Loading…

Flash Player 9 (or above) is needed to view presentations.
We have detected that you do not have it on your computer. To install it, go here.

Like this presentation? Why not share!

The use of whole body irradiation to reduce tumour development in a mouse model of prostate cancer lawrence

on

  • 597 views

 

Statistics

Views

Total Views
597
Views on SlideShare
597
Embed Views
0

Actions

Likes
0
Downloads
5
Comments
0

0 Embeds 0

No embeds

Accessibility

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

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 lawrence Presentation Transcript

  • The use of whole body irradiation to reduce tumour development in a mouse model of prostate cancer Mark Lawrence 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 • Dose, dose-rate, and timing of irradiation. • Haematological cancer studied, almost exclusively. 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).
  • Prostate cancer • Most common cancer in Australian men (>29% of all diagnoses). • High incidence in Western countries versus Asian countries. • Dietary and environmental factors. • Familial, early onset, prostate cancer is infrequent (<10% cases). • Age is most significant predictor of prostate cancer. Australian Institute of Health and Welfare: http://www.aihw.gov.au/cancer
  • 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 adenocarcinomas. • TRAMP tumours transiently regress following androgen withdrawal, but recur as androgen-independent prostate cancer (as observed in man).
  • Experiments Determine high dose inducing and promoting potential; in this model. High dose Traditional experimental approach. Adaptive response Test low dose radiation tumour Low dose suppressing effect. Investigate phenomenon in Castration conjunction with standard therapy.
  • Endpoints • Prostate/GUT weight and volume. • Time to palpable tumour. • Histopathological grade. • Cell proliferation. • Programmed cell death (apoptosis). • DNA damage and repair.
  • Immunofluorescence for Ki-67
  • Automated Image Analysis
  • Immunofluorescence γH2AX Large T-antigen
  • The mouse genitourinary tract
  • Light microscopy of whole mouse prostate sections
  • Proliferation pilot study on archival TRAMP prostate tissue •TRAMP mice treated with 50 mGy or sham and tissues taken 3 days following irradiation. • 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 Figure: Mean proliferation frequency (±SE) in prostate analysis. lobes of 50 mGy and sham treated TRAMP mice, 3 days following treatment. n=10/group – optimised image analysis method.
  • High dose experiment 2 Gy or Sham irradiated Remove prostate (and other tissues) 6 weeks Mice 6 weeks old (carcinogenic process beginning) Little is known regarding: • radiation-induced prostate cancer • radiation sensitivity of the TRAMP mouse
  • Prostate weight increase following 2 Gy whole body irradiation of TRAMP mice 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
  • Dorso-lateral prostate proliferation six weeks following 2 Gy irradiation Proliferation index (+/- SE) N=10-11/treatment group • Still to analyse other lobes and histopathology. • Further high dose experiments with >6 weeks between irradiation and tissue collection.
  • Summary • Radiation adaptive response. – Can modulate a range of biological processes (including cancer) • Expand investigation of adaptive response to an epithelial cancer. – 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.
  • Acknowledgments Supervisors Royal Adelaide Hospital A/Prof Pamela Sykes A/Prof Eva Bezak Dr Rebecca Ormsby DOE lab Dr Benjamin Blyth Dame Roma Mitchell Cancer Alex Staudacher Research Laboratories Michelle Newman Ami-Louise Cochrane Prof. Wayne Tilley Monica Dreimanis Dr Lisa Butler Katrina Bexis Low Dose Radiation Research Program, Biological and Environmental Research, US Department of Energy Grant DE-FG02-05ER64104 and The Cancer Council of South Australia.