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Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity
in ovarian cancer cells
Lorenzi, P.L., Reinhold, W.C., Rudelius, M., Gunsior, M., Shankavaram, U., Bussey, K.J., Scherf,
U., Eichler, G.S., Martin, S.E., Chin, K., Gray, J.W., Kohn, E.C., Horak, I.D., Von Hoff, D.D., Raffeld, M., Goldsmith, P.K.,
Caplen, N.J., and Weinstein, J.N.
Mol Cancer Ther. 2006;5:2613-2623
Abstract:
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.
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