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Palbociclib: an evidence-based review of its potential in the treatment of breast cancer.

Cadoo KA, Gucalp A, Traina TA - Breast Cancer (Dove Med Press) (2014)

Bottom Line: This machinery includes cyclin-dependent kinases (CDKs) which complex with their cyclin partners, allowing the cell cycle to progress.Palbociclib is a potent and selective inhibitor of CDK4 and -6 with significant activity in breast cancer models.Furthermore, it has been shown to significantly prolong progression-free survival when combined with letrozole in the management of estrogen receptor-positive metastatic breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, USA.

ABSTRACT
Cellular proliferation, growth, and division following DNA (deoxyribonucleic acid) damage are tightly controlled by the cell-cycle regulatory machinery. This machinery includes cyclin-dependent kinases (CDKs) which complex with their cyclin partners, allowing the cell cycle to progress. The cell-cycle regulatory process plays a critical role in oncogenesis and in the development of therapeutic resistance; it is frequently disrupted in breast cancer, providing a rational target for therapeutic development. Palbociclib is a potent and selective inhibitor of CDK4 and -6 with significant activity in breast cancer models. Furthermore, it has been shown to significantly prolong progression-free survival when combined with letrozole in the management of estrogen receptor-positive metastatic breast cancer. In this article we review the cell cycle and its regulatory processes, their role in breast cancer, and the rationale for CDK inhibition in this disease. We describe the preclinical and clinical data relating to the activity of palbociclib in breast cancer and the plans for the future development of this agent.

No MeSH data available.


Related in: MedlinePlus

Palbociclib, or PD-0332991, a CDK4/6 inhibitor from Pfizer, Inc. (New York, NY, USA).
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f2-bctt-6-123: Palbociclib, or PD-0332991, a CDK4/6 inhibitor from Pfizer, Inc. (New York, NY, USA).

Mentions: Palbociclib, or PD-0332991 (Pfizer, Inc., New York, NY, USA), is an orally available inhibitor of CDK4 and -67 (Figure 2). PD-0332991 was developed from a group of pyridopyrimidine compounds due to its favorable physical and pharmaceutical properties.7 PD-0332991 potently and equally inhibits both CDK4– and CDK6–cyclin D1 kinase activity.7 In addition, it is highly selective for CDK4/6, with little activity against a panel of multiple other protein kinases. PD-0332991 inhibits cell growth and suppresses DNA replication at low nanomolar concentrations in a number of RB proficient human cancer cells, including breast cancer. As expected, no activity is seen in RB-deficient cells.7 Consistent with the anticipated impact of a CDK4/6 inhibitor on cell-cycle progression, these cells show significant increase in the proportion of cells in G1. In vivo, significant antitumor activity is demonstrated in breast cancer xenografts, with near to complete suppression of tumor growth. In addition, sustained inhibition of tumor RB phosphorylation is possible.7 The specificity of PD-0332991 in targeting CDK4/6–cyclin D is important, allowing inhibition of oncogenic events while sparing normal tissue which is in a relatively inactive, non-cycling state.16


Palbociclib: an evidence-based review of its potential in the treatment of breast cancer.

Cadoo KA, Gucalp A, Traina TA - Breast Cancer (Dove Med Press) (2014)

Palbociclib, or PD-0332991, a CDK4/6 inhibitor from Pfizer, Inc. (New York, NY, USA).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128689&req=5

f2-bctt-6-123: Palbociclib, or PD-0332991, a CDK4/6 inhibitor from Pfizer, Inc. (New York, NY, USA).
Mentions: Palbociclib, or PD-0332991 (Pfizer, Inc., New York, NY, USA), is an orally available inhibitor of CDK4 and -67 (Figure 2). PD-0332991 was developed from a group of pyridopyrimidine compounds due to its favorable physical and pharmaceutical properties.7 PD-0332991 potently and equally inhibits both CDK4– and CDK6–cyclin D1 kinase activity.7 In addition, it is highly selective for CDK4/6, with little activity against a panel of multiple other protein kinases. PD-0332991 inhibits cell growth and suppresses DNA replication at low nanomolar concentrations in a number of RB proficient human cancer cells, including breast cancer. As expected, no activity is seen in RB-deficient cells.7 Consistent with the anticipated impact of a CDK4/6 inhibitor on cell-cycle progression, these cells show significant increase in the proportion of cells in G1. In vivo, significant antitumor activity is demonstrated in breast cancer xenografts, with near to complete suppression of tumor growth. In addition, sustained inhibition of tumor RB phosphorylation is possible.7 The specificity of PD-0332991 in targeting CDK4/6–cyclin D is important, allowing inhibition of oncogenic events while sparing normal tissue which is in a relatively inactive, non-cycling state.16

Bottom Line: This machinery includes cyclin-dependent kinases (CDKs) which complex with their cyclin partners, allowing the cell cycle to progress.Palbociclib is a potent and selective inhibitor of CDK4 and -6 with significant activity in breast cancer models.Furthermore, it has been shown to significantly prolong progression-free survival when combined with letrozole in the management of estrogen receptor-positive metastatic breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, USA.

ABSTRACT
Cellular proliferation, growth, and division following DNA (deoxyribonucleic acid) damage are tightly controlled by the cell-cycle regulatory machinery. This machinery includes cyclin-dependent kinases (CDKs) which complex with their cyclin partners, allowing the cell cycle to progress. The cell-cycle regulatory process plays a critical role in oncogenesis and in the development of therapeutic resistance; it is frequently disrupted in breast cancer, providing a rational target for therapeutic development. Palbociclib is a potent and selective inhibitor of CDK4 and -6 with significant activity in breast cancer models. Furthermore, it has been shown to significantly prolong progression-free survival when combined with letrozole in the management of estrogen receptor-positive metastatic breast cancer. In this article we review the cell cycle and its regulatory processes, their role in breast cancer, and the rationale for CDK inhibition in this disease. We describe the preclinical and clinical data relating to the activity of palbociclib in breast cancer and the plans for the future development of this agent.

No MeSH data available.


Related in: MedlinePlus