Monitoring histone deacetylase inhibition in vivo: noninvasive magnetic resonance spectroscopy method.
Histone deacetylase inhibitors (HDACis) are emerging as promising and selective antitumor agents. However, HDACis can lead to tumor stasis rather than shrinkage, in which case, traditional imaging methods are not adequate to monitor response. Consequently, novel approaches are needed. We have shown in cells that (19)F magnetic resonance spectroscopy (MRS)-detectable levels of the HDAC substrate Boc-Lys-TFA-OH (BLT) are inversely correlated with HDAC activity. We extended our investigations to a tumor xenograft model. Following intraperitoneal injection of BLT, its accumulation within the tumor was monitored by in vivo (19)F MRS. In animals treated with the HDACi suberoylanilide hydroxamic acid (SAHA), tumoral BLT levels were higher by 77% and 132% on days 2 and 7 of treatment compared with pretreatment levels (n = 6; p < .05). In contrast, tumoral BLT levels remained unchanged in control animals and in normal tissue. Thus, (19)F MRS of BLT detected the effect of HDACi treatment as early as day 2 of treatment. Importantly, tumor size confirmed that SAHA treatment leads to inhibition of tumor growth. However, difference in tumor size reached significance only on day 6 of treatment. Thus, this work identifies BLT as a potential molecular imaging agent for the early noninvasive MRS detection of HDAC inhibition in vivo.
Sankaranarayanapillai
Madhuri
M
Experimental Diagnostic Imaging, Imaging Physics, and Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Tong
William P
WP
Yuan
Qing
Q
Bankson
James A
JA
Dafni
Hagit
H
Bornmann
William G
WG
Soghomonyan
Suren
S
Pal
Ashutosh
A
Ramirez
Marc S
MS
Webb
Douglas
D
Kaluarachchi
Kumaralal
K
Gelovani
Juri G
JG
Ronen
Sabrina M
SM
D000818:Animals; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D051379:Mice; D008819:Mice, Nude
D005456:Fluorescent Dyes; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases