Development of resistance and characteristics of a human colon carcinoma subline resistant to mitoxantrone in vitro.

A subline of human colon carcinoma cells (WiDr/R) resistant to the cytotoxic effects of mitoxantrone in vitro, was developed by continuous exposure to increasing concentrations of drug. After 16 culture passages in the presence of mitoxantrone, a cell population emerged which was 30-40 times more resistant to the cytolytic effect of mitoxantrone than the mitoxantrone-sensitive parent (WiDr/S) line. Resistance to mitoxantrone was retained by WiDr/R cells propagated for more than 40 cell generations in mitoxantrone-free medium. Decreased drug sensitivity was strongly associated with reduced intracellular accumulation of mitoxantrone. Moderate differences in drug retention by sensitive and resistant cells were demonstrated. However, decreased uptake due to alterations at the cell membrane which impair transport of drug into the cell, reducing interaction with DNA, appears to be the principal basis of resistance in these cells.