Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status.

Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Research Abstract Details 

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Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Abstract Text:

Hans Minderman,Yunfei Zhou,Kieran L O'Loughlin,Maria R Baer,

PURPOSE: The proteasome inhibitor bortezomib may be effective in combination with cytarabine and anthracyclines in the treatment of acute myeloid leukemia (AML) by virtue of targeting aberrantly activated NF-kappaB in AML stem cells. We tested whether bortezomib cytotoxicity is affected by multidrug resistance (MDR) proteins expressed in AML cells. We also tested whether bortezomib interactions with cytarabine and anthracyclines are affected by p53, because proteasome inhibition stabilizes p53 and may thus cause cell cycle arrest. EXPERIMENTAL DESIGN: Bortezomib sensitivity of cell lines overexpressing P-glycoprotein, multidrug resistance protein-1, breast cancer resistance protein and lung resistance protein was studied in the presence and absence of established modulators of these transport proteins. Drug interactions during simultaneous and sequential exposure to bortezomib and anthracyclines or cytarabine in diverse ratios were evaluated by isobologram and combination index analyses in AML cell lines with wild type and inactive p53 and were correlated with cell cycle perturbations induced by bortezomib. RESULTS: Of the MDR mechanisms studied, only P-glycoprotein conferred resistance to bortezomib, and resistance was only twofold. Interactions between bortezomib and anthracylines and cytarabine changed from antagonistic to additive or synergistic with increasing drug activity levels and were not affected by p53 status. CONCLUSIONS: MDR proteins and p53 do not affect bortezomib cytotoxicity or in vitro interactions with anthracyclines or cytarabine, but these interactions are concentration-dependent, and this concentration-dependency should be considered in the design of combination regimens.

Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Publishing Authors By Initials

H Minderman,Y Zhou,KL O'Loughlin,MR Baer,

For similar proteins: dna-binding proteins: tumor suppressor protein p53 research abstracts see: proteins: dna-binding proteins: tumor suppressor protein p53 research

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Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer chemotherapy and pharmacology

VOLUME: 60

Page Numbers: 245-55

Journal Abbreviation: Cancer Chemother. Pharmacol.

ISSN: 0344-5704

DAY: 10

MONTH: 11

YEAR: 2006

Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Information

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LANGUAGE: eng

NlmUniqueID: 7806519

Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Keywords Mesh Terms:

KEYWORDS: Tumor Suppressor Protein p53

MESH TERMS: metabolism

Chemical & Substance for Abstract: Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Information

Substance Name: Cytarabine

Registry Number: 147-94-4

Grant and Affiliation Information for Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status.

AFFILIATION: Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. hans.minderman@roswellpark.org

Country: Germany

AGENCY: United States NCI

GRANT: P30 CA16056

ACRONYM: CA

MEDLINETA: Cancer Chemother Pharmacol

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