Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin.
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 METHOD...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2002
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| _version_ | 1797078847636635648 |
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| author | Seymour, L Ferry, DR Anderson, D Hesslewood, S Julyan, P Poyner, R Doran, J Young, A Burtles, S Kerr, D |
| author_facet | Seymour, L Ferry, DR Anderson, D Hesslewood, S Julyan, P Poyner, R Doran, J Young, A Burtles, S Kerr, D |
| author_sort | Seymour, L |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:37:23Z |
| format | Journal article |
| id | oxford-uuid:81e3cad4-d252-4801-90a3-31866156ad84 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:37:23Z |
| publishDate | 2002 |
| record_format | dspace |
| spelling | oxford-uuid:81e3cad4-d252-4801-90a3-31866156ad842022-03-26T21:33:21ZHepatic drug targeting: phase I evaluation of polymer-bound doxorubicin.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:81e3cad4-d252-4801-90a3-31866156ad84EnglishSymplectic Elements at Oxford2002Seymour, LFerry, DRAnderson, DHesslewood, SJulyan, PPoyner, RDoran, JYoung, ABurtles, SKerr, D 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. |
| spellingShingle | Seymour, L Ferry, DR Anderson, D Hesslewood, S Julyan, P Poyner, R Doran, J Young, A Burtles, S Kerr, D Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. |
| title | Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. |
| title_full | Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. |
| title_fullStr | Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. |
| title_full_unstemmed | Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. |
| title_short | Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. |
| title_sort | hepatic drug targeting phase i evaluation of polymer bound doxorubicin |
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