[Therapeutic approach against drug-resistant tumors and their biochemical nature].

One of the major causes of failure of cancer chemotherapy is the proliferation of specific drug-resistant tumor cells during treatment. Drug-resistant tumor cells, however, usually bear biochemical changes which are related to the resistance mechanisms. New modalities against resistant cells could be possible if we were able to characterize these biochemical changes. Vincristine (VCR)- and adriamycin (ADM)-resistant tumor sublines show cross-resistance (pleiotropic drug resistance) to other unrelated drugs. VCR- and ADM-resistant sublines possess an enhanced outward transport of antitumor agents, which results in a low accumulation of antitumor agents in the cells. The cells express unique glycoproteins in the plasma membrane, and possess a higher calcium content in the cells. They also have double-minute chromosomes and homogeneously staining regions in chromosomes. By targeting for these biochemical changes, we have established new modalities against drug-resistant tumor cells. Calcium channel blockers inhibited the enhanced outward transport of VCR and ADM from resistant tumor cells, and thus overcame resistance to these agents. This approach showed potential usefulness in clinical trials. Another possible approach against drug-resistant tumor cells could be the utilization of monoclonal antibodies against unique glycoproteins in the plasma membrane of resistant tumor cells. We have developed monoclonal antibodies against adriamycin-resistant human myelogenous leukemia K562. Our recent progress with work on calcium channel blockers and monoclonal antibodies are discussed in this paper.