Abstract
Simple SummaryThe number of children and adults with cancer that are completely cured is still increasing thanks to effective anti-cancer therapy, but they may be confronted with the negative lasting effects of the treatment later in life. In this review, we provide an overview of major clinical symptoms and toxic side-effects observed in cancer survivors. We describe which types of anti-cancer treatments—primarily DNA-damaging chemotherapeutics—might cause these toxicities and what the (potential) underlying mechanisms are. These treatments not only damage cancer cells in their attempt at tumor killing but also harm healthy cells and tissues. Observations of side-effects in cancer patients and survivors strengthen the hypothesis that the primary induced DNA damage can lead to varying toxicities while also accelerating features of aging, depending on type and dose of chemotherapeutic, clearing method, and affected organ.Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence of numerous features of accelerated aging, seriously affecting quality of life, has now become one of the most pressing problems associated with (pediatric) cancer treatment. Chemotherapies frequently target and damage the DNA, causing mutations or genome instability, a major hallmark of both cancer and aging. However, there are numerous types of chemotherapeutic drugs that are genotoxic and interfere with DNA metabolism in different ways, each with their own biodistribution, kinetics, and biological fate. Depending on the type of DNA lesion produced (e.g., interference with DNA replication or RNA transcription), the organ or cell type inflicted (e.g., cell cycle or differentiation status, metabolic state, activity of clearance and detoxification mechanisms, the cellular condition or micro-environment), and the degree of exposure, outcomes of cancer treatment can largely differ. These considerations provide a conceptual framework in which different classes of chemotherapeutics contribute to the development of toxicities and accelerated aging of different organ systems. Here, we summarize frequently observed side-effects in (pediatric) ex-cancer patients and discuss which types of DNA damage might be responsible.
Highlights
In the current era of medical treatments, the cure rate of cancer has reached approximately 80% in children [1,2,3] and 67% in adults [4]
FS = Fanconi syndrome; NDI = nephrogenic diabetes insipidus; AKI = acute kidney injury; CKD = chronic kidney disease; TMA = thrombotic microangiopathy; HUS = hemolytic uremic syndrome; SIADH = syndrome of inappropriate anti-diuretic hormone secretion; ATN = acute tubular necrosis; AIN = acute interstitial nephritis; VOD = veno-occlusive disease; SOS = sinusoidal obstruction syndrome; Radiation-induced liver disease (RILD) = radiation-induced liver damage; AMS = arthralgia-myalgia syndrome; CHF = congestive heart failure; MI = myocardial infarction; HF = heart failure; * acute pancerebellar syndrome is characterized by ataxia, dysarthria, and oculomotor alterations [68]; ** retinoic acid syndrome is characterized by fever, respiratory distress, bodyweight gain, peripheral oedema, pleural-pericardial effusions, and MI [51]
Children with inborn mutations in DNA repair processes or nuclear integrity show segmental progeroid aging, affecting only a subset of tissues and organs [157,164,165,166]. Both the type of mutation and type of repair process affected in children with progeria syndromes and the classes of chemotherapeutics used for the treatment of cancers result in a specific accumulation of persisting DNA lesions and as such drive accelerated aging across various organs and tissues (Figure 3)
Summary
In the current era of medical treatments, the cure rate of cancer has reached approximately 80% in children [1,2,3] and 67% in adults [4]. FS = Fanconi syndrome; NDI = nephrogenic diabetes insipidus; AKI = acute kidney injury; CKD = chronic kidney disease; TMA = thrombotic microangiopathy; HUS = hemolytic uremic syndrome; SIADH = syndrome of inappropriate anti-diuretic hormone secretion; ATN = acute tubular necrosis; AIN = acute interstitial nephritis; VOD = veno-occlusive disease; SOS = sinusoidal obstruction syndrome; RILD = radiation-induced liver damage; AMS = arthralgia-myalgia syndrome; CHF = congestive heart failure; MI = myocardial infarction; HF = heart failure; * acute pancerebellar syndrome is characterized by ataxia, dysarthria, and oculomotor alterations [68]; ** retinoic acid syndrome is characterized by fever, respiratory distress, bodyweight gain, peripheral oedema, pleural-pericardial effusions, and MI [51]. Renal tissue is exposed to higher concentrations of most drugs than blood and likely other organs, frequently leading to acute kidney injury (AKI) or late-life nephrotoxicity [24,27,31,42,69]
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