Seliciclib (CYC202, R‐roscovitine) enhances the antitumor effect of doxorubicin in vivo in a breast cancer xenograft model

We sought to determine whether seliciclib (CYC202, R‐roscovitine) could increase the antitumor effects of doxorubicin, with no increase in toxicity, in an MCF7 breast cancer xenograft model. The efficacy of seliciclib combined with doxorubicin was compared with single agent doxorubicin or seliciclib...

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Bibliographic Details
Published in:International journal of cancer 2009-01, Vol.124 (2), p.465-472
Main Authors: Appleyard, Maria Virginia C.L., O'Neill, Mary A., Murray, Karen E., Paulin, Fiona E.M., Bray, Susan E., Kernohan, Neil M., Levison, David A., Lane, David P., Thompson, Alastair M.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological and medical sciences
Breast Neoplasms - drug therapy
CDK inhibitor
Cell Line, Tumor
combination therapy
Cyclin-Dependent Kinase Inhibitor p27 - metabolism
Cyclin-Dependent Kinases - metabolism
Doxorubicin - administration & dosage
Drug Synergism
Female
Gynecology. Andrology. Obstetrics
Humans
Mammary gland diseases
Mammary Neoplasms, Animal - drug therapy
Medical sciences
Mice
Mice, Nude
Neoplasm Transplantation
Protein Kinase Inhibitors - administration & dosage
Purines - administration & dosage
seliciclib
Tumors
xenograft
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Summary:We sought to determine whether seliciclib (CYC202, R‐roscovitine) could increase the antitumor effects of doxorubicin, with no increase in toxicity, in an MCF7 breast cancer xenograft model. The efficacy of seliciclib combined with doxorubicin was compared with single agent doxorubicin or seliciclib administered to MCF7 cells and to nude mice bearing established MCF7 xenografts. Post‐treatment cells and tumors were examined by cell cycle analysis, immunohistochemistry and real‐time PCR. Seliciclib significantly enhanced the antitumor effect of doxorubicin without additional murine toxicity. MIB1 (ki67) immunohistochemistry demonstrated reduced proliferation with treatment. The levels of p21 and p27 increased after treatment with doxorubicin or seliciclib alone or in combination, compared to untreated controls. However, no changes in p53 protein (DO1, CM1), survivin or p53 phosphorylation (SER15) were observed in treated tumors compared with controls. In conclusion, the CDK inhibitor seliciclib (R‐roscovitine) enhances the antitumor effect of doxorubicin in MCF7 tumors without increased toxicity with a mechanism that involves cell cycle arrest rather than apoptosis. © 2008 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.23938