Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin.
Expression of multidrug resistance (MDR) features by acute myeloid leukemia (AML) cells predicts a poor response to many treatments. The MDR phenotype often correlates with expression of P-glycoprotein (Pgp), and Pgp antagonists such as cyclosporine (CSA) have been used as chemosensitizing agents in AML. Gemtuzumab ozogamicin, an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, is effective monotherapy for CD33(+) relapsed AML. However, the contribution of Pgp to gemtuzumab ozogamicin resistance is poorly defined. In this study, blast cell samples from relapsed AML patients eligible for gemtuzumab ozogamicin clinical trials were assayed for Pgp surface expression and Pgp function using a dye efflux assay. In most cases, surface expression of Pgp correlated with Pgp function, as indicated by elevated dye efflux that was inhibited by CSA. Among samples from patients who either failed to clear marrow blasts or failed to achieve remission, 72% or 52%, respectively, exhibited CSA-sensitive dye efflux compared with 29% (P =.003) or 24% (P <.001) among samples from responders. In vitro gemtuzumab ozogamicin--induced apoptosis was also evaluated using an annexin V--based assay. Low levels of drug-induced apoptosis were associated with CSA-sensitive dye efflux, whereas higher levels correlated strongly with achievement of remission and marrow blast clearance. In vitro drug-induced apoptosis could be increased by CSA in 14 (29%) of 49 samples exhibiting low apoptosis in the absence of CSA. Together, these findings indicate that Pgp plays a role in clinical resistance to gemtuzumab ozogamicin and suggest that treatment trials combining gemtuzumab ozogamicin with MDR reversal agents are warranted. (Blood. 2001;98:988-994)
Linenberger
M L
ML
Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA. linen@u.washington.edu
Hong
T
T
Flowers
D
D
Sievers
E L
EL
Gooley
T A
TA
Bennett
J M
JM
Berger
M S
MS
Leopold
L H
LH
Appelbaum
F R
FR
Bernstein
I D
ID
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism / Q000502:physiology; D000208:Acute Disease; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000473:pathology; D002232:Carbocyanines / Q000493:pharmacokinetics; D017322:Clinical Trials, Phase II as Topic; D016572:Cyclosporine / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics* / Q000276:immunology*; D004357:Drug Synergism; D005456:Fluorescent Dyes; D000079982:Gemtuzumab; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000473:pathology; D010641:Phenotype; D012044:Regression Analysis; D012074:Remission Induction; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002232:Carbocyanines; D005456:Fluorescent Dyes; D000922:Immunotoxins; C081554:3,3'-diethyloxacarbocyanine; D016572:Cyclosporine; D000079982:Gemtuzumab