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Sci Rep. 2017 Aug 11;7(1):7865. doi: 10.1038/s41598-017-07609-7.

Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH.

Rao JU1,2, Coman D3,4, Walsh JJ5,6, Ali MM7, Huang Y5,8, Hyder F9,10,11.

Author information

1
Magnetic Resonance Research Center, Yale University, New Haven, CT, USA. jyotsna.u.rao@gmail.com.
2
Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA. jyotsna.u.rao@gmail.com.
3
Magnetic Resonance Research Center, Yale University, New Haven, CT, USA. daniel.coman@yale.edu.
4
Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA. daniel.coman@yale.edu.
5
Magnetic Resonance Research Center, Yale University, New Haven, CT, USA.
6
Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
7
Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
8
Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
9
Magnetic Resonance Research Center, Yale University, New Haven, CT, USA. fahmeed.hyder@yale.edu.
10
Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA. fahmeed.hyder@yale.edu.
11
Department of Biomedical Engineering, Yale University, New Haven, CT, USA. fahmeed.hyder@yale.edu.

Abstract

Gliomas maintain an acidic extracellular pH (pHe), which promotes tumor growth and builds resistance to therapy. Given evidence that acidic pHe beyond the tumor core indicates infiltration, we hypothesized that imaging the intratumoral pHe in relation to the peritumoral pHe can provide a novel readout of therapeutic influence on the tumor microenvironment. We used Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which utilizes chemical shifts of non-exchangeable protons from macrocyclic chelates (e.g., DOTP8-) complexed with paramagnetic thulium (Tm3+), to generate pHe maps in rat brains bearing U251 tumors. Following TmDOTP5- infusion, T2-weighted MRI provided delineation of the tumor boundary and BIRDS was used to image the pHe gradient between intratumoral and peritumoral regions (ΔpHe) in both untreated and temozolomide treated (40 mg/kg) rats bearing U251 tumors. Treated rats had reduced tumor volume (p < 0.01), reduced proliferation (Ki-67 staining; p < 0.03) and apoptosis induction (cleaved Caspase-3 staining; p < 0.001) when compared to untreated rats. The ΔpHe was significantly higher in untreated compared to treated rats (p < 0.002), suggesting that temozolomide, which induces apoptosis and hinders proliferation, also normalizes intratumoral pHe. Thus, BIRDS can be used to map the ΔpHe in gliomas and provide a physiological readout of the therapeutic response on the tumor microenvironment.

PMID:
28801587
PMCID:
PMC5554228
DOI:
10.1038/s41598-017-07609-7
[Indexed for MEDLINE]
Free PMC Article

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