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.
Issue Date
2002
Metadata
Show full item recordAbstract
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): 1668-1676Publisher
American Society of Clinical OncologyJournal
Journal of Clinical OncologyPubMed ID
11896118Additional Links
http://jco.ascopubs.org/cgi/content/full/20/6/1668Type
Journal articleLanguage
enISSN
0732-183XCollections
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