Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells

被引:80
作者
Lorenzi, Philip L.
Reinhold, William C.
Rudelius, Martina
Gunsior, Michele
Shankavaram, Uma
Bussey, Kimberly J.
Scherf, Uwe
Eichler, Gabriel S.
Martin, Scott E.
Chin, Koei
Gray, Joe W.
Kohn, Elise C.
Horak, Ivan D.
Von Hoff, Daniel D.
Raffeld, Mark
Goldsmith, Paul K.
Caplen, Natasha J.
Weinstein, John N. [1 ]
机构
[1] NCI, Genom & Bioinformat Grp, Mol Pharmacol Lab, NIH,Ctr Canc Res, Bethesda, MD 20892 USA
[2] NCI, Antibody & Prot Purificat Unit, NIH, Ctr Canc Res, Bethesda, MD 20892 USA
[3] NCI, Gene Silencing Sect, NIH, Off Sci & Technol Partnerships,Off Director,Ctr C, Bethesda, MD 20892 USA
[4] NCI, Mol Signaling Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA
[5] Univ Calif San Francisco, Canc Res Inst, San Francisco, CA 94143 USA
[6] Enzon Pharmaceut Inc, Piscataway, NJ USA
[7] Translat Genom Res Inst, Phoenix, AZ USA
关键词
D O I
10.1158/1535-7163.MCT-06-0447
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
L-Asparaginase (L-ASP), a bacterial enzyme used since the 1970s to treat acute lymphoblastic leukemia, selectively starves cells that cannot synthesize sufficient asparagine for their own needs. Molecular profiling of the NCI-60 cancer cell lines using five different microarray platforms showed strong negative correlations of asparagine synthetase (ASNS) expression and DNA copy number with sensitivity to L-ASP in the leukemia and ovarian cancer cell subsets. To assess whether the ovarian relationship is causal, we used RNA interference to silence ASNS in three ovarian lines and observed 4- to 5-fold potentiation of sensitivity to L-ASP with two of the lines. For OVCAR-8, the line that expresses the least ASNS, the potentiation was > 500-fold. Significantly, that potentiation was > 700-fold in the multidrug-resistant derivative OVCAR-8/ADR, showing that the causal relationship between ASNS expression and L-ASP activity survives development of classical multidrug resistance. Tissue microarrays confirmed low ASNS expression in a subset of clinical ovarian cancers as well as other tumor types. Overall, this pharmacogenomic/pharmacoproteomic study suggests the use Of L-ASP for treatment of a subset of ovarian cancers (and perhaps other tumor types), with ASNS as a biomarker for patient selection.
引用
收藏
页码:2613 / 2623
页数:11
相关论文
共 54 条
  • [1] Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling
    Alizadeh, AA
    Eisen, MB
    Davis, RE
    Ma, C
    Lossos, IS
    Rosenwald, A
    Boldrick, JG
    Sabet, H
    Tran, T
    Yu, X
    Powell, JI
    Yang, LM
    Marti, GE
    Moore, T
    Hudson, J
    Lu, LS
    Lewis, DB
    Tibshirani, R
    Sherlock, G
    Chan, WC
    Greiner, TC
    Weisenburger, DD
    Armitage, JO
    Warnke, R
    Levy, R
    Wilson, W
    Grever, MR
    Byrd, JC
    Botstein, D
    Brown, PO
    Staudt, LM
    [J]. NATURE, 2000, 403 (6769) : 503 - 511
  • [2] ALLEY MC, 1988, CANCER RES, V48, P589
  • [3] A comparison of selected mRNA and protein abundances in human liver
    Anderson, L
    Seilhamer, J
    [J]. ELECTROPHORESIS, 1997, 18 (3-4) : 533 - 537
  • [4] Selective apoptosis of natural killer-cell tumours by L-asparaginase
    Ando, M
    Sugimoto, K
    Kitoh, T
    Sasaki, M
    Mukai, K
    Ando, J
    Egashira, M
    Schuster, SM
    Oshimi, K
    [J]. BRITISH JOURNAL OF HAEMATOLOGY, 2005, 130 (06) : 860 - 868
  • [5] Asparagine synthetase expression alone is sufficient to induce L-asparaginase resistance in MOLT-4 human leukaemia cells
    Aslanian, AM
    Fletcher, BS
    Kilberg, MS
    [J]. BIOCHEMICAL JOURNAL, 2001, 357 : 321 - 328
  • [6] BATIST G, 1986, J BIOL CHEM, V261, P5544
  • [7] COMPLETE SEQUENCING OF THE P53 GENE PROVIDES PROGNOSTIC INFORMATION IN BREAST-CANCER PATIENTS, PARTICULARLY IN RELATION TO ADJUVANT SYSTEMIC THERAPY AND RADIOTHERAPY
    BERGH, J
    NORBERG, T
    SJOGREN, S
    LINDGREN, A
    HOLMBERG, L
    [J]. NATURE MEDICINE, 1995, 1 (10) : 1029 - 1034
  • [8] Pharmacogenomic analysis: Correlating molecular substructure classes with microarray gene expression data
    Blower P.E.
    Yang C.
    Fligner M.A.
    Verducci J.S.
    Yu L.
    Richman S.
    Weinstein J.N.
    [J]. The Pharmacogenomics Journal, 2002, 2 (4) : 259 - 271
  • [9] BOYD MR, 1989, CANC PRINCIPLES PRAC, P1
  • [10] Buerger H, 2000, CANCER RES, V60, P854