30 research outputs found
ELECTROPHORETIC SEPARATION OF MULTIPLE FORMS OF PARTICLE ASSOCIATED ACID PHOSPHATASE
The acid phosphatases of rat liver mitochondrial-lysosomal fractions have been examined by quantitative and electrophoretic means. Disruption of mitochondrial-lysosomal material by freeze-thawing, sonication, or by blendor treatment released approximately 55.0 to 65.0 per cent of the total acid phosphatase activity of the fraction into the unsedimentable phase. Electrophoretic preparations of this material showed a single acid phosphatase-active site. Treatment of mitochondrial-lysosomal fractions with 5.0 per cent Triton X-100 released 98.0 per cent of the total acid phosphatase activity of the fraction into the unsedimentable phase. Electrophoretic preparations of this material showed two major sites of acid phosphatase activity. One of these was identical to that resolved following physical disruption. The other site was characteristically seen only after treatment with Triton X-100. This acid phosphatase was also released by treatment with digitonin but to a lesser extent. Quantitative and electrophoretic examination indicated that both components of acid phosphatase were concentrated in the mitochondrial-lysosomal fraction. Physical separation of the acid phosphatase released by detergent treatment from the acid phosphatase released by physical disruption was achieved. It was concluded that two categories of acid phosphatase may reside in lysosomal particles. These phosphatases differ in the nature of their binding to lysosomal structure as well as in their electrophoretic properties.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72869/1/j.1749-6632.1964.tb14230.x.pd
Phase II open label study of the oral vascular endothelial growth factor-receptor inhibitor PTK787/ZK222584 (vatalanib) in adult patients with refractory or relapsed diffuse large B-cell lymphoma
PTK787/ZK222584 (Vatalanib), an orally active inhibitor of vascular endothelial growth factor receptors (VEGF-Rs), was evaluated in this phase II study of 20 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received once daily PTK787/ZK222584 at a target dose of 1250mg. Eighteen patients were evaluable for response: 1 patient had a complete response (CR), 6 patients had stable disease but subsequently progressed, 10 patients had progressive disease by 3 cycles, and 1 subject withdrew before response evaluation. The patient who attained a CR underwent autologous stem cell transplantation and remains disease free 76 months after study completion. There were no grade 4 toxicities. Grade 3 thrombocytopenia occurred in 20% and grade 3 hypertension occurred in 10%. There were no episodes of grade 3 proteinuria. In conclusion, PTK787/ZK222584 was well tolerated in a heavily pretreated population of DLBCL patients, though its therapeutic potential as a single agent in DLBCL appears limited
Measurement of the Third Component of Complement Bound to Red Blood Cells in Patients with the Cold Agglutinin Syndrome
Abstract CT207: Phase I dose escalation and pharmokinetic study of 14-O-phosphonooxymethyltriptolide
Abstract
Introduction: We are conducting a phase I, first-in-human trial of 14-O-phosphonooxymethyltriptolide (Minnelide,) a water-soluble prodrug of triptolide, a diterpene derived from the thunder god vine (tripterygium wilfordii). Triptolide is a potent inhibitor of heat shock protein 70 (HSP70) and pancreatic ductal adenocarcinoma over-expresses HSP70 as a protective mechanism. We have previously shown Minnelide to be effective and well tolerated in preclinical models of pancreatic carcinoma.
Methods: The study uses a 3+3 dose escalation scheme, enrolling subjects with gastrointestinal malignancies refractory to standard therapies. The drug is administered as a daily, brief IV infusion for 21 days out of a 28 day cycle. The primary endpoint is toxicity, with secondary endpoints of pharmokinetics and response.
Results: To date we have enrolled 27 subjects (17 pancreas, 7 colorectal, 3 other GI) at doses from 0.16 to 0.8 mg/m2, with 24 evaluable for toxicity. The therapy has been generally well tolerated with the only common toxicity being hematologic, but one patient experienced reversible cerebellar dysfunction at the highest dose. Pharmokinetics (n = 21) indicate rapid conversion of Minnelide to triptolide, with all Minnelide cleared within 30 minutes and peak triptolide levels achieved within 5 minutes of completion of infusion. Triptolide was rapidly cleared with a half-life of less than 30 minutes, and complete clearance by 6 hours, except in the patient with cerebellar toxicity who demonstrated delayed clearance of the drug. All subjects, except those in the lowest dose cohort, have had a reduction in HSP70 levels. The 9 patients in the first 3 dose cohorts all progressed by the end of cycle two. Tumor response by PET after cycle 1 (n = 19), shows a partial metabolic response in 36%, and stable metabolic disease in 52%. Response after 2 cycles by RECIST criteria (n = 10) shows a 10% PR (gastric) and 60% SD (5 pancreas, 1 rectal) rate with disease control for up to 6 months. 5 patients remain on study, with ongoing enrollment planned.
Conclusions: We have seen promising evidence of significant clinical activity in this group of heavily pretreated patients with refractory GI malignancies. The toxicity profile and optimal dosing of Minnelide are being defined.
Citation Format: Edward Greeno, Erkut Borazanci, Jon Gockerman, Ronald Korn, Ashok Saluja, Daniel Von Hoff. Phase I dose escalation and pharmokinetic study of 14-O-phosphonooxymethyltriptolide. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT207. doi:10.1158/1538-7445.AM2015-CT207</jats:p
Phase I dose escalation and pharmokinetic study of a modified schedule of 14-o-phosphonooxymethyltriptolide
TPS472 Background: We are conducting a phase I trial of a modified dosing schedule of 14-O-phosphonooxymethyltriptolide (Minnelide,) a water-soluble prodrug of triptolide, a diterpene derived from the thunder god vine (tripterygium wilfordii). Triptolide is a potent inhibitor of heat shock protein 70 (HSP70) and pancreatic ductal adenocarcinoma over-expresses HSP70 as a protective mechanism. We have previously shown Minnelide to be effective and well tolerated in preclinical models of pancreatic carcinoma. We have previously presented our results from the initial phase I study of 27 patients using a daily dosing schema. That study demonstrated promising clinical activity with documented reductions in HSP70 levels. The common and dose limiting toxicity was neutropenia, which though cumulative, was also rapidly reversible early in the course of therapy with brief treatment interruptions. Several patients with disease control in the highest dose cohorts (0.67 and 0.8 mg/m2) progressed after dose reductions or prolonged treatment breaks mandated by the study protocol for cytopenias. Because of these observations we have revised the treatment schedule with short, early treatment breaks to allow more sustained therapy, and describe here the new study protocol. Methods: The study uses a 3+3 dose escalation scheme, enrolling subjects with gastrointestinal malignancies refractory to standard therapies. The drug is administered as a daily, brief IV infusion for 5 of 7 days for 3 weeks of a 4 week cycle. The initial dose cohort begins at 0.67mg/m2, above the MTD defined in the prior study and one step below the highest level achieved in our previous study of 0.8 mg/m2. The primary endpoint is toxicity, in order to define the MTD for this dosing schedule. Secondary endpoints being measured include: pharmokinetics of the study drug and its active metabolite triptolide; suppression of HSP70 levels; and tumor response. Cohort 1 at 0.67mg/m2 has been completed without DLT, enrollment to cohort 2 at 0.8mg/m2 is complete without DLT to date, and cohort 3 is anticipated to begin November of 2015. Clinical trial information: NCT01927965