Exploration of Medicine

Table 2

Anticancer drugs effects on renal, retinal, neuronal and cardiovascular events

Class	Agents	Adverse outcomes	Mechanisms	References
Nephropathy
mTOR inhibitors	Everolimus Temsirolimus	Increased creatinine Increased UAE	Hyperglycaemia and urinary infections	[67, 104, 105]
Multi-target TKIs	Pazopanib Sunitinib Sorafenib Axitinib	Increased UAE Nephrotic syndrome	Glomerular endothelial damage; Podocyte damage	[67, 104, 107, 108]
Anti-VEGF	Bevacizumab Aflibercept	Increased UAE	Glomerular endothelial damage; Podocyte damage	[104, 107, 108]
ICIs	Ipilimumab Nivolumab Pembrolizumab	Acute interstitial nephritis	Delayed hyper-sensitivity with granulomatous reaction (CD4⁺ T cells and macrophage activation, gamma-interferon production); Podocyte damage	[108–110]
Retinopathy
Anti-oestrogen	Tamoxifen	Retinal exudates and haemorrhages	Retinal thromboembolism	[111–114]
Alkylating agents	Cisplatin Carboplatin Carmustine	Retinal ischaemia and neovascularization	Retinal thrombosis with vascular occlusion (phospholipase A2 and platelet hyperactivation)	[114, 115]
ICIs	Nivolumab	Retinal vessels occlusion Retinal thinning	Autoimmune (abs against retinal proteins)	[116]
Oral anti-VEGF	Pazopanib Sunitinib Sorafenib	Retinal vessels bleeding/occlusion Retinal detachment Macular oedema	Alterations of choroidal vascular permeability; Microvascular events (microemboli)	[119]
MAPK inhibitors	Selumetinib Binimetinib Pimasertib	Retinal vessels occlusion Retinal detachment Subretinal fluid	Alterations of choroidal vascular permeability; Autoimmune (abs against retinal proteins)	[117–120]
Neuropathy
IMIDs	Talidomide	Sensory neuropathy	Inhibition neurotrophic factors (NGF, NF-kB); Reduced angiogenic factors	[121, 122]
Proteasome inhibitor	Bortezomib	Sensory and autonomic neuropathy	Inhibition neurotrophic factors (NF-kB); Autoimmune; miRNA dysregulation (miR-20a, -29b, -34a, -128, -181, -342-3p, -17-92)	[121–123]
Cardiovascular disease
Anthracyclines	Doxorubicin Epirubicin Idarubicin	LV dysfunction/HF	Increased ROS; Mitochondrial dysfunction; Apoptosis	[124, 125, 128, 129]
Anti-HER2 drugs	Trastuzumab Lapatinib Pertuzumab	LV dysfunction/HF Hypertension	ErbB2 inhibition with apoptosis of cardiomyocytes	[124, 125, 128, 130]
Anti-VEGF and Multi-target TKIs	Bevacizumab Pazopanib Sunitinib Sorafenib Vandetanib Regorafenib Axitinib	LV dysfunction/HF Hypertension Myocardial ischemia (rare) Atherosclerosis	NO-mediated dysregulation of endothelial homeostasis	[124, 128]
Anti BCR-ABL1	Imatinib Nilotinib Ponatinib	QTc prolongation HF	Increased ROS; Mitochondrial dysfunction; Cardiomyocytes apoptosis	[124, 128]
ICIs	Ipilimumab Nivolumab Pembrolizumab	Rare cases of: - Myocardial fibrosis - Immune myocarditis - Cardiomyopathy - Acute HF - Lethal myocarditis	Immune-mediated damages^*	[124, 132]
Proteasome inhibitors	Bortezomib Carfilzomib Ixazomib Oprozomib	LV dysfunction Hypertension Myocardial infarction (rare) Cardiac arrest (rare)	Increased ROS; Mitochondrial dysfunction	[128, 131]
Antimetabolites	5-FU Capecitabine Gemcitabine	Coronary spasms/ischemia	Increased ROS; NO reduction; Increased thrombogenicity	[127, 128]
Taxanes	Docetaxel Paclitaxel	Bradycardia LV dysfunction Ischemia	Alteration of tubulin polymerisation and cell division; Stimulation of histamine receptors	[126, 128]

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indicates the uncertainty of the evidence on this item; mTOR: mammalian target of rapamycin; UAE: urinary albumin excretion; TKIs: tyrosine kinase inhibitors; VEGF: vascular endothelial growth factor; ICIs: immune checkpoint inhibitors; Abs: antibodies; MAPK: mitogen-activated protein kinase; IMIDs: immunomodulatory drugs; NGF: nerve growth factor; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; miRNA: microRNA; LV: left ventricular; HF: heart failure; ROS: reactive oxygen species; HER2: human epidermal growth factor receptor 2; NO: nitric oxide; BCR-ABL: breakpoint cluster region Abelson gene; QTc: corrected QT; 5-FU: 5-Fluorouracil