Thymidine concentrations in serum and urine of different animal species and man

Nottebrock, Helene; Then, Rudolf L.

doi:10.1016/0006-2952(77)90271-4

Cited by 99 publications

(47 citation statements)

References 10 publications

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“…However, the importance of TdR salvage in humans is unknown. Early reports indicated that plasma levels of TdR in normal subjects and advanced solid tumour patients exhibited marked variation (>20-fold) in the range of 50-900 nmol l −1 [46][47][48][49][50][51]. However, using sophisticated mass spectrometry techniques, we have shown no significant difference in basal plasma TdR concentrations among normal subjects and CRC cancer patients [39].…”

Section: Discussioncontrasting

confidence: 58%

Altered deoxyuridine and thymidine in plasma following capecitabine treatment in colorectal cancer patients

Rivory

Hoskins

et al. 2006

Brit J Clinical Pharma

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AimsTo investigate the relationship between changes in plasma deoxynucleoside concentrations and response and toxicity in patients treated with capecitabine. MethodsTwenty-six patients received 2 g capecitabine twice daily orally for 2 weeks of a 3-week cycle. Blood samples were collected on day 0 (baseline), day 8, day 15 and day 22 of the first cycle for the determination of plasma thymidine (TdR) and deoxyuridine (UdR) concentrations. Patients were reviewed weekly during the first cycle, then 3-weekly for toxicity assessment. Response was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. ResultsThe plasma UdR and UdR/TdR ratios were significantly elevated ( P < 0.001) compared with baseline (49.3 ± 20.8 nmol l − 1 ) for the entire 3-week treatment period. In contrast, the plasma TdR concentrations of these patients were significantly reduced only on day 8 ( P < 0.01) compared with baseline (12.1 ± 3.83 nmol l − 1 ), but returned gradually to basal levels by day 15. There were no significant correlations demonstrated between pretreatment or maximal post-treatment plasma nucleoside ratio and either toxicity or response. The TSER genotype frequencies of homozygous TSER*2, TSER*3 and heterozygous TSER*2/*3 were 7.7%, 42.3% and 50%, respectively. These preliminary data also indicate no direct relationship between thymidylate synthase (TS) genotype and plasma nucleoside levels. ConclusionsCapecitabine mimics continuous infusion of 5-FU to achieve sustained cellular TS inhibitory effects and suggests the antiproliferative mechanism of capectabine is at least partly due to TS inhibition through its active metabolite FdUMP. Although plasma UdR and TdR concentrations and the UdR/TdR ratio can provide some pharmacodynamic indication of TS inhibition, they are unlikely to predict therapeutic response or toxicity accurately following capecitabine treatment in cancer patients.

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Section: Discussioncontrasting

confidence: 58%

Altered deoxyuridine and thymidine in plasma following capecitabine treatment in colorectal cancer patients

Rivory

Hoskins

et al. 2006

Brit J Clinical Pharma

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“…Kinetic and computer analysis suggest that the transport of nucleosides is rate limiting at low (< 1IM) concentrations of extracellular nucleosides (Wiley et al, 1985;White et al, 1987). Nucleoside levels of this order occur in human serum (Nottebrock and Then, 1977), suggesting that nucleoside transporter expression might be an important rate-limiting step in the cellular utilisation of nucleosides by the salvage pathway in man.…”

mentioning

confidence: 99%

Modulation of the equilibrative nucleoside transporter by inhibitors of DNA synthesis

Pressacco

Wiley²,

Jamieson³

et al. 1995

Br J Cancer

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In contrast, cytosine arabinoside (ara-C) and aphidicolin, which directly inhibit DNA synthesis, produced no significant increase in es expression. Thymidine (TdR), which is an allosteric inhibitor of ribonucleotide reductase that depletes dATP, dCTP and dGTP pools while repleting the dTTP pool, had no significant effect on es expression. These data suggest that surface expression of the es nucleoside transporter is regulated by a mechanism which is sensitive to the supply of deoxynucleotides. Because 5-FU (which specifically depletes dTTP pools) causes a large increase in expression whereas TdR (which depletes all precursors except dTTP) does not, this mechanism might be particularly sensitive to dTTP pools.

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“…Thymidine levels in rodents are tenfold higher than in humans. 28 As FLT is transported and phosphorylated in a similar way as thymidine, high levels of thymidine might result in reduced FLT uptake. 37 Van Waarde et al 33 reported decreased thymidine levels after TP infusion with a concomitant increase in FLT uptake in tumor tissue.…”

Section: Discussionmentioning

confidence: 99%

“…27 Thymidine phosphorylase. When using this model for FLT studies, plasma thymidine levels have to be taken into account, as levels are 10 times higher in rodents than in humans 28 and thymidine may compete with FLT uptake. Therefore, the possibility to lower thymidine levels with the enzyme thymidine phosphorylase was investigated.…”

Section: Methodsmentioning

confidence: 99%

A new rat model of human breast cancer for evaluating efficacy of new anti-cancer agents in vivo

Direcks

Gelder²,

Lammertsma

et al. 2008

Cancer Biology & Therapy

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Purpose: Advanced stage breast cancer patients may benefit from high dose chemotherapy, but only a minority will respond. A method to select non-responders as early as possible is essential for preventing unnecessary toxicity, possibly enabling a switch to an alternative treatment. Positron emission tomography (PET), a noninvasive molecular imaging modality, is able to detect functional changes well before anatomical changes are visible. The purpose of the present study was to develop a rat model of human breast cancer suitable for PET. This model, together with PET, would provide a means for investigating the efficacy of new anti-cancer drugs in an experimental setting.Methods: Human breast cancer cells MDA MB231 were injected subcutaneously into nude rats. Tumor take, tumor doubling time and growth inhibition after treatment with maximum tolerable doses of 5-fluorouracil, doxorubicin, cyclophosphamide and paclitaxel were established. As thymidine competes with 18 FLT and plasma thymidine levels are high in rodents, this could affect 18 FLT uptake. Therefore, use of thymidine phosphorylase to lower plasma thymidine levels was investigated. Finally, as an illustration of the potential use of the model, a pilot PET study was performed using 18 FDG and 18 FLT.Results: Tumor take rate was 68% when matrigel was coinjected. Tumor doubling time was 6 days. Treating animals with anti-cancer drugs resulted in tumor growth inhibition ranging from 7 to 68%, depending on the type of drug. Using thymidine phosphorylase, plasma concentrations of thymidine could be decreased by more than 80% and these reduced levels were stable for more than an hour, i.e., long enough for a PET study. Tumors could clearly be visualised using 18 FDG and 18 FLT PET.Conclusions: A new in vivo breast cancer model was successfully established in nude rats, allowing for quantitative PET studies of anti-cancer agents.

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Thymidine concentrations in serum and urine of different animal species and man

Cited by 99 publications

References 10 publications

Altered deoxyuridine and thymidine in plasma following capecitabine treatment in colorectal cancer patients

Altered deoxyuridine and thymidine in plasma following capecitabine treatment in colorectal cancer patients

Modulation of the equilibrative nucleoside transporter by inhibitors of DNA synthesis

A new rat model of human breast cancer for evaluating efficacy of new anti-cancer agents in vivo

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