Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased by combination with ionising radiation or
chemotherapy. Various parameters such as
oxygen tension and timing of administration of the drugs could play a crucial role in the efficacy of combined treatment modalities. The aim of this study was to define the
oxygen dependency of cell survival after in vitro irradiation and incubation with
tirapazamine, a bioreductive
drug, and
cisplatin given alone or simultaneously. Two human cell lines were studied: one cell line sensitive to
tirapazamine, Na11+, a pigmented
melanoma with a high percentage of hypoxic cells, and a less sensitive cell line to
tirapazamine, HRT18, a rectal
adenocarcinoma. Gas changes were made to study cell survival at four different
oxygen concentrations (pO2): air (20.9% O2), 10.2 and 0.2% O2. Cells were incubated with
tirapazamine and
cisplatin alone or combined for one hour at 37 degrees C, then irradiated and cultured. For Na11+, cell survival after irradiation was comparable in air and
at 10%
oxygen with the two drugs given alone or combined. At 2 and 0.2%
oxygen, cell killing was largely increased by
tirapazamine and was not modified by the addition of
cisplatin. For HRT18, cell survival was not modified when
cisplatin was added to radiation, whatever the
oxygen partial pressure. At low pO2 (2 and 0.2%) the cytotoxic effect of
tirapazamine was not significantly decreased by the addition of
cisplatin. When cytotoxic and bioreductive drugs are combined to radiation, the magnitude of the observed effect is highly dependent on the partial
oxygen pressure and on the sensitivity of the cell line to the individual drugs. This has very important implications for clinical strategies based on combined chemo-
radiotherapy.