Carboxylesterase-mediated sensitization of human tumor cells to CPT-11 cannot override ABCG2-mediated drug resistance.
The recently introduced camptothecin-derived chemotherapeutic agents have demonstrated remarkable promise in cancer therapy and as such have been approved for use in humans for the treatment of ovarian, lung, and colon cancer. CPT-11 is a prodrug that is activated by esterases to yield the potent topoisomerase I inhibitor, SN-38. Considerable success has been achieved in the treatment of both naïve and drug-resistant colon cancer with CPT-11. However, mechanisms of resistance to this agent have not been explored in detail. The role of the ATP-dependent drug transporter ABCG2 in CPT-11 cytotoxicity is unclear because some ABCG2 mutants confer camptothecin resistance, whereas others do not. Because CPT-11 is activated by carboxylesterases (CEs), we assessed the relative contribution of each protein in mediating CPT-11 toxicity by both drug accumulation and cell growth-inhibition assays. Our results indicate that the expression of ABCG2 protects cells from CPT-11 toxicity, even in the presence of high levels of a rabbit liver carboxylesterase (rCE), which can efficiently activate the drug. However, this can be partially overcome by the ABCG2 inhibitor reserpine. These studies indicate that overexpression of ABCG2 in vivo would probably overcome any increased drug activation that might be achieved by gene delivery or antibody-directed enzyme prodrug therapy methods using rCE.
Wierdl
Monika
M
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
Wall
Amelia
A
Morton
Christopher L
CL
Sampath
Janardhan
J
Danks
Mary K
MK
Schuetz
John D
JD
Potter
Philip M
PM
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D000077146:Irinotecan; D009363:Neoplasm Proteins; D011817:Rabbits; D014407:Tumor Cells, Cultured
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; C017807:bisbenzimide ethoxide trihydrochloride; D002166:Camptothecin