Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism
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cancers Review Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism Nikolaos Tsesmetzis 1, Cynthia B. J. Paulin 2, Sean G. Rudd 2,* ID and Nikolas Herold 1,3,* ID 1 Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, 171 77 Stockholm, Sweden; [email protected] 2 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, Sweden; [email protected] 3 Paediatric Oncology, Theme of Children’s and Women’s Health, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden * Correspondence: [email protected] (S.G.R.): [email protected] (N.H.) Received: 1 July 2018; Accepted: 20 July 2018; Published: 23 July 2018 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. Keywords: chemoresistance; sensitisation; novel therapy; combination therapy; antimetabolites; nucleoside analogues; nucleobase analogues; cytarabine; gemcitabine; clofarabine; fludarabine; nelarabine; cladribine; 5-fluorouracil; capecitabine; SAMHD1; ribonucleotide reductase; precision medicine 1. Introduction 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. Combination chemotherapy still constitutes the current paradigm to achieve systemic disease control in clinical oncology, even though immunotherapeutic approaches are becoming a viable complement at least for a subset of patients [2,3]. Antimetabolites were the first class of cytotoxic drugs systematically tested in clinical trials that elicited complete clinical responses as monotherapies, albeit with inevitable relapse [4]. Even though this review will–with few exceptions–mainly focus on monotherapy, it is important to keep in mind that, empirically, combination of chemotherapeutic agents is a sine qua non for the cure of the vast majority of cancers. On the other hand, a reductionist understanding of the mechanisms underlying the insufficiency of monotherapies is a prerequisite to rationally improve existing therapy Cancers 2018, 10, 240; doi:10.3390/cancers10070240 www.mdpi.com/journal/cancers CancersCancers 20182018, 10,,10 x , 240 2 of2 37 of 38 understanding of the mechanisms underlying the insufficiency of monotherapies is a prerequisite to rationallymodalities. improve This reviewexisting aims therapy to give modalities. an overview This ofreview the current aims to understanding give an overview of chemoresistance, of the current understandingbut will exclusively of chemoresistance, focus on nucleoside but will and exclusively nucleobase analoguesfocus on (Figurenucleoside1), the and major nucleobase subgroup analoguesof antimetabolites. (Figure 1), the major subgroup of antimetabolites. FigureFigure 1. 1.StructuresStructures of ofnucleobase nucleobase and and nucleoside nucleoside analogues analogues discussed discussed in inthis this review. review. Endogenous Endogenous nucleobase/nucleosidesnucleobase/nucleosides are arelabelled labelled in inbold bold and and synthetic synthetic analogues analogues with with sugar sugar-modifications‐modifications (indicated(indicated in inblue) blue) or orbase base-modifications‐modifications (indicated (indicated in inred) red) are are shown. shown. AntimetabolitesAntimetabolites can can be be grouped grouped into into folate folate antagonists antagonists and and nucleobase/nucleoside nucleobase/nucleoside analogues. analogues. DueDue to totheir their structural structural similarity, similarity, folate folate antagonists, antagonists, or orantifolates, antifolates, either either inhibit inhibit conversion conversion of of dihydrofolatedihydrofolate to to tetrahydrofolate tetrahydrofolate by by targeting targeting dihydrofolate reductasereductase (DHFR)(DHFR) or or directly directly inhibit inhibit one oneor moreor ofmore the enzymesof the that enzymes require tetrahydrofolatethat require astetrahydrofolate a co-factor, e.g., phosphoribosylglycinamideas a co‐factor, e.g., phosphoribosylglycinamideformyltransferase (GARFT) formyltransferase and thymidylate synthase(GARFT) (TS);and keythymidylate enzymes insynthase de novo (TS); synthesis key of enzymesnucleic acidin de precursors novo synthesis (discussed of nucleic in more acid detail precursors below) [5 ,(discussed6]. Antifolates in more are, however, detail below) not within [5,6]. the Antifolatesscope of the are, current however, review not article;within the comprehensive scope of the reviews current arereview to be article; found comprehensive elsewhere [7,8]. reviews are to beNucleobase found elsewhere and nucleoside [7,8]. analogues exert their cytotoxic effects by mimicking endogenous nucleosidesNucleobase (and and following nucleoside phosphorylation, analogues exert nucleotides). their cytotoxic This effects can either by mimicking be mediated endogenous by enzyme nucleosidesinhibition (and or by following substituting phosphorylation, endogenous nucleoside nucleotides). species This as can substrates, either be leading mediated to DNA by enzyme and RNA inhibitiondamage or and by interference substituting with endogenous DNA methylation. nucleoside Nucleosidespecies as substrates, analogues leading have to to reach DNA tumour and RNA sites, damageniches and and interference sanctuaries with at sufficient DNA methylation. concentration Nucleoside (delivery) analogues and in a non-degraded have to reach formtumour (stability), sites, nichesbe taken and sanctuaries up into the at cancer sufficient cell (usuallyconcentration by nucleoside (delivery) transport and in a proteins),non‐degraded and beform converted (stability), into betheir taken active up into metabolites the cancer (activation) cell (usually before by nucleoside they can hit transport their molecular proteins), target and be (pharmacodynamic converted into theiractivity) active (Figure metabolites2 and Table(activation)1). Both before disease- they and can patient-specific hit their molecular treatment target failure (pharmacodynamic to one or several activity)nucleobase (Figure or nucleoside2 and Table analogues 1). Both disease can be caused‐ and patient at one‐specific or more treatment of these steps. failure Strategies to one or to rationallyseveral nucleobaseimprove antimetabolicor nucleoside treatments analogues have can thusbe caused to take at into one account or more all ofof these these mechanisms steps. Strategies and assess to rationallytheir relative improve contribution. antimetabolic treatments have thus to take into account all of these mechanisms and assess their relative contribution. Cancers 2018, 10, 240 3 of 38 Cancers 2018, 10, x 3 of 37 Figure 2. Schematic representation of the levels of resistance to nucleobase/nucleoside analogues. Figure 2. Schematic representation of the levels of resistance to nucleobase/nucleoside analogues. Resistance to nucleobase/nucleoside analogues can occur at the pharmacokinetic levels of delivery Resistance to nucleobase/nucleoside analogues can occur at the pharmacokinetic levels of (e.g., due to the blood‐brain barrier), stability (e.g., due to plasmatic catabolic activity), membrane delivery (e.g., due to the blood-brain barrier), stability (e.g., due to plasmatic catabolic activity), transport (e.g., due to down‐regulation of influx transporters), and intracellular activation (due to an membrane transport (e.g., due to down-regulation of influx transporters), and intracellular activation imbalance in anabolic and catabolic enzymes). Further downstream, pharmacodynamic resistance (due to an imbalance in anabolic and catabolic enzymes). Further downstream, pharmacodynamic can occur (e.g., due to overexpression of drug targets). Drug efficacy critically depends on the resistance can occur (e.g., due to overexpression of drug targets). Drug efficacy critically depends underlying tumour biology that determines the general susceptibility to cytotoxicity (for details, see on the underlying tumour biology that determines the general susceptibility to cytotoxicity text). Examples for re‐sensitisation strategies are given. NsA, nucleoside analogue; TDM, therapeutic (for details, see text). Examples for re-sensitisation strategies are given. NsA, nucleoside analogue;