Normal tissue response to low doses of radiotherapy assessed by molecular markers--a study of skin in patients treated for prostate cancer.
The aim of this study was to evaluate normal tissue response by molecular markers to multifraction low doses of ionizing radiation, with the focus on changes in repopulation, estimated using Ki-67 as the proliferation marker, and on expressions of the p53 and p21 proteins, identified as key proteins in the DNA damage checkpoint. Repeated skin biopsies were taken from patients treated for prostate cancer with radiotherapy. The expressions of Ki-67, p53 and p21 of the keratinocytes in the basal cell layer of the epidermis were quantified immunohistochemically. The dose to the basal layer was 1.1 Gy per fraction, given five times per week for seven weeks. The indices of the three markers were determined over the whole period. A significant suppression of the Ki-67 index was observed during the first weeks, followed by a significant gradual increase in the Ki-67 index over the last weeks. The p53 and p21 protein levels were almost zero in the unirradiated skin. Upon irradiation, both the p53 and p21 index increased in a pattern very congruent to the Ki-67 index. In conclusion, daily fractions of about 1 Gy to the skin resulted in, for the keratinocytes in the basal layer, a cell growth arrest for a couple of weeks and a subsequent acceleration in repopulation during the following weeks of irradiation. The present findings also provided novel insights into the role of the p53/p21 pathway in the response of a normal epithelium to ionizing radiation as it is applied in radiotherapy.
Turesson
I
I
Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, Sweden.
Bernefors
R
R
Book
M
M
Flogegård
M
M
Hermansson
I
I
Johansson
K A
KA
Lindh
A
A
Sigurdardottir
S
S
Thunberg
U
U
Nyman
J
J
D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D004249:DNA Damage; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis / Q000096:biosynthesis*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis / Q000096:biosynthesis*; D011832:Radiation Injuries / Q000175:diagnosis* / Q000503:physiopathology*; D012867:Skin / Q000473:pathology / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis*
D015415:Biomarkers; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)