Mapping of metastasis suppressor genes for prostate cancer by microcell-mediated chromosome transfer

Aim: To identify the metastasis suppressor genes for prostate cancer. Methods: A copy of human chromosomeswas introduced into the highly metastatic Dunning R-3327 rat prostate cancer cells by the use of microcell-mediatedchromosome transfer. Relationships between the size of human chromosomes introduced into microcell hybrid clonesand the number of lung metastases produced by the clones were analyzed to determine which part of human chromo-somes contained the metastasis suppressor gene (s) for prostate cancer. To determine portions of human chromosomesintroduced, G-banding chromosomal analysis, fluorescence in sim hybridization analysis, and polymerase chain reac-tion analysis were performed. Results: Each of microcell hybrid clones containing human chromosomes 7, 8, 10,11, 12, or 17 showed decreased ability to metastasize to the lung without any loss of tumorigenicity. This demonstratesthat these human chromosomes contain metastasis suppressor genes for prostate cancer. Spontaneous deletion of portionsof human chromosomes was observed in the human chromosome 7, 10, 11, 12, and 17 studies. In the human chromo-some 8 study, irradiated microcell-mediated chromosome transfer was performed to enrich chromosomal arm deletionsof human chromosome 8. Molecular and cytogenetic analyses of microcell hybrid clones demonstrated that metastasissuppressor genes on human chromosomes were located on 7q21-22, 7q31.2-32, 8p21-12, 10q11-22, 11p13-11.2,12p11-q13, 12q24-ter, and 17pter-q23. KAII and MKK4/SEKI were identified as metastasis suppressor genes from11p11. 2 and 17p12, respectively. Conclusion: This assay system is useful to identify metastasis suppressor gene(s) for prostate cancer.

Treatment strategy for metastatic prostate cancer with extremely high PSA level： reconsidering the value of vintage therapy

The prognostic significance of initial prostate-specific antigen （PSA） level for metastatic prostate cancer remains uncertain. We investigated the differences in prognosis and response to hormonal therapies of metastatic prostate cancer patients according to initial PSA levels. We analyzed 184 patients diagnosed with metastatic prostate cancer and divided them into three PSA level groups as follows： low （〈100 ng ml-1）, intermediate （100–999 ng ml-1）, and high （≥1000 ng ml-1）. All patients received androgen deprivation therapy （ADT） immediately. We investigated PSA progression-free survival （PFS） for first-line ADT and overall survival （OS） within each of the three groups. Furthermore, we analyzed response to antiandrogen withdrawal （AW） and alternative antiandrogen （AA） therapies after development of castration-resistant prostate cancer （CRPC）. No significant differences in OS were observed among the three groups （P = 0.654）. Patients with high PSA levels had significantly short PFS for first-line ADT （P = 0.037）. Conversely, patients in the high PSA level group had significantly longer PFS when treated with AW than those in the low PSA level group （P = 0.047）. Furthermore, patients with high PSA levels had significantly longer PFS when provided with AA therapy （P = 0.049）. PSA responders to AW and AA therapies had significantly longer survival after CRPC development than nonresponders （P = 0.011 and P 〈 0.001, respectively）. Thus, extremely high PSA level predicted favorable response to vintage sequential ADT and AW. The current data suggest a novel aspect of extremely high PSA value as a favorable prognostic marker after development of CRPC.