An investigation of the possibility of chemosensitization by clinically achievable concentrations of misonidazole

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Abstract
Experiments have been carried out both in vitro and in vivo to examine the possibility of chemosensitization by misonidazole (MISO) at concentrations which are achievable in the clinic. Using multicellular tumour spheroids in vitro we found that a 16 h pre-incubation with 100 micrograms ml-1 MISO under hypoxic conditions led to a considerable enhancement of sensitivity to melphalan (MEL) but not to CCNU. Pre-incubation for 16 h under hypoxia alone also produced a degree of sensitization to MEL, but there was no effect of oxic pre-incubation with MISO. in vivo experiments using the KHT or RIF-1 tumours in C3H mice were designed so that repeated administration of MISO maintained blood concentrations of around 100 micrograms ml-1 for either 7 h or 16 h. For the 7 h regime, cytotoxic drugs were administered at the 4 h point. In most experiments the tumour response to MEL, cyclosphosphamide (CTX), chlorambucil or CCNU was no greater in mice receiving multiple MISO than in mice receiving multiple injections of a balanced salt solution. In the occasional experiment where there was an apparent increase in response, the effect was only small (dose modifying factor less than 1.5). For the 16 h regime the effect was studied of administering CTX (100 mg kg-1) at various times during the regime. There was a clear trend towards increased CTX response in mice receiving multiple MISO compared with controls. There was, however, no clear tendency for the effect to increase with length of MISO pre-exposure.