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1.
Invest New Drugs ; 30(4): 1591-6, 2012 Aug.
Article in English | MEDLINE | ID: mdl-21863237

ABSTRACT

PURPOSE: This phase I trial assessed the safety, dose limiting toxicity (DLT) and pharmacodynamics of PX-12 in adult patients with advanced refractory cancers. METHODS: PX-12 was administered to sequential cohorts as a 72-h infusion utilizing a portable infusion pump on days 1, 2, and 3 of a 21-day cycle at a starting dose level of 300 mg/m(2)/day and escalating dose levels till DLT was observed. Plasma thioredoxin (Trx-1), vascular endothelial growth factor (VEGF) and FGF-2 (fibroblast growth factor) levels were measured predose and during infusion of PX-12. RESULTS: Patients (n = 14) were enrolled to the following dose cohorts, 300 mg/m(2) (n = 3), 400 mg/m(2) (n = 10) and 500 mg/m(2) (n = 1). Common grade 1/2 toxicities included fatigue, taste alteration and odor caused by expired drug metabolite. DLTs were one episode each of grade 3 hypoxia at the 400 mg/m(2) and grade 3 reversible pneumonitis at the 500 mg/m(2) dose levels. Best response was stable disease in a patient with rectal cancer. Predose Trx-1 levels (n = 12) ranged from 5.1 to 30.0 ng/mL (median 12.6 ng/mL). CONCLUSION: PX-12 administered at 400 mg/m(2)/day by 72-hour infusion appears safe and tolerable. Inhibition of thioredoxin is a strategy worth evaluation with next generation of inhibitors.


Subject(s)
Disulfides/pharmacology , Disulfides/therapeutic use , Imidazoles/pharmacology , Imidazoles/therapeutic use , Neoplasms/drug therapy , Neoplasms/pathology , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Thioredoxins/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/blood , Disulfides/administration & dosage , Disulfides/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Resistance, Neoplasm/drug effects , Female , Fibroblast Growth Factor 2/blood , Humans , Imidazoles/administration & dosage , Imidazoles/adverse effects , Infusions, Intravenous , Male , Middle Aged , Neoplasm Staging , Neoplasms/blood , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/adverse effects , Thioredoxins/blood , Thioredoxins/metabolism , Vascular Endothelial Growth Factor A/blood
2.
Tissue Eng Part A ; 14(3): 433-40, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18333795

ABSTRACT

Islet transplantation for the purpose of treating insulin-sensitive diabetes is currently limited by several factors, including islet survival posttransplantation. In the current study, a tissue-engineered prevascularized pancreatic encapsulating device (PPED) was developed. Isolated islets were placed in collagen gels, and they exhibited fourfold more insulin release than islets not in collagen. The insulin released by beta-cells in islets encapsulated in collagen exhibited unobstructed diffusion within the collagen gels. Subsequent studies evaluated the ability to create a sandwich comprised of two layers of prevascularized collagen gels around a central collagen gel containing islets. In vitro characterization of the islets showed that islets are functional and responded to glucose stimulation. The PPEDs were implanted subcutaneously into severe combined immunodeficient mice. Islet survival was assessed after 7, 14, and 28 days. Immunohistochemical analysis was performed on the implants to detect insulin and the presence of intraislet endothelial cells. At all time points, insulin was localized in association with intact and partially dissociated islets. Moreover, cells that exhibited insulin staining were colocalized with intraislet endothelial cells. These data indicate that the PPED enhances islet survival by supporting islet viability and maintaining intraislet endothelial cell structures.


Subject(s)
Islets of Langerhans/blood supply , Prostheses and Implants , Animals , Collagen/metabolism , Diffusion/drug effects , Female , Fluorescent Antibody Technique , Gels/metabolism , Glucose/pharmacology , Insulin/metabolism , Islets of Langerhans/drug effects , Male , Mice , Mice, SCID , Rats , Rats, Sprague-Dawley , Tissue Survival/drug effects
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