Abstract
Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, in combination with other chemotherapeutics, have revolutionised clinical oncology and transformed cancer into a curable disease. However, even though combination chemotherapy, together with radiation, surgery and immunotherapy, can nowadays cure almost all types of cancer, we still fail to achieve this for a substantial proportion of patients. The understanding of differences in metabolism, pharmacokinetics, pharmacodynamics, and tumour biology between patients that can be cured and patients that cannot, builds the scientific basis for rational therapy improvements. Here, we summarise current knowledge of how tumour-specific and patient-specific factors can dictate resistance to nucleobase/nucleoside analogues, and which strategies of re-sensitisation exist. We revisit well-established hurdles to treatment efficacy, like the blood-brain barrier and reduced deoxycytidine kinase activity, but will also discuss the role of novel resistance factors, such as SAMHD1. A comprehensive appreciation of the complex mechanisms that underpin the failure of chemotherapy will hopefully inform future strategies of personalised medicine.
Highlights
Since metastatic potential is a hallmark of cancer [1], management of malignant disease usually requires systemic treatment in order to prevent and treat tumour spread
The efficacy of the blood-brain barrier (BBB) to shield the central nervous system (CNS) from antimetabolites is historically best documented by children with ALL who–despite achieving complete remission when treated with antifolates [4]—almost universally relapsed with CNS disease
The thiopurine nucleobases and 5-FU need to be glycosylated by means of purine salvage and pyrimidine salvage pathways, respectively. 5-FU can be transformed into 5-F-uridine (5-FUrd) or 5-F-20 -deoxyuridine (5-FdUrd) by uridine phosphorylase 1 (UP1) or TP, respectively [286]
Summary
Since metastatic potential is a hallmark of cancer [1], management of malignant disease usually requires systemic treatment in order to prevent and treat tumour spread. This review to give an overview the current of chemoresistance, rationally improve existingaims therapy modalities This of review aims tounderstanding give an overview of the current but will exclusively focus on nucleoside and nucleobase analogues Their cytotoxic effects by mimicking endogenous inhibition (and or byfollowing substituting endogenous nucleoside species as can substrates, leading to DNA and RNA nucleosides phosphorylation, nucleotides). Both diseasetreatment to one or several their active(Figure metabolites before theyand canpatient-specific hit their molecular targetfailure Patient‐specific failure to one or several improve antimetabolic to take at into account all of and assess nucleobase or nucleosidetreatments analogueshave can be caused one or more ofthese thesemechanisms steps Histone deacetylase inhibitors (HDACi) reduce TYMS expression and synergise with fluoropyrimidines [130,131]
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