Transcription factor Ets1 cooperates with estrogen receptor α to stimulate estradiol-dependent growth in breast cancer cells and tumors.

The purpose of this study was to explore the role of transcription factor Ets1 in estrogen receptor α (ERα)-positive breast cancer progression. We expressed human Ets1 or empty vector in four human ERα-positive breast cancer cell lines and observed increased colony formation. Further examination of cellular responses in stable Ets1-expressing MCF7 clones displayed increased proliferation, migration, and invasion.

Anthracycline-formaldehyde conjugates and their targeted prodrugs.

The sequence of research leading to a proposal for anthracycline cross-linking of DNA is presented.The clinical anthracycline antitumor drugs are anthraquinones, and as such are redox active. Their redoxchemistry leads to induction of oxidative stress and drug metabolites.

Doxazolidine induction of apoptosis by a topoisomerase II independent mechanism.

The mechanism of doxorubicin is compared with that of doxazolidine, a doxorubicin-formaldehyde conjugate. The IC(50) for growth inhibition of 67 human cancer cell lines, but not cardiomyocytes, is 32-fold lower with doxazolidine than with doxorubicin. Growth inhibition by doxazolidine correlates better with growth inhibition by DNA cross-linking agents than with growth inhibition by doxorubicin.

Design, synthesis, and preliminary evaluation of doxazolidine carbamates as prodrugs activated by carboxylesterases.

The synthesis and tumor cell growth inhibition by doxazolidine carbamate prodrugs are reported. The carbamates were designed for selective hydrolysis by one or more human carboxylesterases to release doxazolidine (Doxaz), the formaldehyde-oxazolidine of doxorubicin that cross-links DNA to trigger cell death. Simple butyl and pentyl, but not ethyl, carbamate prodrugs inhibited the growth of cancer cells that overexpress carboxylesterase CES1 (hCE1) and CES2 (hiCE).

Doxorubicin-formaldehyde conjugates targeting alphavbeta3 integrin.

We have reported the synthesis and biological evaluation of a prodrug to a doxorubicin active metabolite. Under physiologic conditions, release of the active metabolite, a conjugate of doxorubicin with formaldehyde, occurs with a half-life of 1 hour. To direct this prodrug to tumor, we designed two conjugates of the prodrug, doxsaliform, with the alphavbeta3-targeting peptides, CDCRGDCFC (RGD-4C) and cyclic-(N-Me-VRGDf) (Cilengitide).

Antiestrogen binding site and estrogen receptor mediate uptake and distribution of 4-hydroxytamoxifen-targeted doxorubicin-formaldehyde conjugate in breast cancer cells.

The anthracycline antitumor drug, doxorubicin (DOX), has long been used as a broad spectrum chemotherapeutic. The literature now documents the role of formaldehyde in the cytotoxic mechanism, and anthracycline-formaldehyde conjugates possess substantially enhanced activity in vitro and in vivo. We have recently reported the design, synthesis, and preliminary evaluation of a doxorubicin-formaldehyde conjugate targeted, via 4-hydroxytamoxifen, to the estrogen receptor (ER) and antiestrogen binding site (AEBS), which are commonly present in breast cancer cells.