IN-VITRO ANTINEOPLASTIC ACTIVITY OF A NOVEL LANTHIONINE-CONTAINING PEPTIDE

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 stabl e peptide structurally related to somatostatin that contains a lanthio nine 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 cel l 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 mu M. The potency of Lan-7 was comparable to that of TT-232, and both of these agents were two to three times more poten t than octreotide. At concentrations that were highly cytotoxic to tum or cells, Lan-7 produced no significant toxicity to normal human hemat opoietic precursors, Lan-7 induced apoptosis in human ovarian carcinom a 2008 cells over the same concentration range at which it produced cy totoxicity, but it did so without activating G(1), S, or G(2) checkpoi nts, given that it produced no perturbation of cell cycle phase distri bution, Cells engineered to overexpress beta-glycoprotein were not mor e resistant to Lan-7 than isogeneic cells not expressing the mdr1 gene , These results make Lan-7 of interest as a potential cancer chemother apeutic agent.