The use of whole body irradiation to reduce tumour development in a mouse model of prostate cancer lawrence
The use of whole body irradiation
to reduce tumour development in a
mouse model of prostate cancer
Supervisors: Assoc. Prof. Pamela Sykes
and Dr Rebecca Ormsby
The radiation adaptive response
“…a conditioning radiation dose lowers the
biological effect of a subsequent (usually higher)
radiation exposure.” BEIR VII (2006).
• (in vitro) i.e. cell death, DNA repair, mutation
induction, chromosomal aberrations.
• (in vivo) i.e. immune function, survival, cancer
latency and frequency.
Low dose radiation increases latency of
radiation-induced lymphoma in mice
R.E.J. MITCHEL, J.S. JACKSON, D.P. MORRISON and S.M. CARLISLE “Low doses of radiation increase the latency of spontaneous lymphomas
and spinal osteosarcomas in cancer-prone, radiation-sensitive Trp53 heterozygous mice” Radiation Research. 159 320 (2003).
• Dose, dose-rate,
and timing of
• Most common cancer in Australian men (>29% of all
• High incidence in Western countries versus Asian
• Dietary and environmental factors.
• Familial, early onset, prostate cancer is infrequent (<10%
• Age is most significant predictor of prostate cancer.
Australian Institute of Health and Welfare:
The TRAMP mouse
• Transgenic Adenocarcinoma of the Mouse Prostate.
• 100% of mice will get prostate cancer.
• Disease progression is reproducible.
• Model mirrors disease in humans.
PIN (prostatic intraepithelial neoplasia)well moderately poorly differentiated
• TRAMP tumours transiently regress following androgen
withdrawal, but recur as androgen-independent prostate
cancer (as observed in man).
Determine high dose inducing and
promoting potential; in this model.
Traditional experimental approach.
Test low dose radiation tumour
Investigate phenomenon in
conjunction with standard therapy.
• Prostate/GUT weight and volume.
• Time to palpable tumour.
• Histopathological grade.
• Cell proliferation.
• Programmed cell death (apoptosis).
• DNA damage and repair.
Light microscopy of whole mouse
Figure: Mean proliferation frequency (±SE) in prostate
lobes of 50 mGy and sham treated TRAMP mice, 3 days
following treatment. n=10/group
Proliferation pilot study on archival TRAMP prostate tissue
•TRAMP mice treated with 50 mGy
or sham and tissues taken 3 days
• Proliferation rates are lobe specific.
• Micro-dissection of prostate is vital.
• Significant effect observed in
ventral prostate lobes.
- repeat experiment with micro-dissection
and increased animal numbers required.
• Pilot study determined how many
cells/images are required for
– optimised image analysis method.
High dose experiment
(and other tissues)
Mice 6 weeks old
(carcinogenic process beginning)
2 Gy or Sham
Little is known regarding:
• radiation-induced prostate cancer
• radiation sensitivity of the TRAMP mouse
Figure: Prostate weight as a per cent of body weight in sham- and 2 Gy-irradiated
TRAMP mice. P=0.05 Independent Samples T-test. n=10-11/group
Prostate weight increase following 2 Gy whole
body irradiation of TRAMP mice
Dorso-lateral prostate proliferation six weeks
following 2 Gy irradiation
• Still to analyse other lobes and histopathology.
• Further high dose experiments with >6 weeks between
irradiation and tissue collection.
• Radiation adaptive response.
– Can modulate a range of biological processes (including cancer)
• Expand investigation of adaptive response to an epithelial
– Prostate cancer
• Explore a range of dose and timing parameters.
• Through investigation of radiation adaptive response:
– Increased knowledge of fundamental processes in prostate cancer.
– New treatment strategies.
A/Prof Pamela Sykes
Dr Rebecca Ormsby
Dr Benjamin Blyth
Low Dose Radiation Research Program, Biological and
Environmental Research, US Department of Energy
Grant DE-FG02-05ER64104 and The Cancer Council of South Australia.
Royal Adelaide Hospital
A/Prof Eva Bezak
Dame Roma Mitchell Cancer
Prof. Wayne Tilley
Dr Lisa Butler