Clin Cancer Res
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To study a fixed dose (360 mg) of paclitaxel given i.v. over 3 hours to female patients, and to evaluate prospectively the relationships between the following: body surface area and toxicity; body surface area and pharmacokinetics; and pharmacokinetics and toxicity. ⋯ These results suggest that fixed dosing of paclitaxel is feasible in women, which would simplify the administration of this drug.
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Inosine monophosphate dehydrogenase (IMPDH) inhibitors have been used to induce leukemia blast cell differentiation but have not been tested in multiple myeloma for activity. Currently, available IMPDH inhibitor, mycophenolate mofetil (MMF), which is known as an immunosuppressant, was shown to induce apoptosis in myeloma cell lines. On the basis of our preclinical studies, we designed a clinical study to test our hypothesis that MMF has antimyeloma activity. ⋯ MMF at 1 to 5 g/day daily dose is well tolerated by patients with relapsed and refractory multiple myeloma patients. Positive correlation between clinical response and depletion of intracellular dGTP level was shown. Future drug development to target this enzyme maybe useful in treating myelomas.
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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that induces apoptosis in multiple tumor cell types while sparing most normal cells. We determined the effect of ectopic Bcl-2 expression on TRAIL-induced apoptosis and whether the small molecule Bcl-2 inhibitor, HA14-1, could increase TRAIL sensitivity. ⋯ Bcl-2 confers apoptosis resistance to TRAIL by inhibiting a mitochondrial amplification step and by inactivating downstream XIAP in SW480 cells. HA14-1 reversed Bcl-2-mediated TRAIL resistance, suggesting a novel strategy for increasing TRAIL sensitivity in Bcl-2-overexpressing colon cancers.
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Hypoxia plays a critical role in driving tumor malignancy and is associated with poor patient survival in many human cancers. Novel therapies targeting hypoxic tumor cells are urgently needed, because these cells hinder tumor eradication. Here we demonstrate than an anticancer strategy based on intratumoral delivery of a novel type of oncolytic adenovirus targeting tumor hypoxia is therapeutically efficient and can augment standard chemotherapy. ⋯ Combining HYPR-Ad with chemotherapy effective against normoxic cells resulted in strongly enhanced antitumor efficacy. These studies demonstrate that targeting the hypoxic microenvironment of tumors rather than an intrinsic gene expression defect is a viable and novel antitumor therapeutic strategy that can be used in combination with existing treatment regimens. The replication and oncolytic potential of this virus was made dependent on hypoxic/hypoxia-inducible factor, a transcription factor activated in the tumor hypoxic microenvironment, broadening its therapeutic use to solid tumors of any genetic make-up or tissue of origin.
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Our purpose was to explore the contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of IFNalpha and 5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC). ⋯ Our results suggest that modulation of TRAIL/TRAIL receptor-mediated cytotoxic pathway might partially contribute to the anti-HCC effect of IFNalpha and 5-FU combination therapy.