Fractionated radiation therapy can induce a molecular profile for therapeutic targeting.
To examine the possibility of using fractionated radiation in a unique way with molecular targeted therapy, gene expression profiles of prostate carcinoma cells treated with 10 Gy radiation administered either as a single dose or as fractions of 2 Gy × 5 and 1 Gy × 10 were examined by microarray analysis. Compared to the single dose, the fractionated irradiation resulted in significant increases in differentially expressed genes in both cell lines, with more robust changes in PC3 cells than in DU145 cells. The differentially expressed genes (>twofold change; P < 0.05) were clustered and their ontological annotations evaluated. In PC3 cells genes regulating immune and stress response, cell cycle and apoptosis were significantly up-regulated by multifractionated radiation compared to single-dose radiation. Ingenuity Pathway Analysis (IPA) of the differentially expressed genes revealed that immune response and cardiovascular genes were in the top functional category in PC3 cells and cell-to-cell signaling in DU145 cells. RT-PCR analysis showed that a flexure point for gene expression occurred at the 6th-8th fraction and AKT inhibitor perifosine produced enhanced cell killing after 1 Gy × 8 fractionated radiation in PC3 and DU145 cells compared to single dose. This study suggests that fractionated radiation may be a uniquely exploitable, non-oncogene-addiction stress pathway for molecular therapeutic targeting.
John-Aryankalayil
Molykutty
M
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. Aryankalayilm@mail.nih.gov
Palayoor
Sanjeewani T
ST
Cerna
David
D
Simone
Charles B
CB
Falduto
Michael T
MT
Magnuson
Scott R
SR
Coleman
C Norman
CN
D017209:Apoptosis / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D019583:Dose Fractionation, Radiation; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010766:Phosphorylation / Q000528:radiation effects; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy*; D011879:Radiotherapy Dosage; D015203:Reproducibility of Results; D013997:Time Factors
C468783:H2AX protein, human; D006657:Histones; D010767:Phosphorylcholine; C105905:perifosine