In vivo detection of ifosfamide by 31P-MRS in rat tumours: increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas

Abstract

SummaryThe 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-Nnitrosourea (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-' i.v. was calculated to be 0.42 ,umol g-1 wet weight, with a half-life of elimination (t,,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 ,umol g-1 wet weight, although t,,2 elimination rates were unchanged. IF was also detected in the liver in vivo, with a t,,c of about 1 h. Carbogen breathing did not affect the maximum peak area (Cmax) or the t,,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 (C~50 = 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.

Correlation between 5-fluorouracil metabolism and treatment response in two variants of C26 murine colon carcinoma

“…However, we do not have appropriate 31 P-MRS data to address this point for C26. It is known that the effect of carbogen may depend on tumour characteristics such as type, size, vascularisation, perfusion, and pH (Rodrigues et al, 1997), but we do not yet have detailed information concerning oxygenation or pH status for the C26 tumours. Furthermore, it may be necessary to extend the carbogen breathing period to account for the resorption delay associated with i.p.…”

Investigations in vivo of the effects of carbogen breathing on 5-fluorouracil pharmacokinetics and physiology of solid rodent tumours

“…In the GH3 prolactinoma grown in syngeneic rats, carbogen increased the maximum concentration of ifosfamide (C max ) in the tumour by 60% and although time for drug elimination (t 1/2 ) was unchanged, the area under the concentration-time curve (AUC) was significantly increased. Uptake and retention of ifosfamide by the liver [31] and other normal tissues were unchanged [29] showing that the effect of carbogen was selective for tumours. In mouse RIF-1 fibrosarcomas grown in syngeneic mice, carbogen decreased the rate of elimination of 5-fluorouracil (5FU) by 30%, and caused increased 5FU uptake and activation, although the latter effect only occurred in tumours which were considered hypoxic due to high retention of a nitroimadazole [19].…”

“…Breathing carbogen (95% O 2 , 5% CO 2 ) by rats and mice has been shown to increase the uptake of anticancer drugs by solid tumours [13,19,31,32]. In the GH3 prolactinoma grown in syngeneic rats, carbogen increased the maximum concentration of ifosfamide (C max ) in the tumour by 60% and although time for drug elimination (t 1/2 ) was unchanged, the area under the concentration-time curve (AUC) was significantly increased.…”

“…The pharmacokinetic analysis showed that carbogen increased the rate of tumour uptake of 5FU from the plasma but also increased the rate of removal. 31 P-MRS showed there were significant (p £ 0.02) increases in the hepatoma NTP/Pi ratio of 49% and transmembrane pH gradient of 0.11 units. Conclusions: We suggest that carbogen can transiently increase tumour blood flow, but this effect alone may not increase uptake of anticancer drugs without a secondary mechanism operating.…”

“…Physiological effects of carbogen on tumours were studied using 31 P-MRS for energy status (NTP/Pi) and pH, and gradient-recalled echo magnetic resonance imaging (GRE-MRI) for blood flow and oxygenation. Results: In both tumour models, carbogan-induced GRE-MRI signal intensity increases of $60% consistent with an increase in tumour blood oxygenation and/or flow.…”