title: Enhanced uptake of ifosfamide into GH3 prolactinomas with hypercapnic hyperoxic gases monitored in vivo by (31)P MRS.
abstract: Previously, (31)P magnetic resonance spectroscopy (MRS) has been used to detect ifosfamide (IF) in vivo and to show that breathing carbogen (5% CO(2)/95% O(2)) enhances the uptake and increases the efficacy of IF in rat GH3 prolactinomas [Rodrigues LM, Maxwell RJ, McSheehy PMJ, Pinkerton CR, Robinson SP, Stubbs M, and Griffiths JR (1997). In vivo detection of ifosfamide by (31)P MRS in rat tumours; increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas. Br J Cancer 75, 62-68]. We now show that other hypercapnic and/or hyperoxic (5% CO(2) in air, 2.5% CO(2) in O(2)) gas mixtures also increase the uptake of IF into tumors, measured by (31)P MRS. All gases caused an increased uptake (C(max)) of IF compared to air breathing, with carbogen inducing the largest increase (85% (P<.02) compared to 46% with 2.5% CO(2) in O(2) (P<.004) and 48% with 5% CO(2) in air (P<.004)). The T(max) (time of maximum concentration in tumor posintravenous injection of IF) was significantly (P<.04) later in the cohort that breathed 5% CO(2) in air. The increased uptake of IF with carbogen breathing was selective to tumor tissue and there were no significant increases in any of the normal tissues studied, suggesting that any host tissue toxicity would be minimal. Carbogen breathing by patients causes breathlessness. There was no significant difference in IF uptake between breathing carbogen and 2.5% CO(2) in O(2) and, therefore, the ability of 2.5% CO(2) in O(2) to also increase IF uptake may be clinically useful as it causes less patient discomfort.
authors.affiliation: CR UK Biomedical Magnetic Resonance Research Group, Department of Biochemistry and Immunology, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK. lrodrigu@sghms.ac.uk
authors.forename: Loreta M
authors.initials: LM
authors.lastname: Rodrigues
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.forename: Paul M J
authors.initials: PM
authors.lastname: McSheehy
authors.forename: Marion
authors.initials: M
authors.lastname: Stubbs
authors.forename: John R
authors.initials: JR
authors.lastname: Griffiths
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D002245:Carbon Dioxide / Q000008:administration & dosage; D005260:Female; D006935:Hypercapnia / Q000378:metabolism*; D018496:Hyperoxia / Q000378:metabolism*; D007069:Ifosfamide / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy; D010100:Oxygen / Q000008:administration & dosage; D010758:Phosphorus / Q000378:metabolism; D010759:Phosphorus Isotopes / Q000493:pharmacokinetics; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015175:Prolactinoma / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D018906:Antineoplastic Agents, Alkylating; D010759:Phosphorus Isotopes; D002245:Carbon Dioxide; D010758:Phosphorus; C011700:carbogen; D010100:Oxygen; D007069:Ifosfamide