Pharmacokinetics and metabolism of the mixed-function hypoxic cell sensitizer prototype RSU 1069 in mice

Summary The acute toxicity, pharmacokinetics and hypoxic cytotoxicity of RSU-1069 were investigated using the subcutaneous (sc) rat 9L tumour model. The pharmacokinetics were studied after i.p. injection of RSU-1069 (20mgkg-' or 100mgkg-'). For both doses, the elimination of RSU-1069 followed first-order kinetics in both plasma and unclamped tumours. After 100mgkg-', the peak plasma concentration of RSU-1069 was 40 lgml-'; the elimination ti was 39.3± 11.lmin. After 20mgkg', the peak plasma concentration was 3 pg ml-'; the elimination 4 was 47.8 ± 6.3 min. In unclamped tumours, the peak concentration was 50 jig g -' with an elimination 4 of 36.1 ± 9.6 min for the 100 mg kg -' dose, and 4 tg g-with an elimination 4 of 41.9 ± 6.1 min for the 20 mg kg-' dose. The tumour and plasma elimination half-times were not significantly different (P> 0.2) for the two doses. Clamping the tumour 30 min after administration of 100mg kg-' of RSU-1069 decreased the tumour elimination t to 10.9 ± 1.4 min. After releasing the clamp, RSU-1069 returned rapidly to the unclamped tumour concentration. The unclamped tumour/plasma ratio reached a maximum of 4-6, then decreased to a constant value of about 2 for both doses, indicating that RSU-1069 accumulates in these 9L tumours. RSU-1069 kills hypoxic sc 9L cells more efficiently than oxic sc 9L cells; at a surviving fraction of 0.5, the SER was 4.8. For in vitro 9L cells, the SER was ; 50 when the comparison was between those treated in 2.1% 02 and those treated in <7.5 x 10 3% 02; it was ; 100 when the comparison was between those treated in 21% 02 and those treated in <7.5 x 10-3% 03. Tumours treated with RSU-1069 and clamped for various times exhibited biphasic cell-kill kinetics; at 50mg kg-', little additional cell kill was achieved after 40 min of clamping. Our data also indicate that RSU-1069 is 300-1000 fold more efficient than misonidazole or SR2508 for killing hypoxic sc9L tumour cells in situ.

Section: Pharmacokineticscontrasting

confidence: 99%

Section: Rsu-1069 Pharmacokineticsmentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics and cytotoxicity of RSU-1069 in subcutaneous 9L tumours under oxic and hypoxic conditions

Wong

Koch²,

Wallen³

et al. 1991

“…Hypoxia was induced at the time at which the tumour concentrations of bioreductive drug would be expected to be maximal, Miso was given 60 min before (McNally et al, 1978) and RSU1069 (Walton & Workman, 1988;Walling et al, 1989) and SR4233 (Zeman et al, 1988) 15 min before the induction of hypoxia. MMC was also given 15 min before, so as to allow comparison with SR4233 and RSU1069.…”

Section: Methodsmentioning

confidence: 99%

Bioreductive drugs and the selective induction of tumour hypoxia

Bremner

Stratford²,

Bowler³

et al. 1990

Summary In this work tumour hypoxia is induced by physically occluding the tumour vascular supply by clamping, or by giving mice 5 mg kg-' hydralazine. These methods have previously been shown to increase the radiobiological hypoxic fraction in tumours close to 100%. Their effectiveness in potentiating the bioreductive toxicity of: misonidazole (800 mg kg-'), RSU1069 (80 mg kg-'), mitomycin C (5 mg kg-') and SR4233 (50 mg kg-') is assessed in the RIF-1 and KHT tumours using regrowth delay as an assay. Clamping alone for 120 min gives little or no response, but when RSU1069 is administered 15 min before clamping, large growth delays result. RIF-1 tumours clamped for 90 or 120 min with RSU1069 give cure rates of 12.5% and 37.5% respectively. Less effect with clamping is seen for the other bioreductive agents. The effect of hydralazine with RSU1069 although significant in the RIF-1 tumour, is modest compared to that for clamping. Small enhancements of toxicity are seen with hydralazine in combination with misonidazole in the RIF-1 tumour and mitomycin C in both tumours. The varying effectiveness of these treatments is attributed to several factors which include the level and duration of hypoxia, concentration and contact time of the bioreductive drugs, the microenvironment of the tumour and the nature of the reductive metabolic pathways available in the different tumour cell types.

“…RB6145 is completely converted to its active product RSU1069 within minutes of administration in vivo (Jenkins et al, 1990), and the plasma half-life of RSU1069 is about 20 min in C3H mice (Walton and Workman, 1988;Binger and Workman, 1990). It is thought that RSU1069 would reach its maximum tumour concentration within 15 min of administration, hence any interference with tumour blood supply thereafter would not only create hypoxia but also prevent efflux of the drug from the tumour, thereby enhancing tumour toxicity (Bremner et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of bioreductive drug toxicity in murine tumours by inhibition of the activity of nitric oxide synthase

Butler

Wood²,

Cole³

et al. 1997

Summary Nitro-L-arginine inhibits the production of nitric oxide and can thereby cause vasoconstriction in vivo. One consequence of this is that nitro-L-arginine can increase hypoxia in a range of transplantable and spontaneous murine solid tumours. Bioreductive drugs such as RB6145 are more active under hypoxic conditions, and the combination of RB6145 with nitro-L-arginine in vivo shows greater anti-tumour activity than either agent individually. In mice given nitro-L-arginine at 10 mg kg-' i.p. up to 1 h before or after 300 mg kg-' i.p. RB6145, survival of KHT tumour cells was reduced by 3-4 logs when assessed by clonogenic assay 24 h after treatment. RB6145 or nitro-L-arginine alone caused no more than 20% cell kill. Similar effects were found in SCCVII tumours. The tumour response to the drug combination was tumour size dependent, with increased tumour cell sensitivity occurring when the tumour volume at the time of treatment was increased. Further, the response of KHT tumours to the combination of RB6145 and nitro-L-arginine was also dependent on the time interval between treatment and on when tumours were excised for determination of survival in vitro. The relative surviving fraction was about 0.3 for intervals less than 4 h but was reduced to 0.01 at 12 h and 0.001 at 24 h. These results were supported by histological examination of tumours, when necrosis at 2 h after treatment was less than 5% but increased to greater than 90% at 24 h. RB6145-induced normal tissue damage, as measured by CFU-A survival, was not altered by combining with nitro-L-arginine. Hence, this drug combination may provide therapeutic benefit. It is likely that the substantial anti-tumour effects are due to enhancement of bioreductive toxicity through increased tumour hypoxia, although additional mechanism(s) may also contribute to the overall response.