Kinetic resistance to anticancer agents.
Adherent epithelial cancer cells, such as colon cancer cells, are much more resistant to anthracyclines and to many other major anticancer agents when the cell population reaches confluence. Our purpose is to analyze the mechanisms of this confluence dependent resistance (CDR) that is probably the major cause of the natural resistance of solid tumors to chemotherapy. Some drugs (anthracyclines, etoposide and vincristine) but not others (cisplatin, melphalan and 5-fluorouracil) accumulate less in confluent than in nonconfluent cells. A decrease of the passive transmembrane drug transport in confluent cells is associated to a reduced membrane fluidity. However, the predominant mechanism of CDR is an increase in the intrinsic resistance of the DNA to the drug-induced damage. This mechanism is now relatively well understood for anthracyclines and etoposide that act mainly through an inhibition of the topoisomerase II: as the enzyme level is low in slowly proliferating confluent cells, the number of drug-induced DNA strand breaks is lower than in rapidly growing nonconfluent cells which highly express the topoisomerase II gene. Mechanisms of CDR for the other drugs are less clear and could involve an increase in the ability to repair damaged DNA. Attempts to circumvent CDR could consist in the stimulation of the cell proliferation by hormones or growth factors, or in the recruitment of quiescent cells into the S and G2 phases by previous treatment of confluent cells with infratoxic concentration of DNA-damaging agents.
Dimanche-Boitrel
M T
MT
INSERM 252, Faculty of Medicine, Dijon, France.
Garrido
C
C
Chauffert
B
B
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D001692:Biological Transport; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity; D004249:DNA Damage; D004351:Drug Resistance; D006801:Humans; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002945:Cisplatin