Abstract |
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. The lead targeted doxorubicin- formaldehyde conjugate, called DOX-TEG-TAM, was found to possess superior cell growth inhibition characteristics relative to clinical doxorubicin and an untargeted control conjugate, especially in ER-negative, multidrug resistant MCF-7/Adr cells. The enhanced activity in the absence of estrogen receptor raised the possibility that targeting was also mediated via AEBS. Fluorescence microscopy of an ER-negative, AEBS-positive cell line as a function of time showed initial DOX-TEG-TAM localization in cytosol, in contrast to initial DOX and untargeted doxorubicin- formaldehyde conjugate localization in the nucleus. DOX-TEG-TAM was taken up by four AEBS-positive cell lines to a greater extent than doxorubicin and an untargeted doxorubicin- formaldehyde conjugate. Of the four cell lines, three were ER negative. DOX-TEG-TAM uptake was inhibited in a dose-dependent manner by the presence of a competing AEBS ligand. DOX-TEG-TAM retains 60% of the affinity of 4-hydroxytamoxifen for AEBS. DOX-TEG-TAM was also taken up by the AEBS-negative, ER-positive cancer cell line Rtx-6; with these cells uptake was inhibited in a dose-dependent manner by the ER ligand, estradiol. The data support the hypothesis that uptake of 4-hydroxytamoxifen targeted doxorubicin- formaldehyde conjugate is mediated by both the antiestrogen binding site and estrogen receptor.
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Authors | Patrick J Burke, Brian T Kalet, Tad H Koch |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 47
Issue 26
Pg. 6509-18
(Dec 16 2004)
ISSN: 0022-2623 [Print] United States |
PMID | 15588086
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents
- Receptors, Drug
- Receptors, Estrogen
- Tamoxifen
- afimoxifene
- Formaldehyde
- Doxorubicin
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Topics |
- Antineoplastic Agents
(chemical synthesis, metabolism, pharmacokinetics)
- Binding Sites
- Breast Neoplasms
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Doxorubicin
(analogs & derivatives, chemical synthesis, metabolism, pharmacokinetics)
- Female
- Formaldehyde
(analogs & derivatives, chemical synthesis, metabolism, pharmacokinetics)
- Humans
- Microscopy, Fluorescence
- Receptors, Drug
(metabolism)
- Receptors, Estrogen
(metabolism)
- Structure-Activity Relationship
- Tamoxifen
(analogs & derivatives, chemical synthesis, metabolism, pharmacokinetics)
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