Abstract
The effect of Nicotinamide and/or treatment with Fluosol DA and Carbogen breathing on the radiation response of 500-750 mg SCCVII and KHT tumours has been evaluated. Pretreatment with Fluosol DA/Carbogen or Nicotinamide resulted in relatively modest enhancements of radiation damage with enhancement factors of 1.1 and 1.3 being observed using an in vivo/in vitro clonogenic end-point. A combination of Nicotinamide and Fluosol DA/Carbogen resulted in a larger enhancement factor of 1.6 over the radiation dose ranges studied. These modification factors reflect a value close to that expected for a fully aerobic response in this survival range. Growth delay studies in the SCCVII tumour provided similar results. Using a recently developed fluorescence activated cell sorting technique, which utilizes the in vivo pharmacokinetic and DNA binding properties of the bisbenzamide stain Hoechst 33342, the effect of Nicotinamide and/or Fluosol DA/Carbogen schedules on the occurrence of acute hypoxia was assessed. The results clearly show that Nicotinamide significantly reduces the amount of 'acute hypoxia', but has a lesser effect on 'chronic' hypoxic cells. However, combinations of Nicotinamide and Fluosol DA/Carbogen significantly increase the response of both 'acutely' and 'chronically hypoxic' cells. The results provide evidence that a combination of Nicotinamide and Fluosol DA/Carbogen can provide an effective way of reoxygenating both acutely and chronically hypoxic cells.
Highlights
As a consequence of this finding, we have evaluated the effect of a strategy in which Fluosol DA and Carbogen is given together with Nicotinamide
From the same figure it can be seen that administering Fluosol DA and breathing Carbogen for 60 min prior to and during irradiation results in an increased radiation response with an EF
Combination of the two modalities results in a greater enhancement of radiation response and is consistent with a dose modification factor of between 1.5 and 2.0. Subsequent to these studies we extended our investigation to evaluate the effects of Nicotinamide and/or Fluosol DA/ Carbogen on the radiation response of the KHT sarcoma
Summary
SCCVII or KHT tumour cells obtained by enzyme disaggregation were implanted subcutaneously over the sacral region of the back in 6-9 week old female C3H/He mice (Charles River Inc., Quebec, Canada). Tumours were used in the size range 500-750mg for in vivo/in vitro assays and 500-550mg for growth delay studies. The drug was dissolved in sterile phosphate-buffered saline (PBS) and administered intraperitoneally (i.p.) at a dose of 1.0mgg'. An aliquot of the stem emulsion was thawed prior to each experiment and physiological osmolarity was attained by addition of annex solution. Details of the composition of stem emulsion and annex solution have been described previously (Teicher et al, 1989). The resulting emulsion was injected intravenously (i.v.) via the lateral tail vein at a dose of 0.01 ml g-' mouse weight
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