In vitro and in vivo studies indicate that while activated NDPP is an efficient sensitizer of hypoxic mammalian cells in vitro, far better than Ro-07-0582 on a molar basis, the situation is reversed in vivo. Determinations of uptake of radioactive drug indicate that activated NDPP is capable of rapidly accumulating in mammalian cells, but no such effect is seen with Ro-07-0582. The uptake of activated NDPP shows a strong dependence on the cell density, whereas the uptake of Ro-07-0582 is little affected by cell density. These results suggest that the high sensitizing efficiency of activated NDPP is due to its ability to be concentrated by cells in a form which is still capable of sensitization and that the cell density effect is largely due to the depletion of the activated form or forms of NDPP. Evidence is also presented that activated NDPP reacts with cellular constituents, notably sulfhydryl compounds, and that the reaction with glutathione produces a compound which is capable of hypoxic cell sensitization. Such reaction products, which are resistant to washing, may explain the pretreatment sensitization produced by activated NDPP.

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