20 results match your criteria: "The Institute for Drug Development[Affiliation]"

Despite the development of several new agents for multiple myeloma (MM) therapy over the last decade, drug resistance continues to be a significant problem. Patients with relapsed/refractory disease have high mortality rates and desperately need new precision approaches that directly target specific molecular features that are prevalent in the refractory setting. Reolysin is a proprietary formulation of reovirus for cancer therapy that has demonstrated efficacy in multiple clinical trials.

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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.

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Oncolytic virotherapy with reovirus has demonstrated anti-cancer activity and minimal toxicity in clinical trials, but the mechanisms underlying these effects have not been fully elucidated. Reolysin, a proprietary formulation of reovirus for cancer therapy, stimulated selective viral replication and apoptosis in multiple myeloma (MM) cells. Reolysin-mediated apoptosis was associated with an induction of endoplasmic reticular (ER) stress-related gene expression, swelling of the endoplasmic reticulum, increases in intracellular calcium levels and a strong induction of the Bcl-2 homology 3 (BH3)-only pro-apoptotic protein NOXA.

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Targeting aurora kinases in cancer treatment.

Curr Drug Targets

December 2011

The Institute for Drug Development, CTRC at University of Texas Health Science Center, 14960 Omicron Drive, San Antonio, TX 78245, USA.

The Aurora family of serine/threonine kinases is essential for chromosome alignment, segregation, centrosomal maturation, mitotic spindle formation, and cytokinesis during mitosis. Their fundamental role in cell cycle regulation and aberrant expression in a broad range of malignancies prompted the development of small molecules that selectively inhibit their activity. Recent studies have revealed new insights into the cellular effects of Aurora kinase inhibition.

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Purpose: To assess the feasibility of administering troxacitabine, an L-nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity.

Methods: Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m(2)) dose levels 50/4.8, 75/4.

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The histone deacetylase inhibitor SAHA enhances cell death stimulated by the proteasome inhibitor bortezomib (BZ) by disrupting BZ-induced aggresome formation. Here we report that Myc regulates the sensitivity of multiple myeloma (MM) cells to BZ + SAHA-induced cell death. In MM cells, Myc expression directly correlated with intracellular ER content, protein synthesis rates, the percentage of aggresome-positive cells, and the sensitivity to BZ + SAHA-induced cell death.

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Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy.

Cancer Lett

September 2008

The Institute for Drug Development, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 14960 Omicron Drive, San Antonio, TX 78245, USA.

Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression by catalyzing the removal of acetyl groups, stimulating chromatin condensation and promoting transcriptional repression. Since aberrant epigenetic changes are a hallmark of cancer, HDACs are a promising target for pharmacological inhibition. HDAC inhibitors can induce cell-cycle arrest, promote differentiation, and stimulate tumor cell death.

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Background: The purpose of the study was to evaluate the effects of erlotinib on epidermal growth factor receptor (EGFR)-related signaling elements in tumor and skin from patients with advanced squamous cell carcinoma of the head and neck (HNSCC) and seek relationships between relevant clinical, biological, and pharmacokinetic parameters.

Patients And Methods: Immunostaining for EGFR, p-EGFR, p-ERK, p-Akt, and p27 were analyzed semiquantitatively in serial tumor and skin samples from participating patients. Steady-state trough concentrations of erlotinib and its metabolite OSI-420 were also determined.

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Background: The differential sensitivity of some tumors to paclitaxel and docetaxel raises questions regarding the specific mechanisms responsible for the discrepant sensitivity to these taxanes.

Materials And Methods: Docetaxel and paclitaxel were evaluated and compared at maximum tolerated doses (MTD) and 0.5 MTDs against the human pediatric tumor xenograft models SK-N-MC and IMR32 (neuroblastoma), RH1 and RH30 (rhabdomyosarcoma) and KHOS/NP (osteosarcoma), with 8-10 animals per group.

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Background: Farnesyltransferase inhibitor R115777 (Tipifamib, Zarnestra) is active in breast cancer, but its efficacy in drug combinations has not been extensively investigated.

Materials And Methods: The activity of R115777 and paclitaxel, alone and in combination, was studied in the human breast cancer cell lines, BT-474 (overexpressed HER2/neu) and MDA-MB-231 (low HER2/neu), with cell viability and biomarkers for farnesylation (HDJ-2, Rho B), tumor growth (Raf/MEK/ERK), survival (PI3K/Akt) and angiogenesis (VEGF, FGF-2, MMP-1, MMP-2, MMP-9) as the endpoints.

Results: The drug combination resulted in additive cytotoxicity.

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Biomarkers for Sensitivity to Docetaxel and Paclitaxel in Human Tumor Cell Lines .

Cancer Genomics Proteomics

July 2005

Cancer Therapy and Research Center, The Institute for Drug Development, 14960 Omicron Drive, San Antonio, TX 78245, U.S.A.

Background: Paclitaxel and docetaxel affect microtubule polymerization, yet surprising differences in tumor sensitivity to the taxanes have been observed. Docetaxel was superior to paclitaxel in inhibiting in vivo growth of human lung and prostate but not breast cancer models.

Materials And Methods: We compared drug cytotoxicity, effects on β-tubulin isoforms, markers of apoptosis and proteomic profiles in human prostate (LNCaP), lung (SK-MES, MV-522) and breast (MCF-7, MDA-231) cancer cell lines in vitro.

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HMN-176, (E)-4-(2-[2-(N-[4-methoxybenzene-sulfonyl]amino)phenyl]ethenyl) pyridine 1-oxide, is a stilbene derivative which inhibits mitosis without significant effect on tubulin polymerization and displays potent cytotoxicity against a variety of human tumor cell lines. The present study evaluated the activity profile of the antineoplastic agent HMN-176 in an ex-vivo soft agar cloning assay (human tumor colony-forming assay) in a panel of 132 human tumor specimens under 14-day continuous exposure at 0.1, 1.

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Development of novel alkylating drugs as anticancer agents.

Curr Opin Investig Drugs

June 2004

Cancer Therapy and Research Center, The Institute for Drug Development, 14960 Omicron Drive, San Antonio, TX 78245, USA.

Although conventional alkylating drugs have proven efficacy in the treatment of malignancies, the agents themselves are not selective. Therefore, non-specific alkylation of cellular nucleophilic targets may contribute to many of the observed toxic effects. Novel approaches to drug discovery have resulted in candidate agents that are focused on 'soft alkylation'--alkylators with greater target selectivity.

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Impairments of learning and memory following intracerebroventricular administration of AF64A in rats.

Arch Pharm Res

June 2001

College of Pharmacy and the Institute for Drug Development, Chonnam National University, Kwangju, Korea.

Three types of learning and memory tests (Morris water maze, active and passive avoidance) were performed in rats following intracerebroventricular infusion of ethylcholine aziridium (AF64A). In Morris water maze, AF64A-treated rats showed the delayed latencies to find the platform from 6th day after the infusion. In pretrained rats, AF64A caused the significant delay of latency at 7th day, but not 8th day.

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Ambulatory electrocardiogram (ECG) has been recorded in dogs wearing a jacket to protect a Holter recording system, but the jacket was often damaged by dogs. We compared ECG recorded by a Holter recording system and spontaneous activity measured by an accelerometer in Beagle dogs with or without an Elizabethan collar. There were few significant differences in mean values (per hr) of the heart rate and the amount of spontaneous activity between dogs with or without the Elizabethan collar.

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Background: Rhizoxin (NSC 332598) is a novel macrolide antitumor antibiotic that inhibits microtubule assembly and also depolymerizes preformed microtubules. In preclinical evaluations, rhizoxin demonstrated broad antitumor activity in vitro and in vivo including both vincristine- and vindesine-resistant human lung cancers. Prolonged exposure schedules in xenograft models demonstrated optimal efficacy indicating schedule-dependent antitumor activity.

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There is a great need for new therapeutic agents for patients with advanced pancreatic cancer. The new dioxolane analogue troxacitabine was evaluated in two human pancreatic cancer xenograft models. The models used included the Panc-01 and MiaPaCa pancreatic cancer cell lines.

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Effect of dGTP concentration on human and CHO telomerase.

Biochemistry

November 1999

Department of Cancer Biology, Department of Experimental Therapeutics, The Institute for Drug Development, The Cancer Therapy & Research Center, San Antonio, Texas 78229, USA.

Human telomerase produces a long ladder of six-base repeat additions to a primer, while CHO telomerase primarily adds only one or two repeat additions to a primer. Under the standard assay conditions, the concentration of dGTP is very low, so we investigated the effects of increasing dGTP concentration on human and CHO telomerase activities. Increasing dGTP concentration over a range of 1.

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The principal purpose of this study was to evaluate relationships between paclitaxel plasma steady-state concentration (Css) and both disease outcome and toxicity in patients with non-small cell lung cancer (NSCLC) treated with paclitaxel and cisplatin in an Eastern Cooperative Oncology Group (ECOG) Phase III study E5592. Chemotherapy-naive patients with stage IIIb and IV NSCLC were randomized to treatment with either 75 mg/m2 cisplatin i.v.

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