Effects of pretreatment with the radioprotector ortho-phospho-L-tyrosine (pTyr) on Rb+/- mice after radiation exposure - Implication for the treatment of retinoblastoma patients with radiotherapy

Abstract

 

Purpose

 

Retinoblastoma (Rb) is the most frequent ocular tumor in children and if let untreated, can cause death. Like the most head and neck tumors it is sensitive to radiotherapy (RT). However, the therapy has its risks like damage of healthy tissues recurrence and development of treatment-induced secondary tumors.<br /> The aim of this study is to investigate the ability of the radioprotector pTyr to prevent RT-induced secondary tumors and other side-effects observed after RT.

 

Methods

 

B6;129-Rb1^tm3Tyj/J mice having a mutation in one of the Rb -gen allele were used. Although these mice do not develop a Rb, this model was chosen because Rb-patients having a similar mutation have a higher risk of developing secondary tumors induced by RT. One group of mice was treated with intraperitoneal injections of pTyr 16 hours before each irradiation. Another group was only irradiated. Both groups were irradiated over a period of 3 weeks 3 times a week with a dosage of 5 Gy per exposure (Fig.1). All animals were investigated using SLO/OCT and histologically 1, 3, 6 and 9 months after irradiation (Ir) . Radiation-induced tumor induction as well as normal tissue radiation toxicity were evaluated as function of pTyr-treatment.

 

Results

 

The first visible effect of the Ir was the graying of the hair coat in the area of Ir. This effect was reduced in the pTyr treated mice. The results of the OCT- analysis showed that 3 and 6 months after Ir the thickness of the retina of the mice was significantly lower in the untreated group (n=12) compared to the pTyr treated one (n=12) (p<0.05 3 months and p<0.001 6 months after Ir). The histological analysis of the retina showed a significant photoreceptor loss in the untreated group vs. the pTyr treated one (p<0.001 3 months and p<0.0001 6 months after Ir) .

 

Conclusions

 

Our results show, that the application of pTyr before irradiation significantly reduces the negative effects of radiation on the hair coat and retina. The results of the analysis 9 months after Ir, the appearance of secondary tumors as well as the potential benefit of the pretreatment with pTyr are currently under investigation.  

 

fig. 1: (a) linear accelarator Linac-G (Phillips), (b) the mouse fixation units, (c) 6 Rb+/- mice fixed for radiation exposure, (d) scheme of the assembly of the<br /> experiment.