1996 Jul 26;52(2):237–245. [PubMed]
  • Haynes WL, Proia AD, Klintworth GK. Effect of inhibitors of arachidonic acid metabolism on corneal neovascularization in the rat. Invest Ophthalmol Vis Sci. 1989 Jul;30(7):1588–1593. [PubMed]
  • Hudson N, Balsitis M, Everitt S, Hawkey CJ. Angiogenesis in gastric ulcers: impaired in patients taking non-steroidal anti-inflammatory drugs. Gut. 1995 Aug;37(2):191–194. [PMC free article] [PubMed]
  • Kamei S, Okada H, Inoue Y, Yoshioka T, Ogawa Y, Toguchi H. Antitumor effects of angiogenesis inhibitor TNP-470 in rabbits bearing VX-2 carcinoma by arterial administration of microspheres and oil solution. J Pharmacol Exp Ther. 1993 Jan;264(1):469–474. [PubMed]
  • Karim S, Habib A, Lévy-Toledano S, Maclouf J. Cyclooxygenase-1 and -2 of endothelial cells utilize exogenous or endogenous arachidonic acid for transcellular production of thromboxane. J Biol Chem. 1996 May 17;271(20):12042–12048. [PubMed]
  • Kenyon BM, Voest EE, Chen CC, Flynn E, Folkman J, D'Amato RJ. A model of angiogenesis in the mouse cornea. Invest Ophthalmol Vis Sci. 1996 Jul;37(8):1625–1632. [PubMed]
  • Kenyon BM, Browne F, D'Amato RJ. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res. 1997 Jun;64(6):971–978. [PubMed]
  • Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, Duhamel O, Trousset M, Attali P. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology. 1991 Sep;101(3):635–639. [PubMed]
  • Lynch NR, Castes M, Astoin M, Salomon JC. Mechanism of inhibition of tumour growth by aspirin and indomethacin. Br J Cancer. 1978 Oct;38(4):503–512. [PMC free article] [PubMed]
  • Marnett LJ. Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res. 1992 Oct 15;52(20):5575–5589. [PubMed]
  • Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1993 Mar 25;268(9):6610–6614. [PubMed]
  • Minchinton AI, Fryer KH, Wendt KR, Clow KA, Hayes MM. The effect of thalidomide on experimental tumors and metastases. Anticancer Drugs. 1996 May;7(3):339–343. [PubMed]
  • Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11693–11697. [PMC free article] [PubMed]
  • Peterson HI. Tumor angiogenesis inhibition by prostaglandin synthetase inhibitors. Anticancer Res. 1986 Mar-Apr;6(2):251–253. [PubMed]
  • Piazza GA, Rahm AL, Krutzsch M, Sperl G, Paranka NS, Gross PH, Brendel K, Burt RW, Alberts DS, Pamukcu R, et al. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res. 1995 Jul 15;55(14):3110–3116. [PubMed]
  • Sakamoto T, Soriano D, Nassaralla J, Murphy TL, Oganesian A, Spee C, Hinton DR, Ryan SJ. Effect of intravitreal administration of indomethacin on experimental subretinal neovascularization in the subhuman primate. Arch Ophthalmol. 1995 Feb;113(2):222–226. [PubMed]
  • Schumacher H, Smith RL, Williams RT. The metabolism of thalidomide: the fate of thalidomide and some of its hydrolysis products in various species. Br J Pharmacol Chemother. 1965 Oct;25(2):338–351. [PMC free article] [PubMed]
  • Schumacher H, Blake DA, Gillette JR. Disposition of thalidomide in rabbits and rats. J Pharmacol Exp Ther. 1968 Mar;160(1):201–211. [PubMed]
  • Silverman KJ, Lund DP, Zetter BR, Lainey LL, Shahood JA, Freiman DG, Folkman J, Barger AC. Angiogenic activity of adipose tissue. Biochem Biophys Res Commun. 1988 May 31;153(1):347–352. [PubMed]
  • Smith WL, Meade EA, DeWitt DL. Interactions of PGH synthase isozymes-1 and -2 with NSAIDs. Ann N Y Acad Sci. 1994 Nov 15;744:50–57. [PubMed]
  • Szabo KT, Steelman RL. Effects of maternal thalidomide treatment on pregnancy, fetal development, and mortality of the offspring in random-bred mice. Am J Vet Res. 1967 Nov;28(127):1823–1828. [PubMed]
  • Tanaka H, Sukhova GK, Libby P. Interaction of the allogeneic state and hypercholesterolemia in arterial lesion formation in experimental cardiac allografts. Arterioscler Thromb. 1994 May;14(5):734–745. [PubMed]
  • Teicher BA, Korbut TT, Menon K, Holden SA, Ara G. Cyclooxygenase and lipoxygenase inhibitors as modulators of cancer therapies. Cancer Chemother Pharmacol. 1994;33(6):515–522. [PubMed]
  • Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med. 1991 Jan 3;324(1):1–8. [PubMed]

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