title: BIBW 22, a dipyridamole analogue, acts as a bifunctional modulator on tumor cells by influencing both P-glycoprotein and nucleoside transport.
abstract: BIBW 22, a phenylpteridine analogue of dipyridamole (DPM), enhanced vincristine cytotoxicity approximately 10 times more than DPM in a multidrug-resistant (MDR) KB V20C cell line. Using rhodamine 123 accumulation in KB V20C cells as an indicator of MDR phenotype, BIBW 22 was shown to be about 100 times more potent than DPM in inhibiting the MDR-associated efflux of rhodamine 123. Photolabeling of P-glycoprotein in KB V20C plasma membranes with 0.2 microM [3H]azidopine was strongly inhibited by 1 microM BIBW 22, indicating that this compound reverses the MDR phenotype by interfering with MDR-associated P-glycoprotein. In addition, BIBW 22 at 1 microM could also enhance the cytotoxicity of 5-fluorouracil in KB cells about 20-fold. Its potency in inhibiting nucleoside transport is 7-fold more potent than that of DPM. These results suggest that BIBW 22 is a potent bifunctional modulator which influences both P-glycoprotein and nucleoside transport in tumor cells. Potential use of this compound as a modulator of combination chemotherapy involving antimetabolites and drugs affected by MDR should be explored.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: H X
authors.initials: HX
authors.lastname: Chen
authors.forename: U
authors.initials: U
authors.lastname: Bamberger
authors.forename: A
authors.initials: A
authors.lastname: Heckel
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D001692:Biological Transport / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D004176:Dipyridamole / Q000031:analogs & derivatives*; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology*; D009705:Nucleosides / Q000378:metabolism*; D010777:Photochemistry; D013936:Thymidine / Q000378:metabolism; D014223:Triamterene / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D008562:Membrane Glycoproteins; D009025:Morpholines; D009705:Nucleosides; C080982:BIBW 22; D014750:Vincristine; D004176:Dipyridamole; D005472:Fluorouracil; D013936:Thymidine; D014223:Triamterene