J Natl Cancer Inst. 2003 Nov
5;95(21):1624-33.
17aag Magnetic resonance spectroscopic pharmacodynamic
markers of the heat shock protein 90 inhibitor
17-allylamino,17-demethoxygeldanamycin (17AAG) in human colon
cancer models.
Chung YL, Troy H, Banerji U, Jackson LE, Walton MI, Stubbs M,
Griffiths JR, Judson IR, Leach MO, Workman P, Ronen SM.
Cancer Research UK Biomedical Magnetic Resonance Research
Group, Department of Basic Medical Sciences, St. George's
Hospital Medical School, London, UK. ychung@sghms.ac.uk
BACKGROUND: 17-allylamino,17-demethoxygeldanamycin (17AAG) is a
novel anticancer drug that inhibits heat shock protein 90
(Hsp90), resulting in proteasomal degradation of several
oncogenic proteins. We used phosphorus magnetic resonance
spectroscopy (31P-MRS) to determine whether 17AAG treatment
leads to alterations in phospholipids that could serve as
pharmacodynamic markers for tumor response to 17AAG. METHODS:
HCT116, HT29, and SW620 colon cancer cells were treated with
17AAG, and extracts were examined by 31P-MRS. HT29 cells
were also treated with the active metabolite of 17AAG,
17-amino,17-demethoxygeldanamycin (17AG), or the inactive
17AAG analog NSC683666. MF-1 nude mice carrying HT29 xenografts
were examined using in vivo 31P-MRS before and after 17AAG
treatment; xenograft tumor extracts were examined by 31P-MRS and
proton MRS (1H-MRS). Hsp90 client protein expression was
determined by using western blots. Two-tailed t tests were used
to compare metabolite concentrations and ratios, and a
Mann-Whitney U test was used to compare proportions. All
statistical tests were two-sided. RESULTS: 17AAG treatment led
to statistically significantly increased phosphocholine levels
in all three cell lines (P =.02). 17AG treatment also increased
phosphocholine levels in HT29 cells, whereas NSC683666 had no
effect. The phosphomonoester/phosphodiester ratio was
statistically significantly increased in the HT29 xenografts
after 17AAG treatment relative to the pretreatment ratio (P
=.02), whereas no statistically significant change was observed
after vehicle treatment (P =.62). Statistically significant
increases in phosphocholine, phosphoethanolamine, and valine
levels were also observed in tumor extracts treated with 17AAG.
CONCLUSIONS: Inhibition of Hsp90 by 17AAG resulted in altered
phospholipid metabolism in cultured tumor cells and in tumor
xenografts. The increases observed in phosphocholine and
phosphomonoester levels suggest that these metabolites may have
the potential to act as noninvasive pharmacodynamic markers for
analyzing tumor response to treatment with 17AAG or other Hsp90
inhibitors.
PMID: 14600095
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