Water diffusion in a rat glioma during ganciclovir-thymidine kinase gene therapy-induced programmed cell death in vivo: correlation with cell density.
OBJECTIVE
To study the characteristics of diffusion magnetic resonance imaging (MRI) contrast in a rat brain BT4C glioma during progression of ganciclovir (GCV)-thymidine kinase gene therapy-induced programmed cell death (PCD) in vivo.


METHODS
The trace of the diffusion tensor (Dav = 1/3TraceD), T2, and spin density were determined by MRI and the apparent diffusion coefficient (ADC) of water by diffusion nuclear MR (NMR) spectroscopy using largely varying b values and diffusion times (tD) at 4.7 T. Cell count and apoptotic cells were quantified by histological means.


RESULTS
Decline in cell count was strongly associated with increase in both Dav and T2. Spin density ratio between tumor and contralateral parietal cortex increased with a very similar time course as Dav and T2, indicating net water gain into the eradicating tumor. Diffusion spectroscopy showed a nonmonoexponential signal decay at all tD values ranging from 14-192 msec. During PCD, the ADC of the component yielding fast diffusion coefficient (D1), as acquired with tD > or = 47 msec, increased with kinetics similar to those of Dav (tD = 4.8 msec). The fractional size of D1 increased by 10% to 15% throughout the entire tD range. Apparent water residence time of the slow diffusion component, D2, shortened from a value of 38.3 +/- 1.7 msec on day 0 to 33.4 +/- 0.5 msec by day 8.


CONCLUSIONS
The present results show that reduced cell density and increased water content, leading to altered water microenvironment, are associated with increased water diffusion coefficient in eradicating gliomas as a result of PCD.
Valonen
Piia K
PK
Department of Biomedical NMR and National Bio-NMR Facility, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.
Lehtimäki
Kimmo K
KK
Väisänen
Tuula H
TH
Kettunen
Mikko I
MI
Gröhn
Olli H J
OH
Ylä-Herttuala
Seppo
S
Kauppinen
Risto A
RA
D000818:Animals; D017209:Apoptosis; D001834:Body Water / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D002452:Cell Count; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy; D005910:Glioma / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D006561:Herpes Simplex / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D011919:Rats, Inbred Strains; D013937:Thymidine Kinase / Q000235:genetics*; D014162:Transfection
D013937:Thymidine Kinase; D015774:Ganciclovir