Possible relationship between pyrido-pyrrolo-isoquinoline derivative (BD-40) cell uptake and cell viability.

BD-40 is a pyrido-pyrrolo-isoquinoline derivative which possesses an heterocyclic nucleus very closely related to ellipticine and a diethylaminopropyl amino lateral chain (Rivalle et al., 1979). Cellular effects of the drug have been studied. Viability and morphology of the cells were irreversibly impaired by 24 hours drug treatments at concentrations exceeding 0.10 micro M. Spectrofluorimetric determinations of the drug repartition between cytoplasm and nucleus showed that 10 per cent of BD-40 was found in the nucleus for external drug concentrations lower than 0.10 micro M. On the other hand, for cytotoxic doses exceeding 0.10 micro M, 40 to 50 per cent of the total intracellular BD-40 were found in the nuclear fraction. Although possible exchange phenomena during the course of the cell fractionation cannot be excluded, these results suggest that a direct relationship exists between BD-40 nuclear content and cell lethality. Comparisons of intracellular drug contents in the absence and the presence of a metabolic inhibitor, sodium azide, indicated that drug content of azide-treated cells was approximately twice that of untreated cells. Besides, sodium azide blocked the release of the drug when previously loaded cells were placed in BD-40-free medium. These results are in agreement with the existence of an active outward transport (efflux), which is sodium azide-sensitive.