Thymidine Phosphorylase and Fluoropyrimidines Efficacy: A Jekyl and Hyde Story

Ciccolini, Joseph; Evrard, Alexandre; Cuq, Pierre

doi:10.2174/1568011043482089

Cited by 41 publications

(22 citation statements)

References 116 publications

(148 reference statements)

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“…As discussed earlier in this review TP plays a role in cancer progression and angiogenesis, yet it is important in activating capecitabine to its active form 5-FU. These two contradicting roles, best described by one publication as a Jekyll and Hyde story [69], are independently related to TP expression.…”

Section: Tp As a Predictive Biomarkermentioning

confidence: 99%

Thymidine Phosphorylase in Cancer; Enemy or Friend?

Elamin

Rafee

Osman

et al. 2015

Cancer Microenvironment

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Thymidine phosphorylase (TP) is a nucleoside metabolism enzyme that plays an important role in the pyrimidine pathway.TP catalyzes the conversion of thymidine to thymine and 2-deoxy-α-D-ribose-1-phosphate (dRib-1-P). Although this reaction is reversible, the main metabolic function of TP is catabolic. TP is identical to the angiogenic factor platelet-derived endothelial-cell growth factor (PD-ECGF). TP is overexpressed in several human cancers in response to cellular stressful conditions like hypoxia, acidosis, chemotherapy and radiotherapy. TP has been shown to promote tumor angiogenesis, invasion, metastasis, evasion of the immuneresponse and resistance to apoptosis. Some of the biological effects of TP are dependent on its enzymatic activity, while others are mediated through cytokines like interleukin 10 (IL-10), basic fibroblast growth factor (bFGF) and tumour necrosis factor α (TNFα). Interestingly, TP also plays a role in cancer treatment through its role in the conversion of the oral fluoropyrimidine capecitabine into its active form 5-FU. TP is a predictive marker for fluoropyrimidine response. Given its various biological functions in cancer progression, TP is a promising target in cancer treatment. Further translational research is required in this area.

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Section: Tp As a Predictive Biomarkermentioning

confidence: 99%

Thymidine Phosphorylase in Cancer; Enemy or Friend?

Elamin

Rafee

Osman

et al. 2015

Cancer Microenvironment

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“…Capecitabine is an oral prodrug that is ultimately converted to 5-FU by thymidine phosphorylase and uridine phosphorylase. Both enzymes have been shown to have elevated expression in solid tumors, allowing for a locally increased concentration of the active drug at the site of the cancer (6,7). Other 5-FU -based therapies include uracil/ tegafur (UFT; molar ratio, 4:1), S-1 [tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), potassium oxonate; molar ratio, 1:0.4:1], and eniluracil/5-FU treatment, all of which combine 5-FU or its oral derivative, tegafur, with an inhibitor of dihydropyrimidine dehydrogenase (DPD).…”

Section: -Fluorouracil (5-fu) Remains One Of the Most Commonlymentioning

confidence: 99%

Can Inhibiting Dihydropyrimidine Dehydrogenase Limit Hand-Foot Syndrome Caused by Fluoropyrimidines?

Yen-Revollo

Goldberg

McLeod

2008

Clinical Cancer Research

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Hand-foot syndrome (HFS) is a cutaneous adverse event that occurs in some patients treated with fluoropyrimidines. Although it is not life threatening, HFS can severely disrupt the daily lives of patients. HFS appears more frequently with 5-fluorouracil (5-FU) delivered by continuous infusion or with the 5-FU oral derivative capecitabine than with bolus 5-FU therapy. HFS is a leading cause of treatment interruption, dosage reduction, or, even, therapy discontinuation for patients on a capecitabine regimen. Interestingly, addition of a dihydropyrimidine dehydrogenase (DPD) inhibitor, such as uracil, 5-chloro-2,4-dihydroxypyridine, or eniluracil, to the fluoropyrimidine treatment regimen significantly diminishes the incidence of HFS. DPD inhibitors were initially combined with fluoropyrimidines to increase the efficacy of the drugs by impairing the DPDmediated catabolism of 5-FU. However, with the accumulating findings from clinical trials that show the benefits of DPD inhibition on decreasing the risk of HFS, consideration should be given to changing the recommendations for the treatment of cancer patients with fluoropyrimidines to include DPD inhibitor components as standard therapy.

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“…Several attempts to boost tumoural TP levels have been published in an effort to improve cell sensitivity to 5-FU or oral 5-FU (capecitabine), by using either 'Suicide Gene' strategies (Schwartz et al, 1995a, b;Evrard et al, 1999;Ciccolini et al, 2001), co-treating tumour cells with modulators such as IFN, taxoïd drugs, mitomycine C, or with radiotherapy (Ciccolini et al, 2004;Blanquicett et al, 2005). Among the numerous compounds tested as putative modulators, 2 0 -deoxyinosine (d-Ino) is a nontoxic precursor of the TP cofactor, deoxyribose 1-phosphate, that has been shown to enhance 5-FU's antiproliferative activity in several in vitro and in vivo models, when either used alone or combined with gene therapy strategies targeting TP (Ciccolini et al, 2000a, b;Fanciullino et al, 2006).…”

mentioning

confidence: 99%

In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation

Fanciullino¹,

Giacometti²,

Mercier³

et al. 2007

Br J Cancer

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Drug resistance is a major cause of treatment failure in cancer chemotherapy, including that with the extensively prescribed antimetabolite, 5-fluorouracil (5-FU). In this study, we tried to reverse 5-FU resistance by using a double-punch strategy: combining 5-FU with a biochemical modulator to improve its tumoural activation and encapsulating both these agents in one same stealth liposome. Experiments carried out in the highly resistant, canonical SW620 human colorectal model showed a up to 80% sensitisation to 5-FU when these cells were treated with our liposomal formulation. Results with this formulation demonstrated 30% higher tumoural drug uptake, better activation with increased active metabolites including critical-5-fluoro-2-deoxyuridine-5-monophosphate, superior inhibition (98%) of tumour thymidylate synthase, and subsequently, higher induction of both early and late apoptosis. Drug monitoring showed that higher and sustained exposure was achieved in rats treated with liposomal formulation. When examined in a xenograft animal model, our dual-agent liposomal formulation caused a 74% reduction in tumour size with a mean doubling in survival time, whereas standard 5-FU failed to exhibit significant antiproliferative activity as well as to increase the lifespan of tumour-bearing mice. Taken collectively, our data suggest that resistance to 5-FU can be overcome through a better control of its intratumoural activation and the use of an encapsulated formulation.

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Thymidine Phosphorylase and Fluoropyrimidines Efficacy: A Jekyl and Hyde Story

Cited by 41 publications

References 116 publications

Thymidine Phosphorylase in Cancer; Enemy or Friend?

Thymidine Phosphorylase in Cancer; Enemy or Friend?

Can Inhibiting Dihydropyrimidine Dehydrogenase Limit Hand-Foot Syndrome Caused by Fluoropyrimidines?

In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation

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