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Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin.
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|Title: ||Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin.|
|Citation: ||Journal of Clinical Oncology, 20(6): 1668-1676|
|Publisher: ||American Society of Clinical Oncology|
|Journal: ||Journal of Clinical Oncology|
|Issue Date: ||2002 |
|PubMed ID: ||11896118|
|Additional Links: ||http://jco.ascopubs.org/cgi/content/full/20/6/1668|
|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.|
|MeSH: ||Antineoplastic Agents|
Area Under Curve
Chromatography, High Pressure Liquid
Tomography, Emission-Computed, Single-Photon
|Appears in Collections: ||Cancer Research Group|
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