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Hepatic drug targeting : phase I evaluation of polymer-bound doxorubicin
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Seymour, L. W., Ferry, David R., Anderson, David, Hesslewood, Stuart, Julyan, Peter J., Poyner, Richard, Doran, Jayne, Young, Annie M., Burtles, Sally and Kerr, David J. (2002) Hepatic drug targeting : phase I evaluation of polymer-bound doxorubicin. Journal of Clinical Oncology, 20 (6). pp. 1668-1676. doi:10.1200/JCO.20.6.1668 ISSN 0732-183X.
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Official URL: http://dx.doi.org/10.1200/JCO.20.6.1668
Abstract
Purpose: Preclinical studies have shown good anti-cancer 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 (IV) infusion over 1 hour, repeated every 3 weeks. Dose escalation proceeded from 20 to 160 mg/m2 (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/m2, 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. © 2002 by American Society of Clinical Oncology.
Item Type: | Journal Article | ||||
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Subjects: | R Medicine > R Medicine (General) | ||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Journal or Publication Title: | Journal of Clinical Oncology | ||||
Publisher: | American Society of Clinical Oncology | ||||
ISSN: | 0732-183X | ||||
Official Date: | 15 March 2002 | ||||
Dates: |
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Volume: | 20 | ||||
Number: | 6 | ||||
Page Range: | pp. 1668-1676 | ||||
DOI: | 10.1200/JCO.20.6.1668 | ||||
Status: | Not Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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