Molecular mechanisms and possibilities of overcoming drug resistance in gastrointestinal tumors.
Primary and acquired resistance of tumor cells to antineoplastic drugs is a major cause of the limited efficiency of chemotherapy. Gastrointestinal (GI) tumors have proven to express cytostatic drug resistance at an unusually high rate. One major reason for this is the multidrug resistant (MDR) phenotype which is often found in carcinomas of the stomach, bile duct, pancreas, liver, and colon. MDR is due to the overexpression of a membrane-bound glycoprotein, the so called P-glycoprotein. However, this is not the only resistance mechanisms of GI tumor cells, but the intracellular compartmentalization of drugs with subsequent release to the microenvironment represents an additional potent mechanism of drug resistance. This is independent of P-glycoprotein and as yet cannot be reversed. Alterations of glutathione-S-transferase (GST) and topoisomerase I and II may be involved either. Analyses of cell lines for cross resistance against a battery of cytostatic drugs suggest even more mechanisms which may contribute to the marked resistance of gastrointestinal cancer. Only a detailed investigation of all different types of drug insensitivity, if ever possible, might offer a chance to fully understand this multifactorial orchestra of events and to develop complex strategies for overcoming drug resistance.
Institut für Pathologie der Charité, Humboldt Universität zu Berlin, Germany.
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D004351:Drug Resistance; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1