Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin.

2.50
Hdl Handle:
http://hdl.handle.net/10541/79994
Title:
Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin.
Authors:
Seymour, Leonard W; Ferry, David R; Anderson, David; Hesslewood, Stuart; Julyan, Peter J; Poyner, Richard; Doran, Jayne; Young, Annie M; Burtles, Sally; Kerr, David J
Abstract:
PURPOSE: Preclinical studies have shown good anticancer activity following targeting of a polymer bearing doxorubicin with galactosamine (PK2) to the liver. The present phase I study was devised to determine the toxicity, pharmacokinetic profile, and targeting capability of PK2. PATIENTS AND METHODS: Doxorubicin was linked via a lysosomally degradable tetrapeptide sequence to N-(2-hydroxypropyl)methacrylamide copolymers bearing galactosamine. Targeting, toxicity, and efficacy were evaluated in 31 patients with primary (n = 25) or metastatic (n = 6) liver cancer. Body distribution of the radiolabelled polymer conjugate was assessed using gamma-camera imaging and single-photon emission computed tomography. RESULTS: The polymer was administered by intravenous (i.v.) infusion over 1 hour, repeated every 3 weeks. Dose escalation proceeded from 20 to 160 mg/m(2) (doxorubicin equivalents), the maximum-tolerated dose, which was associated with severe fatigue, grade 4 neutropenia, and grade 3 mucositis. Twenty-four hours after administration, 16.9% +/- 3.9% of the administered dose of doxorubicin targeted to the liver and 3.3% +/- 5.6% of dose was delivered to tumor. Doxorubicin-polymer conjugate without galactosamine showed no targeting. Three hepatoma patients showed partial responses, with one in continuing partial remission 47 months after therapy. CONCLUSION: The recommended PK2 dose is 120 mg/m(2), administered every 3 weeks by IV infusion. Liver-specific doxorubicin delivery is achievable using galactosamine-modified polymers, and targeting is also seen in primary hepatocellular tumors.
Affiliation:
Cancer Research UK Institute for Cancer Studies, University of Birmingham, United Kingdom.
Citation:
Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. 2002, 20 (6):1668-76 J. Clin. Oncol.
Journal:
Journal of Clinical Oncology
Issue Date:
15-Mar-2002
URI:
http://hdl.handle.net/10541/79994
PubMed ID:
11896118
Type:
Article
Language:
en
ISSN:
0732-183X
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorSeymour, Leonard W-
dc.contributor.authorFerry, David R-
dc.contributor.authorAnderson, David-
dc.contributor.authorHesslewood, Stuart-
dc.contributor.authorJulyan, Peter J-
dc.contributor.authorPoyner, Richard-
dc.contributor.authorDoran, Jayne-
dc.contributor.authorYoung, Annie M-
dc.contributor.authorBurtles, Sally-
dc.contributor.authorKerr, David J-
dc.date.accessioned2009-09-07T10:32:01Z-
dc.date.available2009-09-07T10:32:01Z-
dc.date.issued2002-03-15-
dc.identifier.citationHepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. 2002, 20 (6):1668-76 J. Clin. Oncol.en
dc.identifier.issn0732-183X-
dc.identifier.pmid11896118-
dc.identifier.urihttp://hdl.handle.net/10541/79994-
dc.description.abstractPURPOSE: Preclinical studies have shown good anticancer activity following targeting of a polymer bearing doxorubicin with galactosamine (PK2) to the liver. The present phase I study was devised to determine the toxicity, pharmacokinetic profile, and targeting capability of PK2. PATIENTS AND METHODS: Doxorubicin was linked via a lysosomally degradable tetrapeptide sequence to N-(2-hydroxypropyl)methacrylamide copolymers bearing galactosamine. Targeting, toxicity, and efficacy were evaluated in 31 patients with primary (n = 25) or metastatic (n = 6) liver cancer. Body distribution of the radiolabelled polymer conjugate was assessed using gamma-camera imaging and single-photon emission computed tomography. RESULTS: The polymer was administered by intravenous (i.v.) infusion over 1 hour, repeated every 3 weeks. Dose escalation proceeded from 20 to 160 mg/m(2) (doxorubicin equivalents), the maximum-tolerated dose, which was associated with severe fatigue, grade 4 neutropenia, and grade 3 mucositis. Twenty-four hours after administration, 16.9% +/- 3.9% of the administered dose of doxorubicin targeted to the liver and 3.3% +/- 5.6% of dose was delivered to tumor. Doxorubicin-polymer conjugate without galactosamine showed no targeting. Three hepatoma patients showed partial responses, with one in continuing partial remission 47 months after therapy. CONCLUSION: The recommended PK2 dose is 120 mg/m(2), administered every 3 weeks by IV infusion. Liver-specific doxorubicin delivery is achievable using galactosamine-modified polymers, and targeting is also seen in primary hepatocellular tumors.en
dc.language.isoenen
dc.subjectLiver Canceren
dc.subject.meshAntineoplastic Agents-
dc.subject.meshArea Under Curve-
dc.subject.meshChromatography, High Pressure Liquid-
dc.subject.meshDoxorubicin-
dc.subject.meshDrug Carriers-
dc.subject.meshFemale-
dc.subject.meshGalactosamine-
dc.subject.meshGamma Cameras-
dc.subject.meshHumans-
dc.subject.meshInfusions, Intravenous-
dc.subject.meshLiver Neoplasms-
dc.subject.meshMale-
dc.subject.meshPolymethacrylic Acids-
dc.subject.meshTomography, Emission-Computed, Single-Photon-
dc.subject.meshTreatment Outcome-
dc.titleHepatic drug targeting: phase I evaluation of polymer-bound doxorubicin.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Institute for Cancer Studies, University of Birmingham, United Kingdom.en
dc.identifier.journalJournal of Clinical Oncologyen

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