| Following
accidental exposure of humans to irradiation, the dose to different parts
of the body is often highly heterogeneous, and regions of the skin may
receive substantially greater doses than other parts of the body. The
goal of this project is to develop biological approaches that can be used
to assess dose to the skin with a particular emphasis on DNA damage in
cells of the dermis and epidermis. |
|
|
| |
Specific
Aims 1 and 2 have been proceeding in parallel as defined in the original
application. We anticipate that these experiments will continue over the
next year of the studies and that at the end of this series of experiments
we will have defined a dose response relationship for low LET irradiation
of skin using both the MN and RIF assays. We expect to have a clear understanding
of the effects of age and gender on this dose response relationship and
to know the likely error associated with estimating skin dose from a single
punch biopsy. These assays would then be potentially suitable to act as
techniques that could be applied at early or late times, as the need arises,
to assess skin dose in individuals suspected of having received significant
doses to skin. As these assays are refined they will also become suitable
to examine the ability of mitigating agents developed both in this program
(Specific Aim 4 of this proposal) and in other centers, which are part
of the CMCR network, to protect specifically against skin (genotoxic)
injury. We have initiated a preliminary study in this area using EUK-189
as a trial for these future studies. Although not part of the current
proposed work, it is potentially possible that these assays could be further
developed as early markers of the probability of developing skin cancers
following radiation exposures. |
|
|
| |
Project
5 is developing assays to characterize epithelial genotoxicity. To this
end, Project 5 has developed the appropriate techniques to accomplish
their Year 2 goal of establishing dose response relationships for micronucleus
formation. These data will complement the physical dosimetry developed
in Project 3, and will allow for comparison of radiation-related genotoxicity
in epithelial vs. hematopoietic tissues. We believe that the genotoxicity
data will also prove useful in the evaluation of the efficacy of the agents
being proposed in Project 1. Work extending from preliminary data on micronucleus
(MN) formation in skin at various times up to 9 months after irradiation
has been completed. These data show that there appears to be a linear
relationship between the number of micronuclei per 1000 binucleate cells
(MN/1000BN) up to doses of approximately 10 Gy and analyzed at time points
between 1 day and 2 months post-radiation. This bodes well for this measurement
as a biodosimeter in any region of the body. Also, following a dose of
10 Gy, the level of MN/1000BN remains constant until approximately 2 months
after irradiation, thus allowing for this assay to be applied at late
times after exposure if necessary. These studies are now being extended
to humans undergoing pre-operative irradiation, using biopsies of irradiated
normal skin incidentally removed at the time of tumor resection. Results
consistent with the pre-clinical studies have already been measured. |
|
|
Project
5 : Communications & Publications
•
Richard P Hill. P. Kaspler, A.M. Griffin, B. O’Sullivan, C. Catton,
H. Alasti, A Abbas, M Heydarian, P. Ferguson, J.S. Wunder and R. S. Bell.
Studies of the in vivo radiosensitivity of human skin fibroblasts. Conditionally
accepted. Radiotherapy and Oncology 2007.
• Robert G Bristow, Hilmi Ozcelik, Farid Jalali, Norman Chan, and
Danny Vesprini. Homologous Recombination and Prostate Cancer: Prostate
Cancer as a Model for Novel DNA Repair Targets and Therapies. In Press,
Radiotherapy and Oncology, 2007.
• Norman Chan, Michael Milosevic, Robert Bristow. Hypoxia, DNA Repair
and Prostate Cancer: New targets and New Strategies. In Press, Future
Oncology, 2007. |
|
