Enhanced Uptake of Ifosfamide into GH3 Prolactinomas with Hypercapnic Hyperoxic Gases Monitored In Vivo by 31P MRS

Abstract

Previously, 31P magnetic resonance spectroscopy (MRS) has been used to detect ifosfamide (IF) in vivo and to show that breathing carbogen (5% CO2/95% O2) 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 31P 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% CO2 in air, 2.5% CO2 in O2) gas mixtures also increase the uptake of IF into tumors, measured by 31P MRS. All gases caused an increased uptake (Cmax) of IF compared to air breathing, with carbogen inducing the largest increase (85% (P<.02) compared to 46% with 2.5% CO2 in O2 (P<.004) and 48% with 5% CO2 in air (P<.004)). The Tmax (time of maximum concentration in tumor posintravenous injection of IF) was significantly (P<.04) later in the cohort that breathed 5% CO2 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% CO2 in O2 and, therefore, the ability of 2.5% CO2 in O2 to also increase IF uptake may be clinically useful as it causes less patient discomfort.

Keywords

• fosfamide
• 31P MRS
• pharmacokinetics
• hypemapnia
• hyperoxia