Postulating favorable antileukemic effect with improved safety, we used intravenous busulfan and fludarabine as conditioning therapy for allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Fludarabine 40 mg/m 2 and intravenous busulfan 130 mg/m 2 were given once daily for 4 days, with tacrolimus-methotrexate as graft-versus-host disease (GVHD) prophylaxis. We treated 74 patients with AML and 22 patients with MDS; patients had a median age of 45 years (range, 19-66 years). Only 20% of the patients were in first complete remission (CR) at transplantation. Donors were HLA-compatible related (n ‫؍‬ 60) or matched unrelated (n ‫؍‬ 36). The CR rate for 54 patients with active disease was 85%. At a median follow-up of 12 months, 1-year regimenrelated and treatment-related mortalities were 1% and 3%, respectively. Two patients had reversible hepatic veno-occlusive disease. Actuarial 1-year overall survival (OS) and event-free survival (EFS) were 65% and 52% for all patients, and 81% and 75% for patients receiving transplants in CR. Recipient age and donor type did not influence OS or EFS. Median

The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.

Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC 50 values for WP1066 were 5.6 lM in U87-MG cells and 3.7 lM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X L and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (Po0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

Overcoming the profound immunosuppression in patients with solid cancers has impeded efficacious immunotherapy. Signal transducers and activators of transcription 3 (STAT3) has recently emerged as a potential target for effective immunotherapy, and in this study, we describe a novel small molecule inhibitor of STAT3 that can penetrate the central nervous system (CNS) in mice and in physiologically relevant doses in vitro and reverse tolerance in immune cells isolated from glioblastoma multiforme (GBM) patients. Specifically, it induces the expression of costimulatory molecules on peripheral macrophages and tumor-infiltrating microglia, stimulates the production of the immune-stimulatory cytokines interleukin 2 (IL-2), IL-4, IL-12, and IL-15, and induces proliferation of effector T cells from GBM patients that are refractory to CD3 stimulation. We show that the functional enhancement of immune responses after STAT3 inhibition is accompanied by up-regulation of several key intracellular signaling molecules that critically regulate T-cell and monocyte activation. Specifically, the phosphorylation of Syk (Tyr 352 ) in monocytes and ZAP-70 (Tyr 319 ) in T cells are enhanced by the STAT-3 inhibitor in marked contrast to toll-like receptor and T-cell receptor agonists, respectively. This novel small molecule STAT3 inhibitor has tremendous potential for clinical applications with its penetration into the CNS, easy parental administration, direct tumor cytotoxicity, and potent immune adjuvant responses in immunosuppressed cancer patients.