Yuzo Furuya

Implications of insulin‐like growth factor‐I for prostate cancer therapies

In the last decade, abundant evidence has suggested that the insulin‐like growth factor (IGF) family comprises a multi‐component network of molecules involved in the regulation of both physiological and pathological growth processes in the prostate. The IGF axis plays an important role in the tumorigenesis and neoplastic growth of prostate cancer. Epidemiological observations indicate that circulating IGF‐I levels are positively associated with increased risk of prostate cancer. Activation of IGF‐I receptor (IGF‐IR) by IGF‐I has mitogenic and anti‐apoptotic effects on normal and malignant prostate cells. Therapeutic alternatives in men with progressive prostate cancer after androgen ablation are very limited and more effective therapies are needed for such patients. Inactivation of the IGF‐I axis represents a potential target to treat androgen‐independent prostate cancer. This review addresses epidemiological studies of IGF‐I and therapeutic strategies including reduction of IGF‐I levels, inhibition of IGF‐IR and the signaling mechanisms involved.

Tissue factor expression and prognosis in patients with metastatic prostate cancer

OBJECTIVES To assess immunohistochemically the pattern of tissue factor (TF) expression in patients with metastatic prostate cancer, because TF is aberrantly expressed in human cancer. TF is the primary initiator of the coagulation cascade. METHODS Seventy-three patients with untreated metastatic prostate cancer who received hormonal therapy were included in the present study. Biopsy specimens were stained with anti-human TF antibody. We evaluated the histologic grade, extent of bony metastasis, clinical response to hormonal therapy, and patient prognosis. RESULTS TF was detected in 75.3% of the tumors of the patients with metastatic prostate cancer. TF expression showed no association with histologic grade, extent of bony metastasis, or clinical response to hormonal therapy. Patients with TF-positive tumors had a poorer cause-specific survival than those with TF-negative tumors. Multivariate analysis showed that TF expression, clinical response to hormonal therapy, and extent of bony metastasis were significant prognostic factors. CONCLUSIONS The TF content measured using immunohistochemical staining was a useful prognostic factor for patients with metastatic prostate cancer treated with androgen withdrawal therapy.

Smoking and Obesity in Relation to the Etiology and Disease Progression of Prostate Cancer in Japan

Background:

Pattern of progression and survival in hormonally treated metastatic prostate cancer

Background: Patients with prostate cancer generally respond to androgen ablation therapy, but progression to androgen‐independence is frequently observed. To further evaluate disease progression, the pattern of progression and survival in hormonally treated metastatic prostate cancer was examined.

Clinical impact of tamsulosin on generic and symptom‐specific quality of life for benign prostatic hyperplasia patients: Using international prostate symptom score and Rand Medical Outcomes Study 36‐item Health Survey

Aim: To examine the efficiency of α1‐blocker treatment on disease‐specific and generic quality of life (QOL) in men with clinically diagnosed benign prostatic hyperplasia (BPH), the improvement of QOL scores with International prostate symptom score (I‐PSS) and Rand Medical Outcomes Study 36‐item Health Survey (SF‐36) was prospectively analyzed.

Metastatic prostate cancer with normal level of serum prostate-specific antigen

The clinical and pathologicalfeatures of metastatic prostate cancer withnormal level of serum prostate-specific antigen(PSA) were investigated. Four patients withmetastatic prostate cancer had serum PSA withinthe normal range at the diagnosis. All tumorswere poorly-differentiated adenocarcinoma. Endocrine therapy was performed as the initialtherapy in all patients. Despite subsequentlytreatment, all cases died of prostate cancer at2, 8, 9 and 38 months. During diseaseprogression, 3 of 4 patients had elevated serummarkers such as carcinoembryonic antigen (CEA),CA19-9, CA15-3, CA125, neuron-specific enolaseand pro-gastrin releasing peptide. Immunohistochemical examination of the initialbiopsy specimens revealed that 4 and 3 caseswere positive for CEA and chromogranin A,respectively. In advanced prostatecancer patients with low PSA level, thosemarkers may aid in the follow up of disease.

Incidence and Characteristics of Antiandrogen Withdrawal Syndrome in Prostate Cancer after Treatment with Chlormadinone Acetate

Objectives: In patients with progressive prostate cancer who have been treated with surgical or medical castration plus an antiandrogen, antiandrogen withdrawal can result in a significant decline in serum prostate-specific antigen (PSA). Although the incidence of antiandrogen withdrawal syndrome after combination treatment with the nonsteroidal antiandrogen flutamide has been thoroughly documented, the phenomenon clearly occurs in many other combination therapies and is presently being widely investigated. This paper would like to contribute to this effort by describing the endocrine withdrawal phenomenon in patients treated with combinations of castration plus chlormadinone acetate, ethynylestradiol or estramustine phosphate. Materials and Methods: Clinical records of 68 prostate cancer patients who had been treated with surgical castration plus the administration of chlormadinone acetate, ethynylestradiol or estramustine phosphate, and who had shown clinical progression associated with a steady increase in serum PSA, were investigated. Forty-one cases were evaluable for changes in PSA after discontinuation of the hormonal agents. Results: Of 28 patients who had been treated with chlormadinone acetate, 12 (42.9%) revealed 50% or more decline in PSA level following withdrawal of the agent. Among these, 5 cases (17.9%) showed subjective and/or objective improvements. There was no significant difference in histological grade of the tumor at diagnosis, mode of progression, time interval from the start of endocrine therapy to discontinuation of the hormonal agents, or PSA levels at withdrawal of the agents between patients who did develop antiandrogen withdrawal syndrome and those who did not. Conclusion: When a steady increase in serum PSA is noted in a prostate cancer patient who has been treated with castration plus a steroidal antiandrogen, discontinuation of the antiandrogen may benefit the patient.

Identification of Histone H2A.X as a Growth Factor Secreted by an Androgen-independent Subline of Mouse Mammary Carcinoma Cells

Shionogi carcinoma 115 (SC 115) cells and Chiba subline 2 (CS 2) cells are clones of an androgen-responsive mouse tumor cell line and its autonomous subline, respectively. We have shown previously that CS 2 cells produce a heparin-binding growth factor that stimulates the growth of SC 115 cells as well as the growth of themselves. In this study, a growth factor was purified from serum-free conditioned media of CS 2 cells cultured without testosterone. A heparin-binding fraction showed growth- promoting activity on SC 115 cells and BALB/3T3 cells. The amino acid sequence analysis revealed that the components were identical to histones H2A.1 and H2A.X. Since histone H2A purified from bovine thymus had almost no growth-promoting activity on SC115 cells, histone H2A.X was assumed to be a growth factor. cDNA of histone H2A.X was cloned from a library of CS 2 cells, and its sequence was confirmed. The expressed product of histone H2A.X cDNA in Escherichia coli showed remarkable stimulatory effects on growth of SC 115 cells cultured in the absence of testosterone. These results indicate that histone H2A.X is secreted from CS 2 cells cultured without testosterone and plays a role as a growth factor.

Radiotherapy for local progression in patients with hormone‐refractory prostate cancer

Purpose: The aim of the present study was to investigate the effect of radiotherapy on the local progression of hormone‐refractory prostate cancer.

Prognosis of Patients with Prostate Carcinoma Presenting as Nonregional Lymph Node Metastases

Objective: The mode of progression in patients with prostate cancer with metastasis to nonregional lymph nodes was examined in order to know whether the site of metastasis effects the prognosis of prostate cancer. Methods: From 1986 to 1995 at the Chiba University Hospital, 205 cases of prostatic cancer with distant metastases were experienced. In 17 of them, nonregional lymph node metastases were observed at the diagnosis, of whom 10 also had bone metastases. Results: There was no statistical difference in prognosis between 17 patients with nonregional lymph node metastases and remaining 188 patients with metastatic prostate cancer. In all patients metastasized to nonregional lymph nodes, serum prostate-specific antigen and/or prostatic acid phosphatase levels were elevated. Anti-androgen therapy was effective in 15 cases and 5-year survival rate was 45.8%. Patients without bone metastases at the initial diagnosis could survive longer than those with metastases to bone (p < 0.05). Conclusions: From these observations, endocrine therapy was effective even in patients with distant lymph node metastases.