Role of P-glycoprotein in dolastatin 10 resistance.
Dolastatin 10, a cytotoxic pentapeptide isolated from the mollusk Dolabella auricularia, exhibits potent antitumor activity. The present studies demonstrated that sublines of murine PC4 and human U-937 leukemia cells expressing a multidrug resistance (MDR) phenotype are cross-resistant to this agent. We also demonstrated that such resistance was reversed by verapamil. While these findings suggested the involvement of the P-glycoprotein (P-gp) in dolastatin 10 resistance, we performed similar studies in a CHO cell line transfected with the human mdr1 cDNA. Expression of P-gp in the transfected cells was associated with resistance to dolastatin 10 by a verapamil-sensitive mechanism. The demonstration that photoaffinity labeling of P-gp was decreased in the presence of dolastatin 10 further supports the interaction of this cytotoxic peptide with P-gp. Taken together, these findings suggest that resistance to dolastatin 10 is conferred, at least in part, by P-gp and that this cytotoxic peptide is a novel member of the MDR phenotype.
Toppmeyer
D L
DL
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
Slapak
C A
CA
Croop
J
J
Kufe
D W
DW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D006224:Cricetinae; D047630:Depsipeptides; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010641:Phenotype; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D047630:Depsipeptides; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D014700:Verapamil; C064570:dolastatin 10