The radioprotector ortho-phospho-L-tyrosine (pTyr) attenuates the side effects of fractionated irradiation in retinoblastoma mouse models but also decreases the local tumour control

Alexander V Tschulakow; Klaus Dittmann; Stephan M Huber; Dominik Klumpp; Benjamin Stegen; Ulrich Schraermeyer; H Peter Rodemann; Sylvie Julien-Schraermeyer

doi:10.1016/j.radonc.2017.06.023

The radioprotector ortho-phospho-L-tyrosine (pTyr) attenuates the side effects of fractionated irradiation in retinoblastoma mouse models but also decreases the local tumour control

Radiother Oncol. 2017 Sep;124(3):462-467. doi: 10.1016/j.radonc.2017.06.023. Epub 2017 Jul 12.

Authors

Alexander V Tschulakow¹, Klaus Dittmann², Stephan M Huber³, Dominik Klumpp³, Benjamin Stegen³, Ulrich Schraermeyer¹, H Peter Rodemann², Sylvie Julien-Schraermeyer⁴

Affiliations

¹ Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Germany.
² Division of Radiobiology & Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Germany.
³ Department of Radiation Oncology, University of Tuebingen, Germany.
⁴ Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Germany. Electronic address: Sylvie.Julien@med.uni-tuebingen.de.

PMID: 28711224
DOI: 10.1016/j.radonc.2017.06.023

Abstract

Background: Radiotherapy (RT) is used to treat retinoblastoma (Rb), the most frequent ocular tumour in children. Besides eradicating the tumour, RT can cause severe side effects including secondary malignancies. This study aimed to define whether the radioprotector ortho-phospho-L-tyrosine (pTyr) prevents RT-induced side effects and affects local tumour control in a xenograft and a genetic orthotopic Rb mouse model.

Methods: B6;129-Rb1tm3Tyj/J (Rb^+/-) and Y79-Rb cell-xenografted nude mice were fractionated external beam irradiated (15 fractions of 5Gy 6MV photons during 3weeks) with or without pTyr pre-treatment (100mg/kg BW, 16h prior to each irradiation). One, three, six and nine months after RT, tumour control and RT toxicity were evaluated using in vivo imaging and histology. We also analysed pTyr dependant post irradiation cell survival and p53 activity in vitro.

Results: In vitro pTyr pre-treatment showed no radioprotection on Y79 cells, but led to p53 stabilisation in unirradiated Y79 cells and to a facilitation of radiation-induced p21 up-regulation, confirming a modulation of p53 activity by pTyr. In both mouse models, secondary tumours were undetectable. In Rb^+/- mice, pTyr significantly lowered RT-induced greying of the fur, retinal thickness reduction and photoreceptor loss. However, in the xenografted Rb model, pTyr considerably decreased RT-mediated tumour control, which was observed in 16 out of 22 control eyes but in none of the 24 pTyr treated eyes.

Conclusions: In Rb^+/- mice pTyr significantly prevents RT-induced greying of the fur as well as retinal degeneration. However, since non-irradiated control mice were not used in our study, a formal possibility exists that the effect shown in the retina of Rb^+/- mice may be due to ageing of the animals and/or actions of pTyr alone. Unfortunately, as tested in a xenograft model, pTyr treatment reduced the control of Rb tumours.

Keywords: Histology; In vivo imaging; Mouse model; Radioprotector pTyr; Radiotherapy; Retinoblastoma.

MeSH terms

Animals
Cell Survival
Disease Models, Animal
Dose Fractionation, Radiation*
Mice
Phosphotyrosine / pharmacology*
Radiation-Protective Agents / pharmacology*
Retinal Neoplasms / radiotherapy*
Retinoblastoma / pathology
Retinoblastoma / radiotherapy*
Tumor Suppressor Protein p53 / physiology

Substances

Radiation-Protective Agents
Tumor Suppressor Protein p53
Phosphotyrosine