Combination Antiangiogenesis Therapy with Marimastat, Captopril and Fragmin in Patients with Advanced Cancer

Overview

Journal Br J Cancer

Specialty Oncology

Date 2004 May 27

PMID 15162145

Citations 10

Authors

P H Jones

K Christodoulos

N Dobbs

P Thavasu

F Balkwill

A D Blann

G J Caine

S Kumar

A J Kakkar

N Gompertz

D C Talbot

T S Ganesan

A L Harris

Affiliations

Soon will be listed here.

Abstract

Marimastat, low molecular weight heparins and captopril have antiangiogenic activity in vitro and in animal models. We studied the safety and efficacy of the combination of these drugs in patients with advanced cancer. In all, 50 patients were enrolled. Captopril was given orally at a dose of 50 mg bd daily. Fragmin was administered as a daily subcutaneous injection of 200 units kg(-1) for the first 28 days and 5000 units thereafter. Marimastat was given at 10 mg bd orally. Serum, plasma and urinary angiogenic factors were measured at baseline and after 1 month of treatment. Inhibition of release of tumour necrosis factor alpha (TNF-alpha) from peripheral lymphocytes was used as a surrogate pharmacodynamic end point. There was one case of haemorrhagic stroke and one upper gastrointestinal haemorrhage. The commonest toxicity was myalgia. One of 10 patients with renal cancer had a partial response, and three patients had a prolonged period of stable disease. The treatment significantly inhibited phytohaemagglutinin (PHA)-stimulated TNF-alpha release from patient's lymphocytes. The combination of marimastat, fragmin and captopril is well tolerated and has in vivo activity. Inhibition of PHA-stimulated TNF-alpha release from lymphocytes is a surrogate pharmacodynamic marker of metalloprotease inhibition.

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References

Fox S, Gasparini G, Harris A . Angiogenesis: pathological, prognostic, and growth-factor pathways and their link to trial design and anticancer drugs. Lancet Oncol. 2002; 2(5):278-89. DOI: 10.1016/S1470-2045(00)00323-5. View

Hii S, Nicol D, Gotley D, Thompson L, Green M, Jonsson J . Captopril inhibits tumour growth in a xenograft model of human renal cell carcinoma. Br J Cancer. 1998; 77(6):880-3. PMC: 2150111. DOI: 10.1038/bjc.1998.145. View

Torri J, Johnson M, Steen V, Marshall J, Ness E, Dickson R . Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. J Clin Oncol. 1998; 16(6):2150-6. DOI: 10.1200/JCO.1998.16.6.2150. View

Volpert O, Ward W, Lingen M, Chesler L, Solt D, Johnson M . Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. J Clin Invest. 1996; 98(3):671-9. PMC: 507476. DOI: 10.1172/JCI118838. View

Pini M, Aiello S, Manotti C, Pattacini C, Quintavalla R, Poli T . Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost. 1994; 72(2):191-7. View

Folkman J . Angiogenesis: initiation and modulation. Symp Fundam Cancer Res. 1983; 36:201-8. View

Kakkar A, Williamson R . Prevention of venous thromboembolism in cancer patients. Semin Thromb Hemost. 1999; 25(2):239-43. DOI: 10.1055/s-2007-994925. View

Folkman J, Langer R, Linhardt R, Haudenschild C, Taylor S . Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science. 1983; 221(4612):719-25. DOI: 10.1126/science.6192498. View

Norrby K, Ostergaard P . Basic-fibroblast-growth-factor-mediated de novo angiogenesis is more effectively suppressed by low-molecular-weight than by high-molecular-weight heparin. Int J Microcirc Clin Exp. 1996; 16(1):8-15. DOI: 10.1159/000179145. View

10.

Thavasu P, Propper D, McDonald A, Dobbs N, Ganesan T, Talbot D . The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients. Cancer Res. 1999; 59(16):3980-4. View

11.

Prontera C, Mariani B, Rossi C, Poggi A, Rotilio D . Inhibition of gelatinase A (MMP-2) by batimastat and captopril reduces tumor growth and lung metastases in mice bearing Lewis lung carcinoma. Int J Cancer. 1999; 81(5):761-6. DOI: 10.1002/(sici)1097-0215(19990531)81:5<761::aid-ijc16>3.0.co;2-1. View

12.

Shaughnessy S, Young E, Deschamps P, Hirsh J . The effects of low molecular weight and standard heparin on calcium loss from fetal rat calvaria. Blood. 1995; 86(4):1368-73. View

13.

Prandoni P, Lensing A, Piccioli A, Bernardi E, Simioni P, Girolami B . Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002; 100(10):3484-8. DOI: 10.1182/blood-2002-01-0108. View

14.

Bramhall S, Hallissey M, Whiting J, Scholefield J, Tierney G, Stuart R . Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer. 2002; 86(12):1864-70. PMC: 2375430. DOI: 10.1038/sj.bjc.6600310. View

15.

Green D, Hull R, Brant R, Pineo G . Lower mortality in cancer patients treated with low-molecular-weight versus standard heparin. Lancet. 1992; 339(8807):1476. DOI: 10.1016/0140-6736(92)92064-m. View

16.

Shepherd F, Giaccone G, Seymour L, Debruyne C, Bezjak A, Hirsh V . Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the.... J Clin Oncol. 2002; 20(22):4434-9. DOI: 10.1200/JCO.2002.02.108. View

17.

Tsuji F, Oki K, Okahara A, Suhara H, Yamanouchi T, Sasano M . Differential effects between marimastat, a TNF-alpha converting enzyme inhibitor, and anti-TNF-alpha antibody on murine models for sepsis and arthritis. Cytokine. 2002; 17(6):294-300. DOI: 10.1006/cyto.2002.1015. View

18.

Miller K, Gradishar W, Schuchter L, Sparano J, Cobleigh M, Robert N . A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer. Ann Oncol. 2002; 13(8):1220-4. DOI: 10.1093/annonc/mdf199. View

19.

Peeters A, Netea M, Kullberg B, Thien T, van der Meer J . The effect of renin-angiotensin system inhibitors on pro- and anti-inflammatory cytokine production. Immunology. 1998; 94(3):376-9. PMC: 1364256. DOI: 10.1046/j.1365-2567.1998.00524.x. View

20.

von Tempelhoff G, Harenberg J, Niemann F, Hommel G, Kirkpatrick C, Heilmann L . Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: A prospective randomized double-blind trial. Int J Oncol. 2000; 16(4):815-24. DOI: 10.3892/ijo.16.4.815. View