Sensitivity of multidrug resistant KB-C1 cells to an antibody-dextran-adriamycin conjugate

Resistance to adriamycin is an important limitation to the use of the drug in cancer therapy. This resistance is often a manifestation of the multidrug resistance phenotype. Studies with multidrug resistant cell lines in vitro may be useful to design approaches for overcoming the drug resistance encountered clinically. We investigated the possibility of overcoming adriamycin resistance in vitro in a multidrug resistant subline (KB-C1) of human epidermal carcinoma (KB-3-1) cells using antibody-mediated drug targeting. Adriamycin was conjugated through a dextran bridge to a monoclonal antibody (mAb), 10B, which bound to KB-3-1 cells with a Ka of 4 x 10(8) M-1. The conjugate retained immunoreactivity with the target cells. Adriamycin (0.2 micrograms/ml) caused a 50% inhibition of DNA synthesis in KB-3-1 cells, but failed to achieve this degree of inhibition in KB-C1 cells at levels as high as 10 micrograms/ml. In contrast, the 10B-dextran-adriamycin conjugate produced 50% inhibition of DNA synthesis in KB-C1 cells at a concentration of 2.5 micrograms/ml. This was significantly more cytotoxic than adriamycin conjugated to control mAb or bovine serum albumin (BSA). Similarly, a 10B-recombinant ricin A (rRA) immunotoxin was more cytotoxic to KB-C1 cells than free rRA. These results indicate that adriamycin resistance in KB-C1 cells in vitro can be partially overcome by specifically targeting adriamycin to the cells using an 10B-dextran-adriamycin conjugate. This approach may be useful in overcoming adriamycin resistance encountered during the course of cancer therapy.