Monitoring the effect of mild hyperthermia on tumour hypoxia by Cu-ATSM PET scanning.
OBJECTIVE
Mild hyperthermia can improve tumour oxygenation and enhance radiosensitivity. Imaging the hypoxic fraction of a tumour can guide hyperthermia treatment planning and facilitate treatment optimization. 64Cu-ATSM (Copper-diacetyl-bis(N4-methylthiosemicarbazone)) is a positron emitting compound that has been demonstrated to have rapid uptake and selective retention in hypoxic cells and has been used for imaging human and animal tumours. The purpose of the present report is to establish methodology that will allow one to use Cu-ATSM PET scanning to detect the impact of hyperthermia on tumour physiology in as little time as possible.


METHODS
EMT6 tumours (mouse mammary carcinoma) were implanted into the subcutaneous tissue of both thighs of 10 BALB/c mice (one heated, one control tumour per animal). The target thermal dose was 41.5 degrees C x 45 min. Without interrupting heating, 64Cu-ATSM (mean activity 1.8 mCi) was then injected and serial PET scans were obtained. In a sub-group of four animals, a low administered activity (approximately 0.3 mCi) 64Cu-ATSM scan was also conducted before heating to permit a direct comparison of the effects of hyperthermia on the same tumours. In another sub-group of five animals, a low activity (approximately 0.3 mCi) 64Cu-PTSM (pyruvaldehyde-bis(N*-methylthiosemicarbazone)) scan was conducted before heating, to confirm a posited correlation between perfusion and early 64Cu-ATSM uptake.


RESULTS
This study corrected for perfusion differences by dividing tumour uptake by the average early (first minute) uptake ('self-normalized uptake'). The 10 heated tumours showed a significantly (p = 0.007) lower self-normalized uptake than control tumours by 2 min. For the four mice with low activity Cu-ATSM scans performed before hyperthermia, the tumours to be heated demonstrated self-normalized uptake consistent with the unheated control tumours and which departed significantly (p < or = 0.02) from their post-hyperthermia scans by 5 min. Comparisons between scans and needle electrode surveys were performed in an additional four animals with eight tumours. For technical reasons electrode surveys were done after the end of hyperthermia-and, therefore, these animals also had comparison scans taken after hyperthermia. Reduced self-normalized uptake on scans was associated with increased pO2 on electrode surveys. These data also suggested a substantial degradation of the effect on tumour hypoxia by approximately 15-45 min after the end of mild hyperthermia.


CONCLUSIONS
Short imaging times of approximately 5 min with modest (approximately 4-10) numbers of mice can discriminate the effects of mild hyperthermia on tumour physiology. The long-term objective is to use this tool to identify as short and mild a hyperthermia session as possible.
Myerson
Robert J
RJ
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA. myerson@radonc.wustl.edu
Singh
Anurag K
AK
Bigott
Heather M
HM
Cha
Bibiana
B
Engelbach
John A
JA
Kim
Joonyoung
J
Lamoreaux
Wayne T
WT
Moros
Eduardo
E
Novak
Petr
P
Sharp
Terry L
TL
Straube
William
W
Welch
Michael J
MJ
Xu
Mai
M
D000818:Animals; D045744:Cell Line, Tumor; D056831:Coordination Complexes; D004566:Electrodes; D005260:Female; D006979:Hyperthermia, Induced; D000860:Hypoxia / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology; D015674:Mammary Neoplasms, Animal / Q000000981:diagnostic imaging* / Q000503:physiopathology / Q000628:therapy*; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds; D010100:Oxygen; D049268:Positron-Emission Tomography / Q000379:methods*; D013882:Thiosemicarbazones; D013997:Time Factors
D056831:Coordination Complexes; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); C052629:copper pyruvaldehyde bis(N(4)-methylthiosemicarbazone) complex; D010100:Oxygen