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Novel Compounds in the Therapy of Breast Cancer: Opportunities for Integration with Docetaxel

Institute of Drug Development, Cancer Therapy Research Center, San Antonio, Texas, USA

Correspondence: Anthony W. Tolcher, M.D., Institute of Drug Development, Cancer Therapy Research Center, 8122 Datapoint, Suite 250, San Antonio, Texas 78229, USA. Telephone: 210-616-5914; Fax: 210-949-5009; e-mail: atolcher{at}saci.org.

Increasingly, novel agents are being developed specifically at inhibition of growth factor receptors and events within the signal transduction pathway. These agents include the epidermal growth factor tyrosine kinase inhibitors, the farnesyl transferase inhibitors, and bcl-2 antisense oligonucleotides. Along with these new approaches to molecular targeting, it will be necessary to develop new study designs for drug evaluation. Target validation in both normal surrogate tissues and tumor tissue becomes increasingly relevant in early clinical trials. Furthermore, antitumor efficacy may no longer correlate with normal hematological or nonhematological toxicity, and it may be more appropriate in phase I trials to identify the maximum target inhibition dose rather than the maximum tolerated dose. Moreover, measures of cytoreduction, such as complete and partial response, may be less relevant than disease stabilization for some of these novel agents which have limited cytotoxic effects and would be considered cytostatic agents. Assessment of single-agent activity and the future role in conjunction with cytostatic agents represents the single most important challenge facing the clinical development of these molecular targeted therapies.

Key Words. Tyrosine kinase inhibitors • Farnesyl transferase inhibitors • bcl-2 antisense oligonucleotides • Docetaxel

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