Multidrug resistance mediated by P-glycoprotein in haematological malignancies.
The phenomenon that a tumour, resistant to a cytotoxic drug, is also resistant to a large number of other drugs used in cancer chemotherapy, is called multidrug resistance. A transmembrane protein, known as P-glycoprotein (P-gp), is involved in this resistance pattern. P-gp is able to pump large, lipophilic molecules out of the cell. 'Naturally occurring' drugs such as the anthracyclines and the Vinca alkaloids meet these criteria. To study the future clinical implications of multidrug resistance, we have gathered data in the literature on the presence of P-gp in haematological malignancies. At diagnosis 14-62% of all patients showed P-gp expression. Of previously treated patients 29-62% was positive for P-gp. A slight tendency to find a higher frequency of P-gp positivity in these previously treated patients was observed (so-called 'acquired resistance'). Early mutation and selection by the cytotoxic drug could account for the higher levels in treated patients. Chemotherapy itself could induce the expression of the P-gp pump. With the use of in vitro work various pharmacological agents have been found that can antagonize P-gp's function. Using these agents in clinical trials, some refractory patients showed a response to chemotherapy. We conclude that P-gp is probably just one of many causes of drug resistance in patients with haematological malignancies. Clinical results in some studies look promising, but many problems have still to be solved before common use.
Pasman
P C
PC
Department of Internal Medicine, University Hospital, Maastricht, Netherlands.
Schouten
H C
HC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D003524:Cyclosporins / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics*; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D002147:Calmodulin; D002352:Carrier Proteins; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D013629:Tamoxifen