Delivery of aclacinomycin A to human glioma cells in vitro by the low-density lipoprotein pathway.

The present study shows that a human malignant glioma cell line (U-251 MG) accumulates and degrades low-density lipoprotein (LDL) by a saturable, high-affinity process (Km approximately equal to 5 micrograms/ml). Accumulation and degradation could be enhanced by preincubating the cells in a lipoprotein-deficient medium. The LDL degradation rate was highest when the cells were proliferating rapidly. An aclacinomycin A:LDL complex containing 150 to 450 drug molecules per LDL particle could be obtained by incubating LDL with a large excess of aclacinomycin A at 40 degrees. When the glioma cells were incubated with the aclacinomycin A:LDL complex, cellular drug accumulation was dependent on the LDL receptor activity. There are four reasons for drawing this conclusion. (a) U-251 MG cells with high LDL receptor activity accumulated more drug than U-251 MG cells with low LDL receptor activity. (b) U-251 MG cells accumulated more drug than a mutant fibroblast line (GM 1915) lacking LDL receptor activity. (c) Aclacinomycin A accumulation was increased when U-251 MG cells were incubated in the presence of chloroquine, an agent that inhibits LDL degradation. (d) Aclacinomycin A accumulation was reduced when U-251 MG cells were incubated in the presence of either an excess of native LDL or heparin, which has been demonstrated to inhibit receptor-mediated binding and degradation of LDL. The aclacinomycin A:LDL complex also inhibited growth of the glioma cells. Our results suggest that the glioma cells studied have LDL receptors and that it may be possible to use LDL as a vehicle for lipophilic antineoplastic drugs in order to increase the drug accumulation in tumor cell populations with high LDL receptor activity.