pyrimidinones and Urinary-Bladder-Neoplasms

AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (Cmax) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609).. AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if ≤ 2 of the first 20 evaluable patients achieved an objective tumor response. Cmax was assessed on days 1 and 8 of cycle 1.. None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for ≥ 8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade ≥ 3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively.. AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Demography; Female; Humans; Kinesins; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Pyrimidinones; Spindle Apparatus; Treatment Outcome; Urinary Bladder Neoplasms; Urothelium

Since genes encoding epigenetic regulators are often mutated or deregulated in urothelial carcinoma (UC), they represent promising therapeutic targets. Specifically, inhibition of Class-I histone deacetylase (HDAC) isoenzymes induces cell death in UC cell lines (UCC) and, in contrast to other cancer types, cell cycle arrest in G2/M. Here, we investigated whether mutations in cell cycle genes contribute to G2/M rather than G1 arrest, identified the precise point of arrest and clarified the function of individual HDAC Class-I isoenzymes. Database analyses of UC tissues and cell lines revealed mutations in G1/S, but not G2/M checkpoint regulators. Using class I-specific HDAC inhibitors (HDACi) with different isoenzyme specificity (Romidepsin, Entinostat, RGFP966), cell cycle arrest was shown to occur at the G2/M transition and to depend on inhibition of HDAC1/2 rather than HDAC3. Since HDAC1/2 inhibition caused cell-type-specific downregulation of genes encoding G2/M regulators, the WEE1 inhibitor MK-1775 could not overcome G2/M checkpoint arrest and therefore did not synergize with Romidepsin inhibiting HDAC1/2. Instead, since DNA damage was induced by inhibition of HDAC1/2, but not of HDAC3, combinations between inhibitors of HDAC1/2 and of DNA repair should be attempted.

Topics: Acrylamides; Benzamides; Cell Cycle Checkpoints; Cell Line, Tumor; Depsipeptides; Drug Synergism; G2 Phase Cell Cycle Checkpoints; Genes, cdc; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Phenylenediamines; Pyrazoles; Pyridines; Pyrimidinones; Urinary Bladder Neoplasms

Bladder cancer (BC), a main neoplasm of urinary tract, is usually inoperable and unresponsive to chemotherapy. As a novel experimental model for muscle-invasive BC, we previously established a culture method of dog BC organoids. In the present study, the detailed in vitro and in vivo anti-tumor effects of trametinib were investigated by using this model. In each BC organoid strain, epidermal growth factor receptor (EGFR)/ERK signaling was upregulated compared with normal bladder cells. Trametinib even at a low concentration inhibited the cell viability of BC organoids and the activation of ERK through decreasing expression of c-Myc, ELK1, SIK1, and PLA2G4A. Trametinib arrested cell cycle of BC with few apoptosis. Dual treatment of BC organoids with trametinib and YAP inhibitor, verteporfin extremely inhibited the cell viability with apoptosis induction. Moreover, trametinib induced basal to luminal differentiation of BC organoids by upregulating luminal markers and downregulating basal ones. In vivo, trametinib decreased the tumor growth of BC organoids in mice and the xenograft-derived organoids from trametinib-administered mice showed enhanced sensitivity to carboplatin due to MSH2 upregulation. Our data suggested a new strategy of trametinib-YAP inhibitor or trametinib-carboplatin combination as a promising treatment of BC.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Dogs; Mice; Organoids; Pyridones; Pyrimidinones; Urinary Bladder Neoplasms

Topics: Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Female; Gene Knockdown Techniques; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Mitosis; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidinones; Transfection; Treatment Outcome; Tumor Suppressor Protein p53; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays

Methyltrioxorhenium mediated oxidative addition/elimination nucleophilic substitution yielded alkylamino and arylamino cambinol derivatives characterized by anti-proliferative activity against wild-type and p53 mutated MGH-U1 and RT112 bladder cancer cell lines. Some of the novel compounds showed an activity higher than that of the lead compound. The reaction was highly regioselective, affording for the first time a panel of C-2 cambinol substitution products. Aliphatic primary and secondary amines, and primary aromatic amines, were used as nitrogen centered nucleophiles. Surprisingly, the antiproliferative activity of C-2 substituted cambinol derivatives was not correlated to the induction of p53 protein, as evaluated by the analysis of the cell viability on wild-type and p53 mutated cancer cell lines, and further confirmed by western blot analyses. These data suggest that they exert their antiproliferative activity by a mechanism completely different from cambinol.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Naphthalenes; Oxidation-Reduction; Pyrimidinones; Structure-Activity Relationship; Urinary Bladder Neoplasms

Topics: Animals; Carcinoma, Transitional Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dog Diseases; Dogs; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; HT29 Cells; Humans; MAP Kinase Signaling System; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quinazolines; Urinary Bladder Neoplasms; Vemurafenib

Antimitotics such as taxanes are being considered as alternatives to conventional cisplatin-based chemotherapy in patients with bladder cancer, but the molecular determinants of sensitivity or resistance to these agents in bladder cancer cells have not been defined. Here we examined the cytotoxic effects of a novel antimitotic, the Eg5 inhibitor AZD4877, in a molecularly diverse panel of human bladder cancer cell lines. The cells displayed heterogeneous responses to the drug that correlated closely with sensitivity to docetaxel but not with sensitivity to cisplatin. Global gene expression profiling identified p63 as the top gene that was differentially expressed between sensitive and resistant cell lines. Stable knockdown of p63 inhibited cell death induced by either AZD4877 or docetaxel and was associated with decreased proliferation and decreased expression of c-myc. Furthermore, c-myc knockdown also rendered cells resistant to AZD4877 or docetaxel. Together, our results implicate p63 and its downstream target c-myc as determinants of sensitivity to anti-mitotics in bladder cancer cells. Our data also suggest that anti-mitotics and cisplatin target different subsets of bladder cancer cells, a conclusion that may have important implications for the therapy of muscle-invasive bladder cancers.

Topics: Antineoplastic Agents; Apoptosis; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Kinesins; Proto-Oncogene Proteins c-myc; Pyrimidinones; Transcription Factors; Tumor Suppressor Proteins; Urinary Bladder Neoplasms

Pyrimidinones are low-molecular-weight compounds which are inducers of interferon in several animal species. They have established antiviral, immunomodulatory, and antitumor effects. Four pyrimidinones as well as another potent interferon inducer, polyriboinosinic-polyribocytidylic acid, and beta-interferon were tested for effects on growth of the transplantable mouse bladder tumor (MBT-2). The pyrimidinones 2-amino-5-bromo-6-phenyl-4(3H)pyrimidinone (ABPP) and 2-amino-5-bromo-6-(3-fluorophenyl)-4(3H)pyrimidinone (ABMFPP) significantly inhibited MBT-2 growth in a dose-dependent manner and with equal potency when injected i.p. every 4 days starting 1 day after tumor cell inoculation. Administration of ABPP p.o. was as effective as i.p. injections. Direct intravesical application of ABPP to transplantable tumors growing in the bladder may be more effective in inhibiting MBT-2 growth than the same dose introduced p.o. Although ABPP (100 mg/kg) has an inhibitory effect comparable to 5000 units of beta-interferon, both pyrimidinones even at 500 mg/kg were less inhibitory of tumor growth than 10 mg of polyriboinosinic-polyribocytidylic acid per kg. The pyrimidinones 2-amino-5-bromo-6-(2,5-difluorophenyl)pyrimidine-4(3H)one (ABDFPP) and 2-amino-5-iodo-6-(2,3-difluorophenyl)pyrimidin-4(3H)one (AIDFPP) were also of comparable potency in inhibiting MBT-2 growth and were more effective on mg/kg basis than both ABPP and ABMFPP. Treatment with ABDFPP or AIDFPP also resulted in long-term cures of up to 40% of mice. In this respect these latter two compounds were superior to treatment with 10 mg of polyriboinosinic-polyribocytidylic acid per kg, a treatment which reduced tumor size but had no effects on tumor incidence. The data suggest that tumors of bladder origin may be particularly sensitive to treatment with pyrimidinones.

Topics: Animals; Female; Interferon Inducers; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Pyrimidinones; Urinary Bladder Neoplasms