title: In vivo detection of ifosfamide by 31P-MRS in rat tumours: increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas.
abstract: The direct detection and monitoring of anti-cancer drugs in vivo by magnetic resonance spectroscopy (MRS) may lead to improved anti-cancer strategies. 31P-MRS has been used to detect and quantify ifosfamide (IF) in vivo in GH3 prolactinomas and N-methyl-N-nitrosourea (MNU)-induced mammary tumours in rats. The average concentration of IF in the GH3 prolactinoma over the first 2 h following a dose of 250 mg kg-1 i.v. was calculated to be 0.42 micromol g-1 wet weight, with a half-life of elimination (t1/2) of 2-4 h. Carbogen (95% oxygen/5% carbon dioxide) breathing increased the amount of IF taken up by the GH3 prolactinoma by 50% (P<0.01) to 0.68 micromol g-1 wet weight, although t1/2 elimination rates were unchanged. IF was also detected in the liver in vivo, with a t1/2 of about 1 h. Carbogen breathing did not affect the maximum peak area (Cmax) or the t1/2 in the liver. Most importantly, the carbogen-induced increase in IF uptake by the tumour caused significant growth delay at all time points in the GH3 tumour growth between day 5 and day 12 (P< 0.01) compared with IF alone. These findings show that carbogen breathing has potential for increasing the efficacy of anti-cancer drugs. Isolated GH3 cells were sensitive to the parent drug (IF) in vitro (IC50 = 1.3 +/- 0.2 mM) suggesting that the GH3 cells may be either expressing P450 enzymes or are sensitive to the parent drug per se.
authors.affiliation: CRC Biomedical Magnetic Resonance Research Group, St George's Hospital Medical School, London, UK.
authors.forename: L M
authors.initials: LM
authors.lastname: Rodrigues
authors.forename: R J
authors.initials: RJ
authors.lastname: Maxwell
authors.forename: P M
authors.initials: PM
authors.lastname: McSheehy
authors.forename: C R
authors.initials: CR
authors.lastname: Pinkerton
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
authors.forename: M
authors.initials: M
authors.lastname: Stubbs
authors.forename: J R
authors.initials: JR
authors.lastname: Griffiths
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000032:analysis / Q000493:pharmacokinetics*; D002245:Carbon Dioxide / Q000008:administration & dosage; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D005260:Female; D007069:Ifosfamide / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D010100:Oxygen / Q000008:administration & dosage; D010758:Phosphorus / Q000378:metabolism; D010759:Phosphorus Isotopes; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000378:metabolism; D015175:Prolactinoma / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D010759:Phosphorus Isotopes; D002245:Carbon Dioxide; D010758:Phosphorus; C011700:carbogen; D010100:Oxygen; D007069:Ifosfamide