The mechanism of inhibition of eukaryotic by itself has no effect on the binding of various forms of DNA to yeast DNA topoisomerase II. When both and ATP are present, however, the enzyme is converted to the closed form, as evidenced by the SV8 endoproteinase cleavage pattern as well as the characteristics of the DNAenzyme complexes. These results suggest that bis(2,6-dioxopiperazines) act by stabilizing eukaryotic DNA topoisomerase II in the closed-clamp form and preventing it from opening again. MATERIALS AND METHODS 1781The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

No abstract

IDC-P in RP specimens was an independent risk factor for PFS and CSS and could predict clinical outcomes.

Abstract. , a novel noncleavable, complexstabilizing type topoisomerase (topo) II inhibitor, has been shown to target topo II in mammalian cells (Ishida, R., T. Miki, T. Narita, R. Yui, S. Sato, K. R. Utsumi, K. Tanabe, and T. Andoh. 1991. Cancer Res. 51:4909--4916). With the aim of elucidating the roles of topo II in mammalian cells, we examined the effects of ICRF-193 on the transition through the S phase, when the genome is replicated, and through the M phase, when the replicated genome is condensed and segregated. Replication of the genome did not appear to be affected by the drug because the scheduled synthesis of DNA and activation of cdc2 kinase followed by increase in mitotic index occurred normally, while VP-16, a cleavable, complex-stabilizing type topo II inhibitor, inhibited all these processes. In the M phase, however, late stages of chromosome condensation and segregation were clearly blocked by . Inhibition at the stage of compaction of 300-nm diameter chromatin fibers to 600-nm diameter chromatids was demonstrated using the drug during premature chromosome condensation (PCC) induced in tsBN2 baby hamster kidney cells in early S and G2 phases. In spite of interference with M phase chromosome dynamics, other mitotic events such as activation of ode2 kinase, spindle apparatus reorganization and disassembly and re, assembly of nuclear envelopes occurred, and the cells traversed an unusual M phase termed "absence of chromosome segregation" (ACS)-M phase. Cells then continued through further cell cycle rounds, becoming polyploid and losing viability. This effect of ICRF-193 on the cell cycle was shown to parallel that of inactivation of topo II on the cell cycle of the ts top2 mutant yeast. The results strongly suggest that the essential roles of topo II are confined to the M phase, when the enzyme decatenates intertwined replicated chromosomes. In other phases of the cycle, including the S phase, topo II may thus play a complementary role with topo I in controlling the torsional strain accumulated in various genetic processes. topoisomerases (topo) t have been implicated in e maintenance of genetic processes such as repliation, transcription, and recombination by controlling the higher order chromosomal structure through the cell cycle (for review, see Wang, , 1987Cozzarelli and Address all correspondence to Ryoji Ishida,

Intraductal carcinoma of the prostate is an adverse prognostic factor in localized prostate cancer patients. However, whether it influences outcome of those patients with distant metastases discovered at initial diagnosis is unclear. Here, we evaluated whether the presence of intraductal carcinoma of the prostate in prostate needle biopsies is an adverse prognostic factor for cancer-specific survival and overall survival in such prostate cancer patients. We retrospectively enrolled 150 eligible patients. All patients received androgen-deprivation therapy and/or chemotherapy. Their age, performance status, pain, metastatic sites, clinical T stage, serum prostatespecific antigen, alkaline phosphatase, hemoglobin, Gleason score, and the presence of Gleason pattern 5 were analyzed. Primary end point was cancer-specific survival; secondary end points included prostate-specific antigen progression-free survival and overall survival. Fine and Gray's model and the Cox proportional hazards model were used as statistical tests. Intraductal carcinoma of the prostate was detected in 100 (67%) patients. At a median follow-up of 38 months, 79 patients (53%) had died of the disease and nine (6%) had died of other causes. The average time interval to cancer-related death was 28 months. On multivariate analysis, only intraductal carcinoma of the prostate was significantly associated with cancer-specific survival (P = 0.018) and overall survival (P = 0.001), and only the presence of Gleason pattern 5 was significantly associated with prostate-specific antigen progression-free survival (P = 0.026). The presence of intraductal carcinoma of the prostate was the only significant prognostic parameter for cancer-specific survival and overall survival in prostate cancer patients with distant metastasis at presentation. These results may prove useful in planning future treatments.