Reversal of multidrug resistance: lessons from clinical oncology.
Modulation of P glycoprotein (Pgp) in clinical oncology has had limited success. Contributing factors have included the limitation in our understanding of the tumours in which Pgp overexpression is mechanistically important in clinical drug resistance; the failure to prove that concentrations of modulators achieved in patients were sufficient to inhibit Pgp; and the inability to conclusively prove that Pgp modulation was occurring in tumours in patients. New approaches are needed to determine the clinical settings in which Pgp overexpression plays a major role in resistance. (Clinical trials with third generation modulators are ongoing, including trials with the compounds LY335979, R101933 and XR9576. Using the Pgp substrate Tc-99m Sestamibi as an imaging agent, increased uptake has been seen in normal liver and kidney after administration of PSC 833, VX710 and XR9576. These studies confirm that the concentrations of modulator achieved in patients are able to increase uptake of a Pgp substrate. Furthermore, CD56+ cells obtained from patients treated with PSC 833 demonstrate enhanced rhodamine retention in an ex vivo assay after administration of the antagonist. Finally, a subset of patients treated with Pgp antagonists show enhanced Sestamibi retention in imaged tumours. These results suggest that Pgp modulators can increase drug accumulation in Pgp-expressing tumours and normal tissues in patients. Using third generation Pgp antagonists and properly designed clinical trials, it should be possible to determine the contribution of modulators to the reversal of clinical drug resistance.
Bates
Susan F
SF
Molecular Therapeutics Section, Medicine Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Chen
Clara
C
Robey
Robert
R
Kang
Min
M
Figg
William D
WD
Fojo
Tito
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003524:Cyclosporins / Q000494:pharmacology / Q000627:therapeutic use; D003986:Dibenzocycloheptenes / Q000494:pharmacology / Q000627:therapeutic use; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019450:Genes, MDR; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D012235:Rhodamines / Q000493:pharmacokinetics; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001552:Benzazepines; D003524:Cyclosporins; D003986:Dibenzocycloheptenes; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D009363:Neoplasm Proteins; D010880:Piperidines; D011725:Pyridines; D011804:Quinolines; D019275:Radiopharmaceuticals; D012235:Rhodamines; C106077:biricodar; C095179:zosuquidar trihydrochloride; D017256:Technetium Tc 99m Sestamibi; C402343:tariquidar; C411474:laniquidar; C070272:valspodar