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Open Access Highly Accessed Research article

Synthesis and preliminary cytotoxicity study of a cephalosporin-CC-1065 analogue prodrug

Yuqiang Wang*, Huiling Yuan, Susan C Wright, Hong Wang and James W Larrick

Author Affiliations

Panorama Research, Inc., 2462 Wyandotte Stree, Mountain View, California, 94043, USA

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BMC Chemical Biology 2001, 1:4  doi:10.1186/1472-6769-1-4

Published: 2 November 2001

Abstract

Background

Antibody-directed enzyme prodrug therapy (ADEPT) is a promising new approach to deliver anticancer drugs selectively to tumor cells. In this approach, an enzyme is conjugated to a tumor-specific antibody. The antibody selectively localizes the enzyme to the tumor cell surface. Subsequent administration of a prodrug substrate of the enzyme leads to the enzyme-catalyzed release of the free drug at the tumor site. The free drug will destroy the tumor cells selectively, thus, reducing side effects.

Results

A CC-1065 analogue was conjugated to a cephalosporin affording prodrug 2. The prodrug and its corresponding free drug, 1, have IC50 values of 0.9 and 0.09 nM, respectively, against U937 leukemia cells in vitro.

Conclusions

For the first time, a prodrug comprised of a cephalosporin and a CC-1065 analogue has been synthesized. The preliminary in vitro studies show that the prodrug was 10-fold less toxic than the free drug. Prodrug 2 has the potential to be useful in cancer treatment using the ADEPT approach.