Possible link between the intrinsic drug resistance of colon tumors and a detoxification mechanism of intestinal cells.
The insensitivity of colon tumors to various anticancer agents was studied in vitro. The activity of Adriamycin (ADR) in several colon tumor cell lines was potentiated by the calcium channel blocker verapamil (VER). In the HCT-8 human colon adenocarcinoma cell line, VER potentiation of the activities of ADR and the anthrapyrazole CI-937 appeared to be related to its ability to enhance the net accumulation of both drugs and inhibit their efflux. VER, which potentiated ADR activity in HCT-8 cells by 4-fold, caused a 3.5-fold stimulation of ADR accumulation and 3.5-fold inhibition of ADR efflux, when compared to non-VER-treated cells. The low level of VER potentiation of CI-937 activity in HCT-8 cells (1.4-fold) was also reflected in CI-937 transport studies which demonstrated a 1.5-fold enhancement of CI-937 accumulation and a 1.4-fold inhibition of its efflux. VER was also found to stimulate ADR activity and accumulation in a normal small intestinal crypt cell line (IEC-6). The mechanism of drug efflux was examined in HCT-8 cells. Agents known to increase the permeability of the plasma membrane did not alter ADR accumulation or its efflux in HCT-8 cells unless these same agents were also capable of interacting with the lysosome. Tween 80 and the lysosomotropic detergent Triton WR-1339 as well as proton ionophores and lysosomotropic amines all stimulated ADR uptake and/or inhibited its efflux from HCT-8 cells. ADR efflux was also partially blocked by cytochalasin B. Based on these observations, we suggest that at least part of the inherent drug resistance of colon tumor cells results from the retention of an enhanced drug efflux mechanism which is found in normal intestinal epithelium where this property may provide protection from plant alkaloids and other xenobiotic agents ingested in the diet. The mechanism of this drug efflux from HCT-8 cells may involve drug partitioning into acidic vesicles within the cell and their subsequent release from these cells by exocytosis.
Klohs
W D
WD
Department of Chemotherapy, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Steinkampf
R W
RW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008658:Inactivation, Metabolic; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D014700:Verapamil / Q000494:pharmacology
D000970:Antineoplastic Agents; D014700:Verapamil