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

2.50
Hdl Handle:
http://hdl.handle.net/2436/29455
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.
Citation:
Journal of Clinical Oncology, 20(6): 1668-1676
Publisher:
American Society of Clinical Oncology
Journal:
Journal of Clinical Oncology
Issue Date:
2002
URI:
http://hdl.handle.net/2436/29455
PubMed ID:
11896118
Additional Links:
http://jco.ascopubs.org/cgi/content/full/20/6/1668
Type:
Article
Language:
en
ISSN:
0732-183X
Appears in Collections:
Cancer Research Group

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.accessioned2008-06-04T09:25:49Z-
dc.date.available2008-06-04T09:25:49Z-
dc.date.issued2002-
dc.identifier.citationJournal of Clinical Oncology, 20(6): 1668-1676en
dc.identifier.issn0732-183X-
dc.identifier.pmid11896118-
dc.identifier.urihttp://hdl.handle.net/2436/29455-
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.publisherAmerican Society of Clinical Oncologyen
dc.relation.urlhttp://jco.ascopubs.org/cgi/content/full/20/6/1668en
dc.subject.meshAntineoplastic Agentsen
dc.subject.meshArea Under Curveen
dc.subject.meshChromatography, High Pressure Liquiden
dc.subject.meshDoxorubicinen
dc.subject.meshDrug Carriersen
dc.subject.meshFemaleen
dc.subject.meshGalactosamineen
dc.subject.meshGamma Camerasen
dc.subject.meshHumansen
dc.subject.meshInfusions, Intravenousen
dc.subject.meshLiver Neoplasmsen
dc.subject.meshMaleen
dc.subject.meshPolymethacrylic Acidsen
dc.subject.meshTomography, Emission-Computed, Single-Photonen
dc.subject.meshTreatment Outcomeen
dc.titleHepatic drug targeting: phase I evaluation of polymer-bound doxorubicin.en
dc.typeArticleen
dc.identifier.journalJournal of Clinical Oncologyen

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