Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer.
BACKGROUND
Secondary analyses of two randomized, controlled phase III trials demonstrated that selenium and vitamin E could reduce prostate cancer incidence. To characterize pharmacodynamic and gene expression effects associated with use of selenium and vitamin E, we undertook a randomized, placebo-controlled phase IIA study of prostate cancer patients before prostatectomy and created a preoperative model for prostatectomy tissue interrogation.


METHODS
Thirty-nine men with prostate cancer were randomly assigned to treatment with 200 microg of selenium, 400 IU of vitamin E, both, or placebo. Laser capture microdissection of prostatectomy biopsy specimens was used to isolate normal, stromal, and tumor cells. Gene expression in each cell type was studied with microarray analysis and validated with a real-time polymerase chain reaction (PCR) and immunohistochemistry. An analysis of variance model was fit to identify genes differentially expressed between treatments and cell types. A beta-uniform mixture model was used to analyze differential expression of genes and to assess the false discovery rate. All statistical tests were two-sided.


RESULTS
The highest numbers of differentially expressed genes by treatment were 1329 (63%) of 2109 genes in normal epithelial cells after selenium treatment, 1354 (66%) of 2051 genes in stromal cells after vitamin E treatment, and 329 (56%) of 587 genes in tumor cells after combination treatment (false discovery rate = 2%). Validation of 21 representative genes across all treatments and all cell types yielded Spearman correlation coefficients between the microarray analysis and the PCR validation ranging from 0.64 (95% confidence interval [CI] = 0.31 to 0.79) for the vitamin E group to 0.87 (95% CI = 0.53 to 0.99) for the selenium group. The increase in the mean percentage of p53-positive tumor cells in the selenium-treated group (26.3%), compared with that in the placebo-treated group (5%), showed borderline statistical significance (difference = 21.3%; 95% CI = 0.7 to 41.8; P = .051).


CONCLUSIONS
We have demonstrated the feasibility and efficiency of the preoperative model and its power as a hypothesis-generating engine. We have also identified cell type- and zone-specific tissue effects of interventions with selenium and vitamin E that may have clinical implications.
Tsavachidou
Dimitra
D
Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
McDonnell
Timothy J
TJ
Wen
Sijin
S
Wang
Xuemei
X
Vakar-Lopez
Funda
F
Pisters
Louis L
LL
Pettaway
Curtis A
CA
Wood
Christopher G
CG
Do
Kim-Anh
KA
Thall
Peter F
PF
Stephens
Clifton
C
Efstathiou
Eleni
E
Taylor
Robert
R
Menter
David G
DG
Troncoso
Patricia
P
Lippman
Scott M
SM
Logothetis
Christopher J
CJ
Kim
Jeri
J
D000368:Aged; D000704:Analysis of Variance; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000097:blood; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis*; D049109:Cell Proliferation; D015986:Confounding Factors, Epidemiologic; D004359:Drug Therapy, Combination; D005240:Feasibility Studies; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D016014:Linear Models; D008297:Male; D042282:Microdissection / Q000379:methods; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011467:Prostate / Q000187:drug effects / Q000473:pathology*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000208:ethnology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D015203:Reproducibility of Results; D012107:Research Design; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012645:Selenomethionine / Q000008:administration & dosage* / Q000097:blood; D017211:Treatment Failure; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D024502:alpha-Tocopherol / Q000008:administration & dosage* / Q000097:blood
D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D005819:Genetic Markers; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; D012645:Selenomethionine; D024502:alpha-Tocopherol