PMID- 16428505
OWN - NLM
STAT- MEDLINE
DCOM- 20060228
LR  - 20161124
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 12
IP  - 2
DP  - 2006 Jan 15
TI  - Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated 
      drug resistance in multiple myeloma and acute myeloid leukemia.
PG  - 591-9
AB  - It has been established in preclinical models of multiple myeloma and acute 
      myeloid leukemia (AML) that the bone marrow microenvironment provides protection 
      from chemotherapy- and death receptor-mediated apoptosis. This form of 
      resistance, termed de novo drug resistance, occurs independent of chronic 
      exposure to cancer-related therapies and likely promotes the development of 
      multidrug resistance. Consequently, it is of major interest to identify compounds 
      or drug combinations that can overcome environment-mediated resistance. In this 
      study, we investigated the activity of tipifarnib (Zarnestra, formerly R115777) 
      combined with bortezomib (Velcade, formerly PS-341) in microenvironment models of 
      multiple myeloma and AML. The combination proved to be synergistic in multiple 
      myeloma and AML cell lines treated in suspension culture. Even in tumor cells 
      relatively resistant to tipifarnib, combined activity was maintained. Tipifarnib 
      and bortezomib were also effective when multiple myeloma and AML cells were 
      adhered to fibronectin, providing evidence that the combination overcomes cell 
      adhesion-mediated drug resistance (CAM-DR). Of importance, activation of the 
      endoplasmic reticulum stress response was enhanced and correlated with apoptosis 
      and reversal of CAM-DR. Multiple myeloma and AML cells cocultured with bone 
      marrow stromal cells also remained sensitive, although stromal-adhered tumor 
      cells were partially protected (relative to cells in suspension or fibronectin 
      adhered). Evaluation of the combination using a transwell apparatus revealed that 
      stromal cells produce a protective soluble factor. Investigations are under way 
      to identify the cytokines and/or growth factors involved. In summary, our study 
      provides the preclinical rationale for trials testing the tipifarnib and 
      bortezomib combination in patients with multiple myeloma and AML.
FAU - Yanamandra, Niranjan
AU  - Yanamandra N
AD  - Department of Interdisciplinary Oncology, Malignant Hematology, Experimental 
      Therapeutics, and Bone Marrow Transplant Divisions, H. Lee Moffitt Cancer Center 
      and Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa, 
      FL 33612, USA.
FAU - Colaco, Nandita M
AU  - Colaco NM
FAU - Parquet, Nancy A
AU  - Parquet NA
FAU - Buzzeo, Robert W
AU  - Buzzeo RW
FAU - Boulware, David
AU  - Boulware D
FAU - Wright, Gabriela
AU  - Wright G
FAU - Perez, Lia E
AU  - Perez LE
FAU - Dalton, William S
AU  - Dalton WS
FAU - Beaupre, Darrin M
AU  - Beaupre DM
LA  - eng
GR  - 5K12 CA 87989-02/CA/NCI NIH HHS/United States
GR  - P20 CA 103676/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Boronic Acids)
RN  - 0 (Fibronectins)
RN  - 0 (Pyrazines)
RN  - 0 (Quinolones)
RN  - 69G8BD63PP (Bortezomib)
RN  - MAT637500A (tipifarnib)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Bone Marrow/drug effects/metabolism
MH  - Boronic Acids/*pharmacology
MH  - Bortezomib
MH  - Cell Adhesion/*drug effects
MH  - *Drug Resistance, Neoplasm
MH  - Drug Synergism
MH  - Drug Therapy, Combination
MH  - Fibronectins/metabolism
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*drug therapy/metabolism
MH  - Multiple Myeloma/*drug therapy/metabolism
MH  - Pyrazines/*pharmacology
MH  - Quinolones/*pharmacology
MH  - Stromal Cells/cytology/drug effects/metabolism
MH  - Tumor Cells, Cultured
EDAT- 2006/01/24 09:00
MHDA- 2006/03/01 09:00
CRDT- 2006/01/24 09:00
PHST- 2006/01/24 09:00 [pubmed]
PHST- 2006/03/01 09:00 [medline]
PHST- 2006/01/24 09:00 [entrez]
AID - 12/2/591 [pii]
AID - 10.1158/1078-0432.CCR-05-1792 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2006 Jan 15;12(2):591-9. doi: 10.1158/1078-0432.CCR-05-1792.