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- Title
Targeted prodrug treatment of HER-2-positive breast tumor cells using trastuzumab and paclitaxel linked by A-Z-CINN<sup>TM</sup> Linker.
- Authors
Gilbert, Carl W.; McGowan, Eleanor B.; Seery, Gerald B.; Black, Kirby S.; Pegram, Mark D.
- Abstract
Targeting drugs for delivery and release has the potential to increase the efficacy of treatment. A bifunctional linker, A-Z-CINNTM Linker was used to create a targeted prodrug, A-Z-CINN 310. A-Z-CINN Linker links to a potent chemotherapeutic agent, paclitaxel, via an energy-reversible ester bond and also binds a targeting agent, the monoclonal antibody trastuzumab (Herceptin® ). This study demonstrates the effectiveness of a single-treatment use of A-Z-CINN 310 in decreasing tumor volume and tumor cell density of human HER-2-positive BT-474 mammary tumor cells implanted in scid mice, compared to treatment with simultaneously administered trastuzumab and paclitaxel and with saline control. After treatment with A-Z-CINN 310, some mice received light exposure at 6 h for 5 min adjacent to the tumor to cause light-accelerated release of paclitaxel. Changes in tumor volume were measured for 28 days following treatment; changes in histology were measured at 31 days. Animals treated with A-Z-CINN 310, then light, showed dose-dependent decreases in tumor volume and tumor cell density which were more rapid and extensive than those seen with A-Z-CINN 310 without light or a 10-fold higher concentration of co-administered trastuzumab plus paclitaxel. This suggests that targeted delivery of paclitaxel using A-Z-CINN 310 kills tumor cells by localized release of paclitaxel at the tumor site, which can be accelerated by light treatment. These results indicate that a targeted prodrug therapy containing trastuzumab as the targeting agent and A-Z-CINN–paclitaxel as the prodrug results in a conjugate that is more effective in killing tumor cells than equivalent concentrations of co-administered trastuzumab and paclitaxel. Targeting of a drug can reduce the dose needed for effective therapy and can increase local bioavailability. This makes targeted therapy using an A-Z-CINN prodrug delivery system feasible for treating both primary and metastatic...
- Subjects
BREAST tumor treatment; CANCER cells; DRUG therapy; PACLITAXEL
- Publication
Journal of Experimental Therapeutics & Oncology, 2003, Vol 3, Issue 1, p27
- ISSN
1359-4117
- Publication type
Article
- DOI
10.1046/j.1359-4117.2003.01064.x