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Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

1
Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, 171 77 Stockholm, Sweden
2
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, Sweden
3
Paediatric Oncology, Theme of Children’s and Women’s Health, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
*
Authors to whom correspondence should be addressed.
Cancers 2018, 10(7), 240; https://doi.org/10.3390/cancers10070240
Received: 1 July 2018 / Revised: 18 July 2018 / Accepted: 20 July 2018 / Published: 23 July 2018
(This article belongs to the Special Issue Drug Resistance in Cancers)
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. View Full-Text
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 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
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Tsesmetzis, N.; Paulin, C.B.J.; Rudd, S.G.; Herold, N. Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism. Cancers 2018, 10, 240.

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