Abstract
This chapter discusses the preclinical and clinical development of trastuzumab as targeted therapy for HER-2 over-expressing breast cancer receptor. HER-2 activates multiple cellular signaling pathways, including the phos-phatidylinositol-3 kinase (PI3K) and mitogen-activated protein kinase cascades. Trastuzumab reduces signaling in these pathways and thus promotes cell-cycle arrest and apoptosis. The cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle, with a concomitant reduction in cell proliferation and reduced expression of proteins involved in sequestering p27 kip1 , including cyclin D1. This results in the release of p27 kip1, allowing it to bind and inhibit cyclin E-cdk2 complexes. The in vitro studies have shown that trastuzumab is synergistic with a variety of chemotherapeutic agents. Single-agent trastuzumab can dramatically reduce tumor size in patients with HER-2 over-expressing metastatic breast cancer. This clinical response is explained by the agent's induction of apoptosis. It is found that response rates to trastuzumab given as a single agent have ranged from 12% to 34%, depending in part on the method used to determine HER-2 status and the prior treatments received by the patients.
Original language | English (US) |
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Title of host publication | Target Validation in Drug Discovery |
Publisher | Elsevier Inc. |
Pages | 69-81 |
Number of pages | 13 |
ISBN (Print) | 9780123693938 |
DOIs | |
State | Published - 2007 |
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)