A phase I study of the nitroimidazole hypoxia marker SR4554 using 19F magnetic resonance spectroscopy.
BACKGROUND
SR4554 is a fluorine-containing 2-nitroimidazole, designed as a hypoxia marker detectable with 19F magnetic resonance spectroscopy (MRS). In an initial phase I study of SR4554, nausea/vomiting was found to be dose-limiting, and 1400 mg m(-2) was established as MTD. Preliminary MRS studies demonstrated some evidence of 19F retention in tumour. In this study we investigated higher doses of SR4554 and intratumoral localisation of the 19F MRS signal.


METHODS
Patients had tumours > or = 3 cm in diameter and < or = 4 cm deep. Measurements were performed using 1H/19F surface coils and localised 19F MRS acquisition. SR4554 was administered at 1400 mg m(-2), with subsequent increase to 2600 mg m(-2) using prophylactic metoclopramide. Spectra were obtained immediately post infusion (MRS no. 1), at 16 h (MRS no. 2) and 20 h (MRS no. 3), based on the SR4554 half-life of 3.5 h determined from a previous study. 19Fluorine retention index (%) was defined as (MRS no. 2/MRS no. 1)*100.


RESULTS
A total of 26 patients enrolled at: 1400 (n=16), 1800 (n=1), 2200 (n=1) and 2600 mg m(-2) (n=8). SR4554 was well tolerated and toxicities were all < or = grade 1; mean plasma elimination half-life was 3.7+/-0.9 h. SR4554 signal was seen on both unlocalised and localised MRS no. 1 in all patients. Localised 19F signals were detected at MRS no. 2 in 5 out of 9 patients and 4 out of 5 patients at MRS no. 3. The mean retention index in tumour was 13.6 (range 0.6-43.7) compared with 4.1 (range 0.6-7.3) for plasma samples taken at the same times (P=0.001) suggesting (19)F retention in tumour and, therefore, the presence of hypoxia.


CONCLUSIONS
We have demonstrated the feasibility of using 19F MRS with SR4554 as a potential method of detecting hypoxia. Certain patients showed evidence of 19F retention in tumour, supporting further development of this technique for detection of tumour hypoxia.
Lee
C P
CP
Cancer Research UK Centre for Cancer Therapeutics, Cancer Research UK Clinical Magnetic Resonance Research Group and Section of Medicine, The Institute of Cancer Research and Drug Development Unit, The Royal Marsden Hospital, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
Payne
G S
GS
Oregioni
A
A
Ruddle
R
R
Tan
S
S
Raynaud
F I
FI
Eaton
D
D
Campbell
M J
MJ
Cross
K
K
Halbert
G
G
Tracy
M
M
McNamara
J
J
Seddon
B
B
Leach
M O
MO
Workman
P
P
Judson
I
I
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015687:Cell Hypoxia / Q000502:physiology; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D009593:Nitroimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D010100:Oxygen / Q000378:metabolism; D010313:Partial Pressure; D055815:Young Adult
D009593:Nitroimidazoles; C095171:SR 4554; D010100:Oxygen