PMID- 14633719
OWN - NLM
STAT- MEDLINE
DCOM- 20040209
LR  - 20131121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 63
IP  - 22
DP  - 2003 Nov 15
TI  - Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance 
      in an isogenic multiple myeloma cell line model.
PG  - 7900-6
AB  - Cancer cell adhesion confers a transient, de novo drug-resistant phenotype 
      referred to as cell adhesion-mediated drug resistance (CAM-DR). In this report, 
      we extend the CAM-DR phenotype to primary specimens from patients with myeloma, 
      providing further evidence that CAM-DR is a viable clinical form of drug 
      resistance. To examine mechanisms of cellular resistance to melphalan, we 
      compared genotypic and phenotypic profiles of acquired and de novo melphalan 
      resistance in an isogenic human myeloma cell line. Acquired melphalan resistance 
      (8226/LR5) was associated with decreased drug-induced DNA damage and a complex 
      gene expression profile showing that genes involved in the Fanconi anemia DNA 
      repair pathway are increased in the LR5 cells compared with drug-sensitive or 
      adherent cells. In contrast, cells adhered to fibronectin accumulate similar 
      amounts of DNA damage compared with drug-sensitive cells but are protected from 
      melphalan-induced mitochondrial perturbations and caspase activation. Levels of 
      the proapoptotic protein Bim were significantly reduced in adherent cells. Gene 
      expression changes associated with de novo resistance were significantly less 
      complex compared with acquired resistance, but a significant overlap in gene 
      expression was noted involving cholesterol synthesis. We propose that myeloma 
      cell adhesion promotes a form of de novo drug resistance by protecting cells from 
      melphalan-induced cytotoxic damage and that this transient protection allows 
      cells to acquire a more permanent and complex drug resistance phenotype 
      associated with a reduction in drug induced DNA damage.
FAU - Hazlehurst, Lori A
AU  - Hazlehurst LA
AD  - Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and 
      Research Institute, at The University of South Florida, 12902 Magnolia Drive, 
      Tampa, FL 33612, USA.
FAU - Enkemann, Steven A
AU  - Enkemann SA
FAU - Beam, Craig A
AU  - Beam CA
FAU - Argilagos, Raul F
AU  - Argilagos RF
FAU - Painter, Jeffrey
AU  - Painter J
FAU - Shain, Kenneth H
AU  - Shain KH
FAU - Saporta, Sara
AU  - Saporta S
FAU - Boulware, David
AU  - Boulware D
FAU - Moscinski, Lynn
AU  - Moscinski L
FAU - Alsina, Melissa
AU  - Alsina M
FAU - Dalton, William S
AU  - Dalton WS
LA  - eng
GR  - CA 77859/CA/NCI NIH HHS/United States
GR  - CA 82533/CA/NCI NIH HHS/United States
GR  - CC5G CA 76292/CC/ODCDC CDC HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Fibronectins)
RN  - 0 (Isoenzymes)
RN  - EC 3.4.22.- (Caspases)
RN  - Q41OR9510P (Melphalan)
SB  - IM
MH  - Antineoplastic Agents, Alkylating/*pharmacology
MH  - Apoptosis/drug effects/physiology
MH  - Caspases/metabolism
MH  - Cell Adhesion/physiology
MH  - Cell Line, Tumor
MH  - DNA Damage
MH  - Drug Resistance, Neoplasm
MH  - Enzyme Activation
MH  - Fibronectins/metabolism
MH  - Gene Expression Profiling
MH  - Humans
MH  - Isoenzymes/metabolism
MH  - Melphalan/*pharmacology
MH  - Mitochondria/physiology
MH  - Multiple Myeloma/*drug therapy/genetics/*pathology
MH  - Oligonucleotide Array Sequence Analysis
EDAT- 2003/11/25 05:00
MHDA- 2004/02/11 05:00
CRDT- 2003/11/25 05:00
PHST- 2003/11/25 05:00 [pubmed]
PHST- 2004/02/11 05:00 [medline]
PHST- 2003/11/25 05:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2003 Nov 15;63(22):7900-6.