The effect of adriamycin and 4'-deoxydoxorubicin on cell survival of human lung tumour cells grown in monolayer and as spheroids.

Using growth delay and clonogenic cell survival as end points, we have shown that the 3-dimensional structure of human lung tumour spheroids confers a degree of resistance to the anthracyclines adriamycin and 4'-deoxydoxorubicin, relative to cells grown as monolayer. 4'-deoxydoxorubicin induces a longer growth delay and greater clonogenic cell kill than adriamycin in spheroids, although it is no more cytotoxic in monolayer (exponential and plateau phase). There is a log linear relationship between clonogenic cell survival and duration of adriamycin exposure in monolayers, and biphasic curve with a lesser degree of cell kill for disaggregated spheroid cells. Using fluorescent microscopy we have demonstrated, qualitatively, that the more lipophilic analogue partitions into the spheroid more rapidly and to a greater degree than adriamycin. It is possible that adriamycin penetration is a relatively important aspect of spheroid drug resistance, which may be related to intraspheroidal pH gradients, and that we have partially overcome this by using a lipophilic analogue.