Preclinical evaluation of the fluorinated 2-nitroimidazole N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR-4554) as a probe for the measurement of tumor hypoxia.
A novel probe, N-(2-hydroxy-3,3,3,-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR-4554), has been used to detect tumor hypoxia noninvasively by 19F magnetic resonance spectroscopy (19F MRS). The compound was designed to undergo a hypoxia-dependent, one-electron reduction to metabolites that are selectively retained in tumors and has attractive pharmacokinetic, toxicological, and detection sensitivity properties. As a prelude to clinical studies, we report here for the first time on the ability to detect a MR signal following SR-4554 administration in various transplantable tumors and describe validation studies, consisting of a correlation between signal retention and radiobiological hypoxic fraction, and the effects of modulating the degree of hypoxia by hydralazine and carbogen breathing. SR-4554 was absorbed and then eliminated from EMT6 tumors with a half-life of 51 min following an injection of 180 mg/kg i.p. of SR-4554. Using a quantitative 19F MRS technique, the 19F retention index (19FRI; 19F signal level at 6 h/45 min) was determined for four commonly used murine tumors (EMT6, SCCVII, KHT, and RIF-1). The retention of high tumor concentrations of fluorinated probe at 6 h, despite the much lower (20-fold) concentration of parent SR-4554 detected by high-performance liquid chromatography, was consistent with the involvement of one or more nitroreduced metabolites and suggested that 19F MRS might give a quantitative measure of tumor hypoxia. In these murine tumors, 19FRI correlated with the reported radiobiological hypoxic fraction of the tumors (r = 0.988; P = 0.01). In addition, changes in tumor microenvironment were detected by 19F MRS. An increase in hypoxia induced by hydralazine treatment of RIF-1 tumor-bearing mice was associated with a 2.4-fold increase in 19FRI compared to untreated controls. In contrast, carbogen breathing by C3H mammary tumor-bearing mice produced a 6-fold decrease in the 19FRI compared to air-breathing mice. The data presented support the preclinical and clinical development of SR-4554 as a noninvasive probe for tumor hypoxia.
Aboagye
E O
EO
Department of Medical Oncology, Beatson Laboratories, Glasgow, United Kingdom.
Maxwell
R J
RJ
Kelson
A B
AB
Tracy
M
M
Lewis
A D
AD
Graham
M A
MA
Horsman
M R
MR
Griffiths
J R
JR
Workman
P
P
D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology; D015687:Cell Hypoxia; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D005260:Female; D005461:Fluorine / Q000032:analysis; D006830:Hydralazine / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology; D015203:Reproducibility of Results
D009593:Nitroimidazoles; D002245:Carbon Dioxide; D006830:Hydralazine; D005461:Fluorine; C011700:carbogen; C095171:SR 4554; D010100:Oxygen