Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Sep 24;79(1):114–118. doi: 10.1038/sj.bjc.6690020

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

H M W Verheul 1, D Panigrahy 1, J Yuan 1, R J D'Amato 1,2
PMCID: PMC2362163  PMID: 10408702

Abstract

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

Full Text

The Full Text of this article is available as a PDF (48.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bossi P., Viale G., Lee A. K., 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] [Google Scholar]
  2. Chiu C. H., McEntee M. F., 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] [Google Scholar]
  3. D'Amato R. J., Loughnan M. S., Flynn E., Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4082–4085. doi: 10.1073/pnas.91.9.4082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Duggan D. E., Hooke K. F., Risley E. A., Shen T. Y., Arman C. G. Identification of the biologically active form of sulindac. J Pharmacol Exp Ther. 1977 Apr;201(1):8–13. [PubMed] [Google Scholar]
  5. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995 Jan;1(1):27–31. doi: 10.1038/nm0195-27. [DOI] [PubMed] [Google Scholar]
  6. Folkman J., Ingber D. E. Angiostatic steroids. Method of discovery and mechanism of action. Ann Surg. 1987 Sep;206(3):374–383. doi: 10.1097/00000658-198709000-00016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Folkman J. Tumor angiogenesis: a possible control point in tumor growth. Ann Intern Med. 1975 Jan;82(1):96–100. doi: 10.7326/0003-4819-82-1-96. [DOI] [PubMed] [Google Scholar]
  8. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990 Jan 3;82(1):4–6. doi: 10.1093/jnci/82.1.4. [DOI] [PubMed] [Google Scholar]
  9. Fulton A. M. In vivo effects of indomethacin on the growth of murine mammary tumors. Cancer Res. 1984 Jun;44(6):2416–2420. [PubMed] [Google Scholar]
  10. Giardiello F. M., Hamilton S. R., Krush A. J., Piantadosi S., Hylind L. M., Celano P., Booker S. V., Robinson C. R., Offerhaus G. J. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993 May 6;328(18):1313–1316. doi: 10.1056/NEJM199305063281805. [DOI] [PubMed] [Google Scholar]
  11. Gross J., Azizkhan R. G., Biswas C., Bruns R. R., Hsieh D. S., 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. doi: 10.1073/pnas.78.2.1176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gutman M., Szold A., Ravid A., Lazauskas T., Merimsky O., Klausner J. M. Failure of thalidomide to inhibit tumor growth and angiogenesis in vivo. Anticancer Res. 1996 Nov-Dec;16(6B):3673–3677. [PubMed] [Google Scholar]
  13. Hanif R., Pittas A., Feng Y., Koutsos M. I., Qiao L., Staiano-Coico L., Shiff S. I., 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. doi: 10.1016/0006-2952(96)00181-5. [DOI] [PubMed] [Google Scholar]
  14. Haynes W. L., Proia A. D., Klintworth G. K. Effect of inhibitors of arachidonic acid metabolism on corneal neovascularization in the rat. Invest Ophthalmol Vis Sci. 1989 Jul;30(7):1588–1593. [PubMed] [Google Scholar]
  15. Hudson N., Balsitis M., Everitt S., Hawkey C. J. Angiogenesis in gastric ulcers: impaired in patients taking non-steroidal anti-inflammatory drugs. Gut. 1995 Aug;37(2):191–194. doi: 10.1136/gut.37.2.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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] [Google Scholar]
  17. 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. doi: 10.1074/jbc.271.20.12042. [DOI] [PubMed] [Google Scholar]
  18. Kenyon B. M., Browne F., D'Amato R. J. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res. 1997 Jun;64(6):971–978. doi: 10.1006/exer.1997.0292. [DOI] [PubMed] [Google Scholar]
  19. Kenyon B. M., Voest E. E., Chen C. C., Flynn E., Folkman J., D'Amato R. J. A model of angiogenesis in the mouse cornea. Invest Ophthalmol Vis Sci. 1996 Jul;37(8):1625–1632. [PubMed] [Google Scholar]
  20. Kidd J. G., Rous P. A TRANSPLANTABLE RABBIT CARCINOMA ORIGINATING IN A VIRUS-INDUCED PAPILLOMA AND CONTAINING THE VIRUS IN MASKED OR ALTERED FORM. J Exp Med. 1940 May 31;71(6):813–838. doi: 10.1084/jem.71.6.813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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. doi: 10.1016/0016-5085(91)90519-q. [DOI] [PubMed] [Google Scholar]
  22. Lynch N. R., Castes M., Astoin M., Salomon J. C. Mechanism of inhibition of tumour growth by aspirin and indomethacin. Br J Cancer. 1978 Oct;38(4):503–512. doi: 10.1038/bjc.1978.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Marnett L. J. Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res. 1992 Oct 15;52(20):5575–5589. [PubMed] [Google Scholar]
  24. Meade E. A., Smith W. L., DeWitt D. L. 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] [Google Scholar]
  25. Minchinton A. I., Fryer K. H., Wendt K. R., Clow K. A., Hayes M. M. The effect of thalidomide on experimental tumors and metastases. Anticancer Drugs. 1996 May;7(3):339–343. doi: 10.1097/00001813-199605000-00015. [DOI] [PubMed] [Google Scholar]
  26. Mitchell J. A., Akarasereenont P., Thiemermann C., Flower R. J., Vane J. R. 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. doi: 10.1073/pnas.90.24.11693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Peterson H. I. Tumor angiogenesis inhibition by prostaglandin synthetase inhibitors. Anticancer Res. 1986 Mar-Apr;6(2):251–253. [PubMed] [Google Scholar]
  28. Piazza G. A., Rahm A. L., Krutzsch M., Sperl G., Paranka N. S., Gross P. H., Brendel K., Burt R. W., Alberts D. S., Pamukcu R. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res. 1995 Jul 15;55(14):3110–3116. [PubMed] [Google Scholar]
  29. Sakamoto T., Soriano D., Nassaralla J., Murphy T. L., Oganesian A., Spee C., Hinton D. R., Ryan S. J. Effect of intravitreal administration of indomethacin on experimental subretinal neovascularization in the subhuman primate. Arch Ophthalmol. 1995 Feb;113(2):222–226. doi: 10.1001/archopht.1995.01100020106040. [DOI] [PubMed] [Google Scholar]
  30. Schumacher H., Blake D. A., Gillette J. R. Disposition of thalidomide in rabbits and rats. J Pharmacol Exp Ther. 1968 Mar;160(1):201–211. [PubMed] [Google Scholar]
  31. Schumacher H., Smith R. L., Williams R. T. 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. doi: 10.1111/j.1476-5381.1965.tb02054.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Silverman K. J., Lund D. P., Zetter B. R., Lainey L. L., Shahood J. A., Freiman D. G., Folkman J., Barger A. C. Angiogenic activity of adipose tissue. Biochem Biophys Res Commun. 1988 May 31;153(1):347–352. doi: 10.1016/s0006-291x(88)81229-4. [DOI] [PubMed] [Google Scholar]
  33. Smith W. L., Meade E. A., DeWitt D. L. Interactions of PGH synthase isozymes-1 and -2 with NSAIDs. Ann N Y Acad Sci. 1994 Nov 15;744:50–57. doi: 10.1111/j.1749-6632.1994.tb52723.x. [DOI] [PubMed] [Google Scholar]
  34. Szabo K. T., Steelman R. L. 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] [Google Scholar]
  35. Tanaka H., Sukhova G. K., 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. doi: 10.1161/01.atv.14.5.734. [DOI] [PubMed] [Google Scholar]
  36. Teicher B. A., Korbut T. T., Menon K., Holden S. A., Ara G. Cyclooxygenase and lipoxygenase inhibitors as modulators of cancer therapies. Cancer Chemother Pharmacol. 1994;33(6):515–522. doi: 10.1007/BF00686511. [DOI] [PubMed] [Google Scholar]
  37. Weidner N., Semple J. P., Welch W. R., Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med. 1991 Jan 3;324(1):1–8. doi: 10.1056/NEJM199101033240101. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES