pyrimidinones and Lymphoma--B-Cell

This Phase I study assessed the safety and maximum tolerated dose (MTD) of the kinesin spindle protein inhibitor AZD4877 in patients with relapsed/refractory solid tumors and lymphoma.. In this multicenter study, a standard 3 + 3 dose-escalation design was used. AZD4877 was given as an intravenous infusion on days 1, 4, 8 and 11 of each 21-day cycle. Responses were assessed with CT scans +/- PET after 6 and 12 weeks, then every 12 weeks while on therapy. An additional four patients with lymphoma were enrolled at the MTD.. 29 patients were enrolled and 22 patients received at least one dose of AZD4877 and were evaluable for safety. The MTD was 11 mg. Dose-limiting toxicity was neutropenia (n = 2 patients, 15 mg cohort). The most common adverse events were grade 1/2 fatigue, nausea, neutropenia and dyspnea. AZD4877 exposure generally increased with dose, with mean elimination half-life approximately 16 h at the MTD. Pharmacodynamic analyses demonstrated moderate correlation between plasma drug concentrations at 6 or 24 h and monoaster formation in peripheral blood mononuclear cells (PBMCs).. AZD4877 is generally well-tolerated with pharmacodynamic evidence of target inhibition in circulating PBMCs.

Topics: Adult; Aged; Benzamides; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Kinesins; Lymphoma, B-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Prognosis; Pyrimidinones; Tissue Distribution

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Brentuximab Vedotin; Diphtheria Toxin; Drug Discovery; Everolimus; Humans; Hydroxamic Acids; Immunoconjugates; Indoles; Inotuzumab Ozogamicin; Interleukin-2; Lenalidomide; Lymphoma; Lymphoma, B-Cell; Nitrogen Mustard Compounds; Purine Nucleosides; Pyrazines; Pyrimidinones; Recombinant Fusion Proteins; Sirolimus; Thalidomide; Vorinostat

Forodesine inhibits purine nucleoside phosphorylase, resulting in an accumulation of intracellular dGTP and consequently cell death. 9-β-D-Arabinofuranosylguanine (ara-G) is an active compound of nelarabine that is intracellularly phosphorylated to a triphosphate form, which inhibits DNA synthesis. Both agents show cytotoxicity toward T-cell malignancies. In the present study, we investigated the cytotoxicity of forodesine in vitro using ara-G-resistant leukemia cells.. T-Lymphoblastic leukemia cell line CCRF-CEM and ara-G-resistant CEM variant cell line CEM/ara-G that we had previously established were used.. A growth-inhibition assay demonstrated that CEM cells were insensitive to single-agent forodesine treatment. The cells were also insensitive to deoxyguanosine at a maximal concentration of 10 μM. CEM/ara-G cells were 80-fold more resistant to ara-G than were CEM cells, and the mode of sensitivity to forodesine and deoxyguanosine was similar to that of CEM cells. In the presence of 10 μM deoxyguanosine, forodesine effectively inhibited the growth of CEM cells but not that of CEM/ara-G cells. Flow cytometric analyses showed that combination of forodesine and deoxyguanosine induced apoptosis of CEM cells but not of CEM/ara-G cells. The addition of ara-G did not augment the cytotoxicity of the forodesine/deoxyguanosine combination towards CEM cells or CEM/ara-G cells. The combination index revealed antagonism between forodesine and ara-G. The intracellular production of ara-G triphosphate was reduced in the presence of forodesine.. Nelarabine-resistant CEM/ara-G cells are insensitive to forodesine.

Topics: Antineoplastic Agents; Arabinonucleosides; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; HL-60 Cells; Humans; Lymphoma, B-Cell; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Biomarkers, Tumor; Cyclophosphamide; DNA; Hepatitis B; Hepatitis B virus; Humans; Lymphoma, B-Cell; Male; Middle Aged; Nucleosides; Prednisolone; Proto-Oncogene Proteins c-bcl-2; Pyrimidinones; Rituximab; Telbivudine; Thymidine; Vincristine