title: In vitro antineoplastic activity of a novel lanthionine-containing peptide.
abstract: It has been a long-term goal to discover peptides that can kill tumor cells while sparing normal tissues. Lan-7 is a novel, chemically stable peptide structurally related to somatostatin that contains a lanthionine bridge between the two cysteines in the peptide; TT-232 is a less stable analogue containing a disulfide bridge. The antitumor activity of Lan-7 was examined, relative to that of TT-232 and the clinically used analogue octreotide, against a panel of malignant human tumor cell lines and normal human hematopoietic precursors. Lan-7 was cytotoxic to all four tumor cell lines, with IC50 values ranging over a 2-fold range from 16 to 36 microM. The potency of Lan-7 was comparable to that of TT-232, and both of these agents were two to three times more potent than octreotide. At concentrations that were highly cytotoxic to tumor cells, Lan-7 produced no significant toxicity to normal human hematopoietic precursors. Lan-7 induced apoptosis in human ovarian carcinoma 2008 cells over the same concentration range at which it produced cytotoxicity, but it did so without activating G1, S, or G2 checkpoints, given that it produced no perturbation of cell cycle phase distribution. Cells engineered to overexpress P-glycoprotein were not more resistant to Lan-7 than isogeneic cells not expressing the mdr1 gene. These results make Lan-7 of interest as a potential cancer chemotherapeutic agent.
authors.affiliation: Cancer Center, Department of Chemistry, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.forename: D
authors.initials: D
authors.lastname: Fink
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.forename: S
authors.initials: S
authors.lastname: Aebi
authors.forename: P
authors.initials: P
authors.lastname: Law
authors.forename: M
authors.initials: M
authors.lastname: Goodman
authors.forename: S B
authors.initials: SB
authors.lastname: Howell
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D015179:Colorectal Neoplasms; D016889:Endometrial Neoplasms; D005260:Female; D006258:Head and Neck Neoplasms; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D010051:Ovarian Neoplasms; D010456:Peptides, Cyclic / Q000633:toxicity*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000633:toxicity; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C117292:Lan-7; D010456:Peptides, Cyclic; C094462:TT2-32; D013004:Somatostatin