Multidrug resistance in leukaemia.
Multidrug resistance hampers successful chemotherapy in many haematological neoplasms and is mediated by several cellular proteins. In some cases, the genes encoding these proteins have been shown to confer resistance on transfer to drug-sensitive cell lines. This is true for the efflux pump product of the MDR1 gene, P-170. Upregulation of enzymes such as GST has been observed, although the contribution of this enzyme in drug resistance expressed by malignant haematopoietic cells is still uncertain. Cells also appear to be able to downregulate enzymes which are drug targets. Examples include the decrease in Topo II which accompanies the resistance shown by cells to VP-16 and VM-26. Although many reports include both presentation and relapsed patients, there are few data on samples drawn from the same patients before and after chemotherapy. While P-170 and GST appear to be raised more often in cells from resistant and relapsed disease, it is quite clear that such mechanisms can be active in de novo malignancy and do not necessarily emerge as a consequence of prior chemotherapy. Methods of detecting drug resistance are reviewed here; these include in vitro cellular assays for drug toxicity, and molecular, immunological and functional detection of P-170 or Topo II. The clinical evaluation of such assays is only just beginning and some of the data are contradictory. To some extent, this may reflect the complex way in which the various resistance mechanisms may interact. Nevertheless, there are some encouraging early signs that the application of these assays to clinical material will yield valuable data on the relative contributions of these mechanisms and on ways in which they may be overcome. At present, much attention has focused on the potential of agents which prevent the P-170 efflux pump from exporting cytotoxics from the cell. This is likely to be only the first of new therapies arising from an improved understanding of multidrug resistance. More immediately, assays for multidrug resistance and its parameters may find their place as routine diagnostic and prognostic tools in the laboratory.
Department of Haematology, University of Wales College of Medicine, Heath Park, Cardiff, UK.
P
P
Baines
P
P
Cumber
R A
RA
Padua
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018118:Chloride Channels; D003524:Cyclosporins / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects; D017354:Point Mutation; D012333:RNA, Messenger / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D018118:Chloride Channels; D003524:Cyclosporins; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D005982:Glutathione Transferase; D004250:DNA Topoisomerases, Type II