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Elevation of radiolabelled thymidine uptake in RIF-1 fibrosarcoma and HT29 colon adenocarcinoma cells after treatment with thymidylate synthase inhibitors

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

We recently showed an increase in tumour uptake of 2-[11C]thymidine in patients with gastrointestinal malignancies after thymidylate synthase (TS) inhibition. To understand the phenomenon in more detail, we investigated whether TS inhibition by different TS inhibitors leads to a dose- and time-dependent change in the uptake of radiolabelled thymidine, and whether radiotracer uptake is related to changes in cell viability resulting from treatment.

Methods

RIF-1 and HT29 cells were treated with the TS inhibitors 5-fluorouracil (5-FU) and AG337 (nolatrexed dihydrochloride), as well as cisplatin as control. The cell viability and net accumulation of [3H]thymidine after a 1-h pulse was determined at different times after drug treatment.

Results

In both cell lines, [3H]thymidine uptake increased after a 2-h treatment with 5-FU, in a dose- and time-dependent manner. [3H]thymidine uptake decreased at 24 and 48 h post treatment. AG337 also produced a similar effect. In contrast to the TS inhibitors, cisplatin decreased [3H]thymidine uptake in RIF-1 and HT29 cells at all time points. Cell viability was compromised only after 24 h.

Conclusion

Using two types of TS inhibitor, we have shown an increase in [3H]thymidine uptake, in a dose-dependent manner, a few hours after TS inhibition when the cell viability was not compromised. This effect was not seen with a non-TS inhibitor. These findings suggest that 2-[11C]thymidine positron emission tomography can be used to study TS inhibition in vivo at early time points when cell viability is not compromised and may therefore be helpful in the development of new TS inhibitors and in differentiating between patients with tumours sensitive to TS inhibitors and those unlikely to respond.

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Acknowledgements

We thank Dr. Alan V. Boddy, Northern Institute for Cancer Research, University of Newcastle, Newcastle, UK and Agouron Pharmaceuticals, San Diego, CA, USA, for the supply of AG337.

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Authors and Affiliations

  1. Imaging Sciences, Imperial College, 242 Cycltron Building, DuCane Road, London, W12 0NN, UK

    Kawai Yau, Patricia Price, Radhakrishma G. Pillai & Eric Aboagye

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  1. Kawai Yau
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  2. Patricia Price
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  3. Radhakrishma G. Pillai
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  4. Eric Aboagye
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Correspondence to Eric Aboagye.

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Yau, K., Price, P., Pillai, R.G. et al. Elevation of radiolabelled thymidine uptake in RIF-1 fibrosarcoma and HT29 colon adenocarcinoma cells after treatment with thymidylate synthase inhibitors. Eur J Nucl Med Mol Imaging 33, 981–987 (2006). https://doi.org/10.1007/s00259-005-0060-8

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  • DOI: https://doi.org/10.1007/s00259-005-0060-8

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