Top

Cancer Chemotherapy and Pharmacology

Published in:

01-01-2012 | Original Article

5-Fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity

Authors: Søren Astrup Jensen, Jens Benn Sørensen

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2012

Abstract

Aim

This study aimed to elucidate the influence of 5-fluorouracil (5-FU)-based therapy on the vascular endothelium and its association with 5-FU-induced heart ischemia.

Methods

The study prospectively accrued patients (n = 106) having completely resected colorectal cancer and receiving adjuvant treatment with 5-FU, folinic acid, and oxaliplatin. The levels of plasma von Willebrand factor (vWf), urine albumin-to-creatinine ratio (UACR), coagulation factor II + VII + X, and fibrin D-dimer were serially assessed before, during, and after chemotherapy.

Results

The vWf level increased from median (range) 1.43 kU/l (0.48 to >3) to 2.64 kU/l (0.23 to >3) (P = 0.001), the UACR increased from 1.1 ± 0.2 mg/mmol (mean ± SE) to 2.1 ± 0.3 mg/mmol (P = 0.001), the coagulation factor II + VII + X activity decreased from 1.00 ± 0.02 to 0.94 ± 0.02 U/l (P = 0.001), and the fibrin D-dimer level increased from 1.1 ± 0.2 to 2.1 ± 0.3 kU/l (P = 0.001) at baseline and during chemotherapy, respectively. The changes in the levels of vWf (P = 0.3), UACR (P = 0.8), coagulation factor II + VII + X (P = 0.8), and fibrin D-dimer (P = 0.6) in nine (8.5%) patients having clinical signs of cardiotoxicity were not significantly different from that of the patients not having cardiotoxicity. The 5-FU-induced rise in plasma biomarkers was not significantly related to the cardiovascular morbidity or its risk factors (P = 0.9).

Conclusions

5-FU therapy induces global reversible endothelial injury leading to a procoagulant state. The ensuing endothelial dysfunction may be of significance to the pathogenesis of 5-FU-induced clinically overt cardiotoxicity. Cardiovascular disease is not significant for the vulnerability of the endothelium to 5-FU-based chemotherapy.

Jensen SA, Sorensen JB (2006) Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol 58:487–493PubMedCrossRef

Wacker A, Lersch C, Scherpinski U, Reindl L, Seyfarth M (2003) High incidence of angina pectoris in patients treated with 5-fluorouracil. A planned surveillance study with 102 patients. Oncology 65:108–112PubMedCrossRef

Tsavaris N, Kosmas C, Vadiaka M, Efremidis M, Zinelis A, Beldecos D, Sakelariou D, Koufos C, Stamatelos G (2002) Cardiotoxicity following different doses and schedules of 5-fluorouracil administration for malignancy–a survey of 427 patients. Med Sci Monit 8:I51–I57

Schober C, Papageorgiou E, Harstrick A, Bokemeyer C, Mugge A, Stahl M, Wilke H, Poliwoda H, Hiddemann W, Kohne-Wompner CH (1993) Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer. Cancer 72:2242–2247PubMedCrossRef

Robben NC, Pippas AW, Moore JO (1993) The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy. Cancer 71:493–509PubMedCrossRef

De Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, Canal P, Chevreau C, Carrie D, Soulie P (1992) Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol 10:1795–1801PubMed

Mosseri M, Fingert HJ, Varticovski L, Chokshi S, Isner JM (1993) In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle. Cancer Res 53:3028–3033PubMed

Porta C, Moroni M, Ferrari S, Nastasi G (1998) Endothelin-1 and 5-fluorouracil-induced cardiotoxicity. Neoplasma 45:81–82PubMed

Kohne CH, Thuss-Patience P, Friedrich M, Daniel PT, Kretzschmar A, Benter T, Bauer B, Dietz R, Dorken B (1998) Raltitrexed (Tomudex): an alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity. Br J Cancer 77:973–977PubMedCrossRef

10.

Kuzel T, Esparaz B, Green D, Kies M (1990) Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin. Cancer 65:885–889PubMedCrossRef

11.

Matsubara I, Kamiya J, Imai S (1980) Cardiotoxic effects of 5-fluorouracil in the guinea pig. Jpn J Pharmacol 30:871–879PubMedCrossRef

12.

Lemaire L, Malet-Martino MC, Longo S, Martino R, De Forni M, Carton M (1991) Fluoroacetaldehyde as cardiotoxic impurity in fluorouracil (Roche). Lancet 337:560PubMedCrossRef

13.

Kinhult S, Albertsson M, Eskilsson J, Cwikiel M (2001) Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation. Scanning 23:1–8PubMedCrossRef

14.

Cwikiel M, Eskilsson J, Wieslander JB, Stjernquist U, Albertsson M (1996) The appearance of endothelium in small arteries after treatment with 5-fluorouracil. An electron microscopic study of late effects in rabbits. Scanning Microsc 10:805–818PubMed

15.

Cwikiel M, Zhang B, Eskilsson J, Wieslander JB, Albertsson M (1995) The influence of 5-fluorouracil on the endothelium in small arteries. An electron microscopic study in rabbits. Scanning Microsc 9:561–576PubMed

16.

Chow AY, Chin C, Dahl G, Rosenthal DN (2006) Anthracyclines cause endothelial injury in pediatric cancer patients: a pilot study. J Clin Oncol 24:925–928PubMedCrossRef

17.

Hayward R, Ruangthai R, Schneider CM, Hyslop RM, Strange R, Westerlind KC (2004) Training enhances vascular relaxation after chemotherapy-induced vasoconstriction. Med Sci Sports Exerc 36:428–434PubMedCrossRef

18.

Sudoh M, Kishimoto Y, Marumoto A, Inoue M, Sano A, Miura N, Horie Y, Hasegawa J, Ryoke K (2004) A new animal model of continuous catheterization for investigating mechanisms of arteritis associated with chemotherapy. Life Sci 74:3025–3032PubMedCrossRef

19.

Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O’Reilly S, Chu L, Azar CA, Wolmark N (2009) Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol 27:3385–3390PubMedCrossRef

20.

Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, Mazier MA, Canon JL, Georgoulias V, Peeters M, Bridgewater J, Cunningham D (2009) Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 20:1842–1847PubMedCrossRef

21.

Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60–65PubMedCrossRef

22.

Zwicker JI, Liebman HA, Neuberg D, Lacroix R, Bauer KA, Furie BC, Furie B (2009) Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 15:6830–6840PubMedCrossRef

23.

Bazo IG, Gonzales VC, Gutierrez AA, Rodriguez JR, Fernandez JAP, Gomez JC, Lizoain JLH, Lopez JG (2005) Impact of surgery and chemotherapy on von Willebrand factor and vascular endothelial growth factor levels in colorectal cancer. Clin Transl Oncol 7:150–155

24.

van Duijnhoven EM, Lustermans FA, van Wersch JW (1993) Evaluation of the coagulation/fibrinolysis balance in patients with colorectal cancer. Haemostasis 23:168–172PubMed

25.

Mochizuki S, Yoshino T, Kojima T, Fuse N, Ikematsu H, Minashi K, Yano T, Tahara M, Kaneko K, Doi T, Koike K, Ohtsu A (2010) Therapeutic significance of a D-dimer cut-off level of >3 {micro}g/ml in colorectal cancer patients treated with standard chemotherapy plus bevacizumab. Jpn J Clin Oncol 40:933–937

26.

Xu G, Zhang YL, Huang W (2004) Relationship between plasma D-dimer levels and clinicopathologic parameters in resectable colorectal cancer patients. World J Gastroenterol 10:922–923PubMed

27.

Oya M, Akiyama Y, Okuyama T, Ishikawa H (2001) High preoperative plasma D-dimer level is associated with advanced tumor stage and short survival after curative resection in patients with colorectal cancer. Jpn J Clin Oncol 31:388–394PubMedCrossRef

28.

Blackwell K, Hurwitz H, Lieberman G, Novotny W, Snyder S, Dewhirst M, Greenberg C (2004) Circulating D-dimer levels are better predictors of overall survival and disease progression than carcinoembryonic antigen levels in patients with metastatic colorectal carcinoma. Cancer 101:77–82PubMedCrossRef

29.

Damin DC, Rosito MA, Gus P, Roisemberg I, Bandinelli E, Schwartsmann G (2002) Von Willebrand factor in colorectal cancer. Int J Colorectal Dis 17:42–45PubMedCrossRef

30.

Wang WS, Lin JK, Lin TC, Chiou TJ, Liu JH, Yen CC, Chen PM (2005) Plasma von Willebrand factor level as a prognostic indicator of patients with metastatic colorectal carcinoma. World J Gastroenterol 11:2166–2170PubMed

31.

Jensen SA, Hasbak P, Mortensen J, Sorensen JB (2010) Fluorouracil induces myocardial ischemia with increases of plasma brain natriuretic peptide and lactic acid but without dysfunction of left ventricle. J Clin Oncol 28:5280–5286. doi:10.1200/JCO.2009.27.3953 PubMedCrossRef

32.

Guidelines Subcommittee (1999) 1999 World Health Organization-international society of hypertension guidelines for the management of hypertension. J Hypertens 17:151–183

33.

American Diabetes Association (2007) Diagnosis and classification of diabetes mellitus Diabetes Care 30(Suppl 1):S42–S47

34.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol (2001) Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) JAMA 285:2486–2497

35.

Dignam JJ, Polite BN, Yothers G, Raich P, Colangelo L, O’Connell MJ, Wolmark N (2006) Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. J Natl Cancer Inst 98:1647–1654PubMedCrossRef

36.

Jensen JS, Clausen P, Borch-Johnsen K, Jensen G, Feldt-Rasmussen B (1997) Detecting microalbuminuria by urinary albumin/creatinine concentration ratio. Nephrol Dial Transplant 12(Suppl 2):6–9PubMed

37.

Millart H, Brabant L, Lorenzato M, Lamiable D, Albert O, Choisy H (1992) The effects of 5-fluorouracil on contractility and oxygen uptake of the isolated perfused rat heart. Anticancer Res 12:571–576PubMed

38.

Feliu J, Safont MJ, Salud A, Losa F, Garcia-Giron C, Bosch C, Escudero P, Lopez R, Madronal C, Bolanos M, Gil M, Llombart A, Castro-Carpeno J, Gonzalez-Baron M (2010) Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer. Br J Cancer 102:1468–1473PubMedCrossRef

39.

Stender MT, Frokjaer JB, Larsen TB, Lundbye-Christensen S, Thorlacius-Ussing O (2009) Preoperative plasma D-dimer is a predictor of postoperative deep venous thrombosis in colorectal cancer patients: a clinical, prospective cohort study with one-year follow-up. Dis Colon Rectum 52:446–451PubMedCrossRef

40.

Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ III (2000) Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 160:809–815PubMedCrossRef

41.

Swystun LL, Shin LY, Beaudin S, Liaw PC (2009) Chemotherapeutic agents doxorubicin and epirubicin induce a procoagulant phenotype on endothelial cells and blood monocytes. J Thromb Haemost 7:619–626PubMedCrossRef

42.

Gordon SG, Cross BA (1981) A factor X-activating cysteine protease from malignant tissue. J Clin Invest 67:1665–1671PubMedCrossRef

43.

Varki A (2007) Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 110:1723–1729PubMedCrossRef

44.

Hron G, Kollars M, Weber H, Sagaster V, Quehenberger P, Eichinger S, Kyrle PA, Weltermann A (2007) Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 97:119–123PubMed

45.

Ozturk M, Sengul N, Dagli M, Kosar A, Bavbek N (2003) Global fibrinolytic capacity in colorectal cancer: a new clue to occult fibrinolysis. Clin Appl Thromb Hemost 9:151–154PubMedCrossRef

46.

Kockar C, Kockar O, Ozturk M, Dagli M, Bavbek N, Kosar A (2005) Global fibrinolytic capacity increased exponentially in metastatic colorectal cancer. Clin Appl Thromb Hemost 11:227–230PubMedCrossRef

47.

Frielingsdorf J, Kaufmann P, Suter T, Hug R, Hess OM (1998) Percutaneous transluminal coronary angioplasty reverses vasoconstriction of stenotic coronary arteries in hypertensive patients. Circulation 98:1192–1197PubMed

48.

Lechner D, Kollars M, Gleiss A, Kyrle PA, Weltermann A (2007) Chemotherapy-induced thrombin generation via procoagulant endothelial microparticles is independent of tissue factor activity. J Thromb Haemost 5:2445–2452PubMedCrossRef

Title: 5-Fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity
Authors: Søren Astrup Jensen
Jens Benn Sørensen
Publication date: 01-01-2012
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1669-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Aim

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2012

Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma

Docetaxel pharmacokinetics and its correlation with two in vivo probes for cytochrome P450 enzymes: the C14-erythromycin breath test and the antipyrine clearance test

Evaluating rational non-cross-resistant combination therapy in advanced clear cell renal cell carcinoma: combined mTOR and AKT inhibitor therapy

In vitro assessment of cytochrome P450 inhibition and induction potential of tanespimycin and its major metabolite, 17-amino-17-demethoxygeldanamycin

Population pharmacokinetics of PM00104 (Zalypsis®) in cancer patients

A phase I trial of oral metronomic vinorelbine plus capecitabine in patients with metastatic breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer