Naohide Sato

Androgen receptor gene mutations in human prostate cancer

To investigate the structural abnormality of the androgen receptor (AR) in human prostate cancers, exons B-H encoding DNA- and hormone-binding domains were examined by single-strand conformation polymorphism analysis of polymerase chain reaction products using originally designed oligoprimers. Tissues from 7 cases of untreated stage B prostate cancer surgically removed and from 8 cases of endocrine therapy-resistant cancers obtained at autopsy were used in the study. Two different mutations were identified in exons D and H in the different cancer foci of the same cancer death patient. One mutation in exon D (at codon 701, Leu to His) was detected in the prostate, and the other in exon H (at codon 877, Thr to Ala) was found in metastatic tissues. In untreated cancer tissues and the other autopsy samples, no mutations were detected. The mutation in exon H was identical to that reported in LNCaP cells. These results indicate that AR gene mutations occur in relation to endocrine therapy-resistance, although the mutation was found in 1 out of 8 resistant cases (12.5%) at autopsy.

Differential transactivation by the androgen receptor in prostate cancer cells

The purpose of this study was to determine the contribution of different transactivating regions of the androgen receptor (AR) to the induction of androgen‐regulated promoters in poorly (PC3 cells) and well‐differentiated (LNCaP cells) prostate cancer cell lines.

Progression of Androgen-sensitive Mouse Tumor (Shionogi Carcinoma 115) to Androgen-insensitive Tumor after Long-term Removal of Testosterone

Shionogi Carcinoma 115 (SC115) is an androgen‐sensitive transplantable mouse tumor. To study the mode of progression from androgen‐sensitive to ‐insensitive tumor, cloned SC115 cells were serially cultured without androgen. Shortly after withdrawal of androgen, SC115 cells showed markedly decreased growth, but growth resumed gradually with loss of response to androgen and the cells 60 weeks after androgen removal [A(—)60 cells] grew faster than SC115 cells cultured in the presence of androgen. A(—)60 cells showed malignant phenotype with morphological changes and tumorigenicity in male and female mice. Although mRNA and binding capacity of androgen receptor were maintained, the cells after removal of androgen rapidly lost expression of mouse mammary tumor virus‐related gene and the loss was irreversible in A(—)60 cells. The stimulating effect of basic flbroblast growth factor (bFGF) temporarily decreased, then recovered to the initial level after long‐term androgen removal. This fluctuation of response to bFGF was accompanied with changes in the number of bFGF receptors and amount of bFGF‐like substance(s) secreted. The substance(s) seemed to be an FGF‐like growth factor different from known factors. It was concluded that progression of SC115 cells to androgen‐insensitive ones under an androgen‐deprived condition proceeded with adaptation by means of increases in production of an FGF‐like growth factor and in binding capacity to this factor.

Loss of androgen dependency with preservation of functional androgen receptors in androgen-dependent mouse tumor (Shionogi carcinoma 115)

Shionogi Carcinoma 115 (SC 115) is an androgen-dependent mouse tumor. Chiba Subline 2 (CS 2) is an androgen-independent subline derived from SC 115. CS 2 contains androgen receptors (AR), but is refractory to androgen and does not exhibit androgen-related responses which are observed in SC 115. In the present study the structure and function of AR in SC 115 and CS 2 are examined using cloned cells. There were no gross rearrangements or deletions in the AR genes of these cell lines when compared by Southern blot analysis with the AR gene in the mouse seminal vesicle. SC 115 and CS 2 expressed AR mRNA of normal size. When the cDNA containing DNA- and androgen-binding domains of the AR genes of both cell lines were amplified by polymerase chain reaction, no mutations were found in these regions. SC 115 and CS 2 were transfected with a plasmid containing a long terminal repeat of mouse mammary tumor virus linked to the chloramphenicol acetyltransferase (CAT) gene. Androgen stimulation of these transfectants resulted in equal elevation of CAT activity. These results indicated that the androgen-independent CS 2 contained functionally normal AR which were identical to those in the androgen-dependent parent tumor.

Clinical effect of naftopidil on the quality of life of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A prospective study

Objectives:  To investigate the benefit of α1‐adrenoceptor antagonist naftopidil on the quality of life (QOL) of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH/LUTS).

Appearance of Malignant Phenotype with Partial Loss of Hormone Dependency in Androgen‐dependent Shionogi Carcinoma 115 Transfected with hst‐1 Gene

Shionogi Carcinoma 115 (SC 115) and Chiba Subline 2 (CS 2) are an androgen‐dependent mouse tumor and an androgen‐independent subline derived from SC 115, respectively. Since new expression of the transforming oncogene hst‐1 might be related with autonomous progression in CS 2, the present study was designed to examine the influence of expression of hst‐1 gene on SC 115. The transfectants of SC 115 with hst‐1 still retained androgen sensitivity of growth, although the cells could grow without androgen. The transfectants, however, developed fibroblast‐like appearance in the absence of androgen, in contrast to SC 115, which showed epithelial‐like appearance after deprivation of androgen. The transfectants acquired an ability to form colonies in soft agar in the absence of androgen. SC 115 could not form tumors in intact mice, but the transfectants formed tumors at a high rate in male mice but not in female ones. From these results, it was concluded that expression of hst‐1 was able to alter the phenotype of the androgen‐dependent tumor with partial loss of androgen‐dependency, and these changes might be advantageous for malignant progression.

Detection of prostate cancer using prostate-specific antigen adjusted for the transition zone volume in patients with intermediate serum prostate-specific antigen levels

AbstractBackground. The prostate-specific antigen (PSA) density of the transition zone (PSATZ) in patients with PSA values of 4.1–10 ng/ml was determined to find whether PSATZ is useful in the detection of prostate cancer. Methods. The PSA, PSA density (PSAD), and PSATZ were determined in 101 patients with intermediate levels of serum PSA. The relationship of these parameters to prostate cancer detection was examined. Results. Patients with prostate cancer had significantly higher PSAD and PSATZ values than those without prostate cancer. In patients with a PSA value of 4.1–10 ng/ml, especially in those without abnormal digital rectal examination findings, PSATZ was superior to PSA as an indicator for positive biopsy when analyzed by receiver operating characteristics curves. In those patients with a cutoff value of 0.3 ng/ml per ml of transition zone volume, PSATZ had a sensitivity of 79% and a specificity of 51%. A cutoff value of 0.3 for PSATZ provided a sensitivity of 88% and a specificity of 51% in patients without abnormal digital rectal examination findings. Conclusion. The present study demonstrated that PSATZ was superior to PSA as an indicator for positive biopsy, especially in patients with normal digital rectal examination findings. PSATZ was not superior to PSAD in the detection of prostate cancer.