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Purpose Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies. Methods Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25-90 mg for 14 or 21 consecutive days plus 14 or 7 days' rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days' rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30-50 mg twice-daily (BID) for 7 days plus 14 days' rest in 21-day cycles. Results Fifty-eight patients were enrolled (PIC n = 28, ECT n = 30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease. Conclusion The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma. [ABSTRACT FROM AUTHOR]

Aim:This study was aimed to assess the in vivo anti-tumoral potency of the novel 6-nitro-2-(3-chloropropyl)-1H-benz[de]isoquinoline- 1,3-dione [Compound 1] that has earlier demonstrated excellent cytotoxicity in 15 out of 17 human tumor cell lines tested. Materials and Methods: Two murine tumors namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) were used to measure its in vivo anti-tumor activity through the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. Drug-induced toxicity in respect of hematological parameters, femoral bone marrow and splenic cellularity as well as biochemical parameters and histopathology of liver and kidney were assessed in vivo in normal and S-180 bearing mice sequentially on days 9, 14 and 19 following drug treatment at the optimum dose of 60 mg/kg administered from day 1 to 7. Results: Results revealed significant tumor regression effects in S-180 and EAC as T/Cmax values of 138 and 189 were obtained at its optimum dose of 60 mg/kg for QD1-7. Toxicity assay indicated no significant cardiotoxicity, hepatotoxicity or nephrotoxicity of the compound in normal and S-180 bearing mice. An initial hyposplenic cellularity and the femoral bone marrow suppression effect observed on day 9 reached normalcy by day 19. HPLC analysis revealed that it has appreciable stability (half-life ~ 3 h) in murine blood plasma in vitro. Conclusion: Above results justify potential candidature of the compound for further drug development. [ABSTRACT FROM AUTHOR]

The development of a rapid-forming in-situ sprayable hydrogel with the functions of tumor treatment and wound healing is essential for eliminating residual tumor tissue and promoting wound healing caused by surgical resection. On account of its semiconductor properties, β-FeSi 2 (FS) was widely explored as a thermoelectric material. In this work, FS was first applied as a bioactive material for the application of tissue engineering. Excitedly, we found that FS could be used as a novel antitumor agent. It exhibited excellent photothermal performance, and the released Fe ions could generate •OH under the acidic conditions and excessive H 2 O 2 in the tumor microenvironment. Moreover, the sprayable β-FeSi 2 -incorporated sodium alginate (FS/SA) hydrogel was prepared as an instant gelation after spraying in situ , contributing to timely tumor-induced skin wound healing and efficiently suppressing tumors through photothermal and chemodynamic therapy (PTT and CDT). Furthermore, the released bioactive Fe and Si ions could promote the migration and differentiation of endothelial cells and the pro-angiogenesis of skin wounds. Accordingly, such sprayable hydrogel played an effective role in emergency wound treatment with the advantage of convenience and portability. Overall, with incorporation of FS into the sprayable FS/SA hydrogel, the composite hydrogel possessed dual functions of tumor therapy and skin wound healing. [ABSTRACT FROM AUTHOR]