Assessment of glucosylifosfamide mustard biodistribution in rats with prostate adenocarcinomas by means of in vivo 31P NMR and in vitro uptake experiments.
A combined in vitro/in vivo study was performed to evaluate the possible application of phosphorus (31P) NMR spectroscopy for therapy monitoring and to investigate glucosylifosfamide mustard (Glc-IPM) transport and biodistribution by radiotracer techniques. Dynamic in vivo 31P NMR measurements were performed in rats with prostate adenocarcinoma after i.v. injection of 1 mmol/kg body weight (bw) of ifosfamide (IFO) (n = 4) and 1 mmol/kg bw (n = 4) or 2.15 mmol/kg bw (n = 9) of Glc-IPM. In a biodistribution study with 14C-labeled Glc-IPM and a final dose of 0.8 mmol Glc-IPM/kg bw, the animals were killed 5, 30, 60, and 120 min after drug administration, an ethanol extraction was performed from several tissues, and the dose per g tissue was calculated. The same tumor cell line was used in saturation and competition experiments to further elucidate the transport mechanism. The 31P NMR signals of IFO and Glc-IPM showed no overlap with the endogenous phosphorus peaks. A rapid washout with a half-life between 25.9 +/- 5.6 min for the lower dose and 34.3 +/- 4.2 min for the higher dose of Glc-IPM was observed in the tumor. No statistically significant change of the pH value was observed during the examination period. The beta-nucleoside 5'-triphosphate (NTP)/inorganic phosphate (Pi) signal intensity ratio showed a tendency to decrease but without statistical significance. A rapid elimination was demonstrated by both the noninvasive NMR technique and the biodistribution study. No saturation was found in vitro for the Glc-IPM uptake, even at the concentration of 5 mM. Furthermore, the Glc-IPM uptake was not inhibited by the presence of 2-deoxyglucose and vice versa. The data show that the pharmacokinetics of Glc-IPM in the tumor can be followed in vivo by 31P NMR. The results presented are evidence for diffusion as the transport mechanism for Glc-IPM in this tumor model. However, the better visualization of Glc-IPM as compared to ifosfamide may be due to metabolic trapping of a negatively charged metabolite after deglycosylation.
Haberkorn
U
U
Department of Oncological Diagnostics and Therapy, German Cancer Research Center (DKFZ), Heidelberg.
Krems
B
B
Gerlach
L
L
Bachert
P
P
Morr
I
I
Wiessler
M
M
van Kaick
G
G
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D005947:Glucose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution
D018906:Antineoplastic Agents, Alkylating; D011355:Prodrugs; C092028:beta-D-glucosylisophosphoramide mustard; D005947:Glucose; D007069:Ifosfamide