Login | Users Online: 85  
Home Print this page Email this page Small font sizeDefault font sizeIncrease font size   
Home | About us | Editorial board | Search | Ahead of print | Current Issue | Archives | Submit article | Instructions | Subscribe | Advertise | Contact us
 


 
Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 22  |  Issue : 2  |  Page : 127-133  

Atherosclerosis, ischemia, and anticancer drugs


1 Department of Cardiology, Fortis Escorts Heart Institute, New Delhi, India
2 Department of Paediatrics, Lal Bahadur Shastri Hospital, New Delhi, India

Date of Submission24-Mar-2021
Date of Acceptance30-Jun-2021
Date of Web Publication19-Aug-2021

Correspondence Address:
Dr. Shailesh Singh
M-429, Ashiana Colony, Lucknow - 226 012, Uttar Pradesh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/HEARTVIEWS.HEARTVIEWS_45_20

Rights and Permissions
   Abstract 


The heart is affected by cardiotoxicity of anticancer drugs. Myocardium, pericardium and endocardium can be affected. Besides these coronary arteries can be affected by accelerated atherosclerosis. Various pathogenic mechanisms have been proposed that underlie the ischemic complications of anticancer drugs. In this review we discuss the atherosclerotic and ischemic complications of anticancer drugs.

Keywords: Accelerated atherosclerosis, anticancer drugs, cardio-oncology, coronary artery disease, myocardial infarction


How to cite this article:
Singh S, Singh K. Atherosclerosis, ischemia, and anticancer drugs. Heart Views 2021;22:127-33

How to cite this URL:
Singh S, Singh K. Atherosclerosis, ischemia, and anticancer drugs. Heart Views [serial online] 2021 [cited 2023 Dec 5];22:127-33. Available from: https://www.heartviews.org/text.asp?2021/22/2/127/324153



Anticancer drugs have been nothing less than a miracle to the patients who have been suffering from cancer. However, the longer life due to these drugs (anticancer drugs) does not come without a price. Various organs such as the skin and the bone marrow take the worst hit. The heart is also affected by the cardiotoxicity of these drugs, and it can be seen any time after the anticancer drugs have been started. This is what the recently emerging field of cardio-oncology aims to study, i.e., the cardiovascular short-term and long-term complications of the cancers and the therapy related to it.[1]

Almost every part of the cardiovascular system can be affected by cancer treatment. All the three layers of the heart – the pericardium, myocardium, and endocardium – can be affected, leading to pericarditis, myocardial fibrosis, and valvular heart disease, respectively. Besides this, the coronary arteries and the conduction system can be adversely affected.[2]

Heart failure, life-threatening arrhythmias, and myocardial ischemia are the most dreaded complication of chemotherapy.[3]

Drugs like 3rd generation Tyrosine kinase inhibitors, VEGF inhibitors and 5- fluorouracil have been found to cause ischemic complications such as myocardial infarction, coronary artery disease, and peripheral arterial disease.

In this review, we discuss the atherosclerotic and ischemic complications of anticancer drugs.


   How Do Anticancer Drugs Cause Ischemia? Top


Various pathogenic mechanisms underlie the ischemic complications of anticancer agents. It includes vasospasm, endothelial dysfunction, decreased nitric oxide (NO) signaling, increased endothelin signaling, increased oxidative stress, decreased PGI2 signaling, and platelet activation.[4]

Apart from these mechanisms, patients receiving chemotherapy may have accelerated atherosclerosis due to chemotherapy-induced dyslipidemia and pro-inflammatory state.[5],[6]

The role of low-density lipoprotein (LDL) cholesterol in the causation of atherosclerotic diseases is well known.[7] An increase in serum LDL level has been found with bevacizumab.[8]

Gonadotropin-releasing hormone (GnRH) agonist therapy, which is used in the treatment of prostate cancer also increases LDL levels.[9] Patients receiving an mTOR-based chemotherapeutic regimen have a higher likelihood of developing dyslipidemia with increased atherogenic small dense Low-density Lipoproteins (sdLDLs).[10]

Similarly, sirolimus therapy has been found to be associated with an elevation in PCSK9 levels.[11]

Recently, the role of triglyceride in the causation of atherosclerosis has been confirmed by various studies.[12],[13] Hypertriglyceridemia is seen with drugs like mTOR inhibitors (inhibits the mechanistic target of rapamycin) like everolimus, which is used in advanced progressive pancreatic neuroendocrine tumors, advanced renal cell carcinoma (RCC), advanced hormone receptor-positive breast cancer, and subependymal giant cell astrocytoma associated with tuberous sclerosis.[14] Capecitabine, a chemotherapy medication which is used in patients with breast, gastric cancers and colorectal cancers,[15] tamoxifen, which is used in the treatment of breast cancer,[16] bexarotene, a retinoid used in the treatment of cutaneous T-cell lymphoma.[17] have been found to cause hypertriglyceridemia.

Drugs which act against vascular endothelial growth factor including those which inhibit tyrosine kinase increase the blood pressure and the rates of cardiovascular events. Anti-metabolites, the group which includes 5-fluorouracil and capecitabine has been found to be associated with chest pain and increased cardiovascular events. Anthracyclines cause heart failure and may increase CVD risk.[18]


   Atherosclerotic Diseases Due to Tyrosine Kinase Inhibitors Top


Tyrosine kinase inhibitors (TKIs) are used in the treatment of chronic myelogenous leukemia, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia, gastrointestinal stromal cell tumor, and various other malignancies. Of these TKIs, imatinib is the oldest and it is found generally well tolerated.[19] However, concerns have been raised regarding the cardiac safety of newer TKIs.[20],[21],[22]

Various cases of arterial occlusive diseases have been reported with TKIs. A study reported that arterial occlusive diseases developed in 25% of the patients who received nilotinib.[23]

Fujioka et al. found that out of 369 chronic myeloid leukemia patients who received TKIs, 6.2% developed various arterial occlusive diseases. The incidence of ischemic heart diseases was most common in patients receiving nilotinib.[24] Stroke has also been reported with TKI.[25]

Among the newer TKIs, dasatinib has been studied and found not to increase the risk for cardiovascular ischemic events compared with external reference populations.[26]

The exact mechanism behind the pathogenesis of the arterial occlusive disease remains unknown. Various hypotheses have been proposed to explain the ischemic events seen in the patients receiving TKIs. These include inhibition of “off-target” tyrosine kinases in cardiac muscle cells and vascular endothelium,[27],[28],[29] induction of an inflammatory/oxidative state,[30] endothelial dysfunction,[31] decreased proliferation of endothelial cells,[32] inhibition of neoangiogenesis by vascular endothelium,[33] increased lipid peroxidation due to LOX-1 polymorphism, and a pro-inflammatory state due to low levels of interleukin-10.[34]

Coronary artery spasm has also been implicated in the causation of ischemic heart diseases.[35]


   Platinum-Based Drugs – Cisplatin Top


Cisplatin is used in the treatment of various malignancies such as carcinoma bladder, head and neck, lung, ovary, and testes. Apart from these, it is also useful in germ cell tumors, lymphomas, and sarcomas.[36] A retrospective study found that of all the chemotherapeutic agents implicated in the causation of stroke, cisplatin was the most common culprit.[37]

Cases of myocardial infarction have also been reported with cisplatin.[38] Another study reported cases of acute arterial occlusion in patients with and without preexisting moderate peripheral artery disease.[39] Various theories have been proposed to explain the atherogenic profile of cisplatin. These include endothelial injury,[40],[41] endothelial dysfunction and decreased NO production,[42] increased levels of fibrinogen, C-reactive protein, von Willebrand factor, plasminogen activator inhibitor-1, and tissue-type plasminogen activator,[43] increased oxidative stress due to lipid peroxidation,[44] and dyslipidemia with increased levels of LDL-C and thyroglobulin.[45],[46]


   Vascular Endothelial Growth Factor Inhibitors Top


VEGF signal plays an important role in the progression of various malignancies.[47] Bevacizumab is used for patients with colon cancer, lung cancer, glioblastoma, and renal cell carcinoma. Sorafenib and axitinib are used in the management of RCC; Ranibizumab is used in patients with diabetic macular edema. Aflibercept is used in colorectal cancers. Other VEFGF signaling inhibitors such as sorafenib and axitinib are used in RCC.

Systemic, as well as intravitreal injection of VEGF inhibitors, have been found to be associated with adverse cardiovascular events. Studies have found that patients receiving either of the two, ranibizumab and aflibercept, are prone to develop ischemic cardiac disease. It is hypothesized that this effect is due to an increase in atheroma stability, which can lead to leading to plaque rupture.[48],[49]

In a study in which bevacizumab was used along with irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer; it was found that bevacizumab group had a numerically higher number of patients affected with thrombotic diseases.[50]

Other studies have shown the complications of systemic administration of VEGF inhibitors for solid tumors and they found that patients receiving VEGF inhibitors were more prone to develop transient ischemic attacks, strokes, and other thrombotic events.[51],[52]

The various hypotheses proposed for explaining these thrombotic episodes have been put forward.

Studies have also found evidence of inflammation,[53] endothelial dysfunction leading to decreased NO and PGI2 production and vasoconstriction,[54] an increase in endothelial cell apoptosis, with disruption of the endothelial lining,[55],[56],[57] platelet activation,[58] dyslipidemia, with increase in total cholesterol and triglycerides.[8]

All of these can result in thrombotic episodes. Systemic VEGF inhibition increases atherosclerotic lesions by 33% and promotes the generation of superoxide from endothelium leading to increased oxidative stress.[59]


   5-Fluorouracil and Capecitabine Top


The antimetabolite fluorouracil is used in the treatment of gastrointestinal, breast, and cervical malignancies. Capecitabine is the prodrug of 5-FU, and similar to fluorouracil, it is used for the treatment of gastric and breast cancers. Both of these drugs have been known to increase the risk of CVDs.[18] Fluorouracil has been known to cause coronary spasm. Fluorouracil related cardiotoxicity has been reported to present as angina as well as ST segment elevation myocardial infarction.[61],[62]

A study reported that 69% of all the cardiac incidents occurred in the first 3 days of the first cycle of 5-FU. Angina was more common than myocardial infarction (45% vs. 22% of patients) whereas myocardial infarction was seen in 22%.[63],[64]

A study by Jensen and Sørensen reported that 4.3% of all the patients who received either 5-FU or capecitabine developed angina or acute coronary syndrome. The authors found that the chances of coronary vasospasm increased with decreasing creatinine clearance.[64]

A calcium channel blocker or sublingual nitroglycerine may be of some benefit in the prevention or treatment of 5-FU cardiotoxicity.[61],[64]

The authors have different opinions on re-administration of these drugs after a coronary event.[62],[64]

Various explanations have been given the vasospasm due to antimetabolites. These include drug-induced endothelial dysfunction and downregulation of endothelial NO synthase (eNOS),[65],[66] increased oxidative stress due to reactive oxygen species (ROS) formation, lipid peroxidation, and rapid glutathione depletion. The increased burden of ROS can cause mitochondrial injury, ultimately culminating in myocardial cell death.[67],[68],[69],[70]


   Programmed Death-1 Inhibitors Top


Cancer immunotherapy is the use of drugs which modulate the immune system to fight cancer. These are the new addition in the armamentarium of anticancer therapy. Immune checkpoint inhibitors (ICIs) are a type of cancer immunotherapy. Currently available ICIs target either of the three molecules, CTLA4, programmed death (PD)-1, and PD-L1.

PD-1 ICIs have been used in patients with various cancers, for example, melanoma, RCC, squamous cell carcinoma, and non-small cell lung cancer (NSCLC), and have been found to increase patient survival when it was compared to conventional chemotherapies.[71]

Animal studies have shown that PD-1 seems to exert significant anti-inflammatory and atheroprotective effects, mostly in early phases of disease progression, and blockade of this molecule for the treatment of cancer may increase cardiovascular risk.[72],[73]

Drugs such as pembrolizumab and nivolumab which block PD-1 signaling and are used in patients with advanced melanoma, NSCLC, Hodgkin's lymphoma, head-and-neck squamous cell carcinoma, and advanced urothelial (bladder) cancer can theoretically lead to progression of atherosclerosis.


   Androgen Deprivation Therapy and Atherosclerosis Top


Androgen deprivation therapy (ADT) which includes luteinizing hormone-releasing hormone (LHRH) agonists like leuprolide, goserelin and LHRH antagonist like degarelix; anti-androgens like flutamide, bicalutamide are used to delay the growth of the prostate tumor and improve survival in patients affected with prostate cancer are also found to be associated with accelerated atherosclerosis.

Keating et al., for the first time in 2006, found that ADT was associated with increased risk of coronary artery disease and myocardial infarction.[74]

Other studies have also confirmed the association between administration of ADT and increased rate of ischemic heart diseases.[75],[76]

CVD risk was highest during the first 6 months of ADT in men who experienced two or more cardiovascular events before therapy.[77]

ADT leads to the development of metabolic abnormalities, such as hyperglycemia, dyslipidemia, and obesity, which ultimately lead to atherosclerosis.[78]

Androgens may inhibit this process by stimulating endothelial production of NO, which inhibits platelet aggregation, and inhibiting platelet secretion of thromboxane A2, which has the opposite effect.[79],[80],[81]

Androgens have been found to be associated with decreased expression of pro-inflammatory cytokines.[82],[83]

Testosterone may also stimulate fibrinolysis and resultant clot degradation by increasing expression of tissue plasminogen activator.[84]

Androgen deprivation is associated with increased total cholesterol and LDL levels.[9],[85],[86]

A nested case–control study in the UK found that combined ADT with both LHRH agonists and anti-androgens was associated with a significant increase in the risk of coronary artery disease and acute myocardial infarction.[87]


   Proteasome Inhibitors Top


The proteasome is a protein complex which breaks down proteins which are marked by ubiquitin. Inhibition of the proteasome complex has been found to be an effective strategy for the treatment of cancers. They have been approved for use in multiple myeloma (MM). This group includes drugs such as bortezomib, carfilzomib, marizomib, and ixazomib.[88]

Bortezomib is a boron-containing peptide. The boron atom in its molecule binds specifically to the catalytic site of 26S proteasome, thereby reversibly inhibiting it.[89] The drug has been approved for the management of MM.[90],[91],[92] Bortezomib's inhibition of proteasome activity may increase endothelial progenitor cell apoptosis and decrease eNOS/NO, thus leading to coronary spasm.[92]

A large retrospective review of almost 4000 patients in seven Phase II and Phase III clinical trials that led to bortezomib's approval reported an ischemic heart disease incidence of 1.5%–2.7% in the bortezomib treatment arms.[93]

More recently, a case report showed that an association between an ischemic heart attack and the bortezomib plus dexamethasone combination might exist. A 79-year-old woman with no past history of CVD developed acute myocardial infarction immediately following bortezomib administration requiring a coronary artery stent.[92]

Carfilzomib was noted in the ASPIRE trial to have a higher incidence of ischemic heart disease when compared to a control group not receiving carfilzomib, 3.3% compared to 2.1%, respectively.[94]

Limited evidence from animal studies suggests an endothelium-dependent mechanism by which carfilzomib induces coronary vasospasm or lack of dilation contributing to ischemia.[95] Nifedipine and nitroglycerin have been found to be effective in treating carfilzomib-induced vasospasm.[95]


   Summary and Conclusion Top


The recognition of cardiac problems related to the treatment of cancer is complex. Identifying patients who are at increased risk for cardiovascular problems associated with the cancer treatment or who develop side effects following treatment is a major component of an evolving area often referred to as cardio-oncology-diagnosing, preventing, and treating patients with cancer and CVDs; the discipline assists in the overall care of cancer patients from cancer diagnosis into survivorship.

Progress in the detection and treatment of cancer has led to an impressive reduction in both mortality and morbidity. Due to their mechanism of action, however, conventional chemotherapeutics and some of the newer anticancer signaling inhibitors carry a substantial risk of cardiovascular side effects that include cardiac dysfunction and heart failure, arterial hypertension, vasospastic and thromboembolic ischemia, dysrhythmia, and QT prolongation. While some of these side effects are irreversible and cause progressive CVD, others induce only temporary dysfunction with no apparent long-term sequelae for the patient.

The challenge for the cardiovascular specialist is to balance the need for lifesaving cancer treatment with the assessment of risk from cancer drug-associated cardiovascular side effects to prevent long-term damage. The management of these complex patients requires careful balance: excessive concern regarding potentially reversible cardiac issues may compromise the administration of highly beneficial anticancer therapies, while underappreciation of cardiac risk may result in lifelong cardiac concerns for a patient who has been cured of their cancer.

Knowledge of the cardiac effects of anticancer agents balanced with knowledge regarding the natural history of the malignancy and the likelihood of tumor response offers such patients the greatest chance for long-term disease-free survival.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Lancellotti P, Suter TM, López-Fernández T, Galderisi M, Lyon AR, der Meer PV, et al. cardio-oncology services: Rationale, organization, and implementation: A report from the ESC Cardio-Oncology Council. Eur Heart J 2019;40:1756-63.  Back to cited text no. 1
    
2.
Gaya AM, Ashford RF. Cardiac complications of radiation therapy. Clin Oncol (R Coll Radiol) 2005;17:153-9.  Back to cited text no. 2
    
3.
Monsuez JJ, Charniot JC, Vignat N, Artigou JY. Cardiac side-effects of cancer chemotherapy. Int J Cardiol 2010;144:3-15.  Back to cited text no. 3
    
4.
Cameron AC, Touyz RM, Lang NN. Vascular complications of cancer chemotherapy. Can J Cardiol 2016;32:852-62.  Back to cited text no. 4
    
5.
Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012;32:2045-51.  Back to cited text no. 5
    
6.
Wolf D, Stachon P, Bode C, Zirlik A. Inflammatory mechanisms in atherosclerosis. Hamostaseologie 2014;34:63-71.  Back to cited text no. 6
    
7.
Schaefer EJ, Tsunoda F, Diffenderfer M, Polisecki E, Thai N, Asztalos B, et al. The Measurement of Lipids, Lipoproteins, Apolipoproteins, Fatty Acids, and Sterols, and Next Generation Sequencing for the Diagnosis and Treatment of Lipid Disorders. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000. Available from: https://www.ncbi.nlm.nih.gov/books/NBK355892/?report=classic. [Last updated on 29 Mar 2016].  Back to cited text no. 7
    
8.
Joerger M, Riesen WF, Thürlimann B. Bevacizumab-associated hyperlipoproteinemia type IIb in a patient with advanced invasive-ductal breast cancer. J Oncol Pharm Pract 2011;17:292-4.  Back to cited text no. 8
    
9.
Smith MR, Finkelstein JS, McGovern FJ, Zietman AL, Fallon MA, Schoenfeld DA, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 2002;87:599-603.  Back to cited text no. 9
    
10.
Zimmermann A, Zobeley C, Weber MM, Lang H, Galle PR, Zimmermann T. Changes in lipid and carbohydrate metabolism under mTOR- and calcineurin-based immunosuppressive regimen in adult patients after liver transplantation. Eur J Intern Med 2016;29:104-9.  Back to cited text no. 10
    
11.
Simha V, Qin S, Shah P, Smith BH, Kremers WK, Kushwaha S, et al. Sirolimus therapy is associated with elevation in circulating PCSK9 levels in cardiac transplant patients. J Cardiovasc Transl Res 2017;10:9-15.  Back to cited text no. 11
    
12.
Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.  Back to cited text no. 12
    
13.
Singh AK, Singh R. Triglyceride and cardiovascular risk: A critical appraisal. Indian J Endocrinol Metab 2016;20:418-28.  Back to cited text no. 13
    
14.
Kasiske BL, de Mattos A, Flechner SM, Gallon L, Meier-Kriesche HU, Weir MR, et al. Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. Am J Transplant 2008;8:1384-92.  Back to cited text no. 14
    
15.
Koutras AK, Habeos IG, Vagenakis AG, Kalofonos HP. Capecitabine-induced hypertriglyceridemia: A report of two cases. Anticancer Res 2006;26:2249-51.  Back to cited text no. 15
    
16.
Liu CL, Yang TL. Sequential changes in serum triglyceride levels during adjuvant tamoxifen therapy in breast cancer patients and the effect of dose reduction. Breast Cancer Res Treat 2003;79:11-6.  Back to cited text no. 16
    
17.
Musolino A, Panebianco M, Zendri E, Santini M, Di Nuzzo S, Ardizzoni A. Hypertriglyceridaemia with bexarotene in cutaneous T cell lymphoma: The role of omega-3 fatty acids. Br J Haematol 2009;145:84-6.  Back to cited text no. 17
    
18.
Min SS, Wierzbicki AS. Radiotherapy, chemotherapy and atherosclerosis. Curr Opin Cardiol 2017;32:441-7.  Back to cited text no. 18
    
19.
Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, et al. Safety and efficacy of imatinib in CML over a period of 10 years: Data from the randomized CML-study IV. Leukemia 2015;29:1123-32.  Back to cited text no. 19
    
20.
Cortes J, Mauro M, Steegmann JL, Saglio G, Malhotra R, Ukropec JA, et al. Cardiovascular and pulmonary adverse events in patients treated with BCR-ABL inhibitors: Data from the FDA Adverse Event Reporting System. Am J Hematol 2015;90:E66-72.  Back to cited text no. 20
    
21.
Chai-Adisaksopha C, Lam W, Hillis C. Major arterial events in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: A meta-analysis. Leuk Lymphoma 2016;57:1300-10.  Back to cited text no. 21
    
22.
Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol 2015;33:4210-8.  Back to cited text no. 22
    
23.
Aprile L, Puccetti L, Galimberti S, Gozzini A, Scarpini F, Defina M, et al. Atherothrombotic risk and TKIs treatment in chronic myeloid leukemia patients: A role for genetic predisposition and pro-inflammatory/Pro-oxidative status. Blood 2013;122:1482.  Back to cited text no. 23
    
24.
Fujioka I, Takaku T, Iriyama N, Tokuhira M, Kimura Y, Sato E, et al. Features of vascular adverse events in Japanese patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: A retrospective study of the CML Cooperative Study Group database. Ann Hematol 2018;97:2081-8.  Back to cited text no. 24
    
25.
Ozaki T, Nakamura H, Izutsu N, Masaie H, Ishikawa J, Kinoshita M. Intracranial stenting for nilotinib treatment-associated cerebrovascular stenosis in chronic myeloid leukemia. Interv Neuroradiol 2017;23:527-30.  Back to cited text no. 25
    
26.
Saglio G, le Coutre P, Cortes J, Mayer J, Rowlings P, Mahon FX, et al. Evaluation of cardiovascular ischemic event rates in dasatinib-treated patients using standardized incidence ratios. Ann Hematol 2017;96:1303-13.  Back to cited text no. 26
    
27.
Henning RJ, Harbison RD. Cardio-oncology: Cardiovascular complications of cancer therapy. Future Cardiol 2017;13:379-96.  Back to cited text no. 27
    
28.
Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol 2007;25:1035-44.  Back to cited text no. 28
    
29.
Rix U, Hantschel O, Dürnberger G, Remsing Rix LL, Planyavsky M, Fernbach NV, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 2007;110:4055-63.  Back to cited text no. 29
    
30.
Bocchia M, Galimberti S, Aprile L, Sicuranza A, Gozzini A, Santilli F, et al. Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients. Oncotarget 2016;7:72311-21.  Back to cited text no. 30
    
31.
Hadzijusufovic E, Albrecht-Schgoer K, Huber K, Hoermann G, Grebien F, Eisenwort G, et al. Nilotinib-induced vasculopathy: Identification of vascular endothelial cells as a primary target site. Leukemia 2017;31:2388-97.  Back to cited text no. 31
    
32.
Katgı A, Sevindik ÖG, Gökbulut AA, Özsan GH, Yüksel F, Solmaz ŞM, et al. Nilotinib does not alter the secretory functions of carotid artery endothelial cells in a prothrombotic or antithrombotic fashion. Clin Appl Thromb Hemost 2015;21:678-83.  Back to cited text no. 32
    
33.
Gover-Proaktor A, Pasvolsky O, Raanani P, Nagler A, Shapira S, Lubin I, et al. Pathogenesis of ponatinib associated vascular disease in chronic myeloid leukemia: An in vitro study. Blood (2015) 126 (23): 2798.  Back to cited text no. 33
    
34.
Arjuman A, Chandra NC. Effect of IL-10 on LOX-1 expression, signalling and functional activity: An atheroprotective response. Diab Vasc Dis Res 2013;10:442-51.  Back to cited text no. 34
    
35.
Fiets RB, Staal AH, Cramer GE, Blijlevens NM. Coronary artery spasms due to tyrosine kinase inhibitors used in chronic myeloid leukemia. Neth J Med 2018;76:330-5.  Back to cited text no. 35
    
36.
Dasari S, Tchounwou PB. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol 2014;740:364-78.  Back to cited text no. 36
    
37.
Li SH, Chen WH, Tang Y, Rau KM, Chen YY, Huang TL, et al. Incidence of ischemic stroke post-chemotherapy: A retrospective review of 10,963 patients. Clin Neurol Neurosurg 2006;108:150-6.  Back to cited text no. 37
    
38.
Hanchate LP, Sharma SR, Madyalkar S. Cisplatin induced acute myocardial infarction and dyslipidemia. J Clin Diagn Res 2017;11:D05-7.  Back to cited text no. 38
    
39.
Mathews J, Goel R, Evans WK, Shamji F, Stewart DJ. Arterial occlusion in patients with peripheral vascular disease treated with platinum-based regimens for lung cancer. Cancer Chemother Pharmacol 1997;40:19-22.  Back to cited text no. 39
    
40.
Vaughn DJ, Palmer SC, Carver JR, Jacobs LA, Mohler ER. Cardiovascular risk in long-term survivors of testicular cancer. Cancer 2008;112:1949-53.  Back to cited text no. 40
    
41.
Shi Y, Inoue S, Shinozaki R, Fukue K, Kougo T. Release of cytokines from human umbilical vein endothelial cells treated with platinum compounds in vitro. Jpn J Cancer Res 1998;89:757-67.  Back to cited text no. 41
    
42.
Sekijima T, Tanabe A, Maruoka R, Fujishiro N, Yu S, Fujiwara S, et al. Impact of platinum-based chemotherapy on the progression of atherosclerosis. Climacteric 2011;14:31-40.  Back to cited text no. 42
    
43.
Nuver J, Smit AJ, Sleijfer DT, van Gessel AI, van Roon AM, van der Meer J, et al. Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer. Eur J Cancer 2004;40:701-6.  Back to cited text no. 43
    
44.
Nuver J, Smit AJ, van der Meer J, van den Berg MP, van der Graaf WT, Meinardi MT, et al. Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer. J Clin Oncol 2005;23:9130-7.  Back to cited text no. 44
    
45.
Wang G, Su C, Yin T. Paclitaxel and platinum-based chemotherapy results in transient dyslipidemia in cancer patients. Mol Clin Oncol 2017;6:261-5.  Back to cited text no. 45
    
46.
Raghavan D, Cox K, Childs A, Grygiel J, Sullivan D. Hypercholesterolemia after chemotherapy for testis cancer. J Clin Oncol 1992;10:1386-9.  Back to cited text no. 46
    
47.
Burger RA. Role of vascular endothelial growth factor inhibitors in the treatment of gynecologic malignancies. J Gynecol Oncol 2010;21:3-11.  Back to cited text no. 47
    
48.
Avery RL. What is the evidence for systemic effects of intravitreal anti-VEGF agents, and should we be concerned? Br J Ophthalmol 2014;98 Suppl 1:i7-10.  Back to cited text no. 48
    
49.
Mones J. A review of ranibizumab clinical trial data in exudative age-related macular degeneration and how to translate it into daily practice. Ophthalmologica 2011;225:112-9.  Back to cited text no. 49
    
50.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42.  Back to cited text no. 50
    
51.
Kuenen BC, Rosen L, Smit EF, Parson MR, Levi M, Ruijter R, et al. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 20;2002:1657-67.  Back to cited text no. 51
    
52.
Heymach JV, Desai J, Manola J, Davis DW, McConkey DJ, Harmon D, et al. Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas. Clin Cancer Res 2004;10:5732-40.  Back to cited text no. 52
    
53.
Arnott C, Punnia-Moorthy G, Tan J, Sadeghipour S, Bursill C, Patel S. The vascular endothelial growth factor inhibitors ranibizumab and aflibercept markedly increase expression of atherosclerosis-associated inflammatory mediators on vascular endothelial Cells. PLoS One 2016;11:e0150688.  Back to cited text no. 53
    
54.
Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 2007;96:1788-95.  Back to cited text no. 54
    
55.
Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 2007;7:475-85.  Back to cited text no. 55
    
56.
Reinmuth N, Liu W, Jung YD, Ahmad SA, Shaheen RM, Fan F, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J 2001;15:1239-41.  Back to cited text no. 56
    
57.
Girardi F, Franceschi E, Brandes AA. Cardiovascular safety of VEGF-targeting therapies: Current evidence and handling strategies. Oncologist 2010;15:683-94.  Back to cited text no. 57
    
58.
Meyer T, Robson T, Amirkhosravi A, Langer F, Desai H, Amaya M, et al. Targeting Angiogenesis in Cancer: Bevacizumab-Induced Platelet Activation as a Possible Cause for Unexpected Arterial Thromboembolic Events in Clinical Trials. Blood (2006) 108 (11): 1091.  Back to cited text no. 58
    
59.
Winnik S, Lohmann C, Siciliani G, von Lukowicz T, Kuschnerus K, Kraenkel N, et al. Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis--implications for cardiovascular safety. Int J Cardiol 2013;168:2453-61.  Back to cited text no. 59
    
60.
Dent RG, McColl I. Letter: 5-Fluorouracil and angina. Lancet 1975;1:347-8.  Back to cited text no. 60
    
61.
Kim SM, Kwak CH, Lee B, Kim SB, Sir JJ, Cho WH, et al. A case of severe coronary spasm associated with 5-fluorouracil chemotherapy. Korean J Intern Med 2012;27:342-5.  Back to cited text no. 61
    
62.
McGlinchey PG, Webb ST, Campbell NP. 5-fluorouracil-induced cardiotoxicity mimicking myocardial infarction: A case report. BMC Cardiovasc Disord 2001;1:3.  Back to cited text no. 62
    
63.
Saif MW, Shah MM, Shah AR. Fluoropyrimidine-associated cardiotoxicity: Revisited. Expert Opin Drug Saf 2009;8:191-202.  Back to cited text no. 63
    
64.
Jensen SA, Sørensen JB. Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol 2006;58:487-93.  Back to cited text no. 64
    
65.
Alter P, Herzum M, Soufi M, Schaefer JR, Maisch B. Cardiotoxicity of 5-fluorouracil. Cardiovasc Hematol Agents Med Chem 2006;4:1-5.  Back to cited text no. 65
    
66.
Hemalatha T, Balachandran C, Manohar BM, Nayeem M, Subramaniam S, Sharma HS, et al. Myocardial expression of PDECGF is associated with extracellular matrix remodeling in experimental myocardial infarction in rats. Biochem Cell Biol 2010;88:491-503.  Back to cited text no. 66
    
67.
de Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: A prospective clinical study. J Clin Oncol 1992;10:1795-801.  Back to cited text no. 67
    
68.
Durak I, Karaayvaz M, Kavutcu M, Cimen MY, Kacmaz M, Buyukkocak S, et al. Reduced antioxidant defense capacity in myocardial tissue from guinea pigs treated with 5-fluorouracil. J Toxicol Environ Health A 2000;59:585-9.  Back to cited text no. 68
    
69.
Tsibiribi P, Bui-Xuan C, Bui-Xuan B, Lombard-Bohas C, Duperret S, Belkhiria M, et al. Cardiac lesions induced by 5-fluorouracil in the rabbit. Hum Exp Toxicol 2006;25:305-9.  Back to cited text no. 69
    
70.
Eskandari MR, Moghaddam F, Shahraki J, Pourahmad J. A comparison of cardiomyocyte cytotoxic mechanisms for 5-fluorouracil and its pro-drug capecitabine. Xenobiotica 2015;45:79-87.  Back to cited text no. 70
    
71.
Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Front Oncol 2018;8:86.  Back to cited text no. 71
    
72.
Gaudy C, Clévy C, Monestier S, Dubois N, Préau Y, Mallet S, et al. Anti-PD1 pembroli- zumab can induce exceptional fulminant type 1 diabetes. Diabetes Care 2015;38:e182-3.  Back to cited text no. 72
    
73.
Cochain C, Chaudhari SM, Koch M, Wiendl H, Eckstein HH, Zer-Necke A. Programmed cell death-1 deficiency exacerbates T cell activation and atherogenesis despite expansion of regulatory T cells in atherosclerosis-prone mice. PLoS One 2014;9:93280.  Back to cited text no. 73
    
74.
Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24:4448-56.  Back to cited text no. 74
    
75.
Tsai HK, D'Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007;99:1516-24.  Back to cited text no. 75
    
76.
Keating NL, O'Malley AJ, Freedland SJ, Smith MR. Diabetes and cardio- vascular disease during androgen deprivation therapy: Observational study of veterans with prostate cancer. J Natl Cancer Inst 2010;102:39-46.  Back to cited text no. 76
    
77.
Nguyen PL, Alibhai SM, Basaria S, D'Amico AV, Kantoff PW, Keating NL, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol 2015;67:825-36.  Back to cited text no. 77
    
78.
Zareba P, Duivenvoorden W, Leong DP, Pinthus JH. Androgen deprivation therapy and cardiovascular disease: What is the linking mechanism? Ther Adv Urol 2016;8:118-29.  Back to cited text no. 78
    
79.
Li S, Li X, Li J, Deng X, Li Y. Inhibition of oxidative-stress-induced platelet aggregation by androgen at physiological levels via its receptor is associated with the reduction of thromboxane A2 release from platelets. Steroids 2007;72:875-80.  Back to cited text no. 79
    
80.
Li S, Li X, Li J, Deng X, Li Y, Cong Y. Experimental arterial thrombosis regulated by androgen and its receptor via modulation of platelet activation. Thromb Res 2007;121:127-34.  Back to cited text no. 80
    
81.
Campelo AE, Cutini PH, Massheimer VL. Testosterone modulates platelet aggregation and endothelial cell growth through nitric oxide pathway. J Endocrinol 2012;213:77-87.  Back to cited text no. 81
    
82.
Qiu Y, Yanase T, Hu H, Tanaka T, Nishi Y, Liu M, et al. Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development. Endocrinology 2010;151:3307-16.  Back to cited text no. 82
    
83.
Corcoran M, Meydani M, Lichtenstein A, Schaefer E, Dillard A, Lamon-Fava S. Sex hormone modulation of proinflammatory cytokine and C-reactive protein expression in macrophages from older men and postmenopausal women. J Endocrinol 2010;206:217-24.  Back to cited text no. 83
    
84.
Jin H, Lin J, Fu L, Mei Y, Peng G, Tan X, et al. Physiological testosterone stimulates tissue plasminogen activator and tissue factor pathway inhibitor and inhibits plasminogen activator inhibitor type 1 release in endothelial cells. Biochem Cell Biol 2007;85:246-51.  Back to cited text no. 84
    
85.
Braga-Basaria M, Muller D, Carducci M, Dobs A, Basaria S. Lipoprotein profile in men with prostate cancer undergoing androgen deprivation therapy. Int J Impot Res 2006;18:494-8.  Back to cited text no. 85
    
86.
Dockery F, Bulpitt CJ, Agarwal S, Donaldson M, Rajkumar C. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clin Sci (Lond) 2003;104:195-201.  Back to cited text no. 86
    
87.
Martín-Merino E, Johansson S, Morris T, García Rodríguez LA. Androgen deprivation therapy and the risk of coronary heart disease and heart failure in patients with prostate cancer: A nested case-control study in UK primary care. Drug Saf 2011;34:1061-77.  Back to cited text no. 87
    
88.
Kubiczkova L, Pour L, Sedlarikova L, Hajek R, Sevcikova S. Proteasome inhibitors – Molecular basis and current perspectives in multiple myeloma. J Cell Mol Med 2014;18:947-61.  Back to cited text no. 88
    
89.
Jackson G, Einsele H, Moreau P, Miguel JS. Bortezomib, a novel proteasome inhibitor, in the treatment of hematologic malignancies. Cancer Treat Rev 2005;31:591-602.  Back to cited text no. 89
    
90.
San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:906-17.  Back to cited text no. 90
    
91.
Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004;127:165-72.  Back to cited text no. 91
    
92.
Takamatsu H, Yamashita T, Kotani T, Sawazaki A, Okumura H, Nakao S. Ischemic heart disease associated with bortezomib treatment combined with dexamethasone in a patient with multiple myeloma. Int J Hematol 2010;91:903-6.  Back to cited text no. 92
    
93.
Laubach JP, Moslehi JJ, Francis SA, San Miguel JF, Sonneveld P, Orlowski RZ, et al. A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: Towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma. Br J Haematol 2017;178:547-60.  Back to cited text no. 93
    
94.
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2014;372:142-52.  Back to cited text no. 94
    
95.
Tarentino AL, Maley F. A comparison of the substrate specificities of endo-beta-N-acetylglucosaminidases from Streptomyces griseus and Diplococcus Pneumoniae. Biochem Biophys Res Commun 1975;67:455-62.  Back to cited text no. 95
    




 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
    How Do Anticance...
    Atherosclerotic ...
    Platinum-Based D...
    Vascular Endothe...
    5-Fluorouracil a...
    Programmed Death...
    Androgen Depriva...
    Proteasome Inhib...
    Summary and Conc...
    References

 Article Access Statistics
    Viewed1685    
    Printed114    
    Emailed0    
    PDF Downloaded39    
    Comments [Add]    

Recommend this journal