Alpha-fetoprotein growth inhibitory peptides: potential leads for cancer therapeutics.
alpha-Fetoprotein (AFP), known largely as a growth-promoting agent, also possesses a growth inhibitory motif recently identified as an occult epitopic segment of the molecule. This segment, a 34-amino acid stretch termed the growth inhibitory peptide (GIP), has been chemically synthesized, purified, and characterized. The purified 34-mer exhibits complex aggregation behaviors; initially, trimeric oligomers were formed that possess growth inhibitory activity in rodent uterine bioassays. These rodent growth assays have served as a prelude to the anticancer studies that followed. In solution, the trimers convert slowly to dimers containing intrapeptide disulfide bonds; such dimers are inactive in the antigrowth assays. Cysteine-to-alanine analogues of the GIP retain the antigrowth properties, while similar cysteine-to-glycine and cysteine-to-serine analogues demonstrate little, if any, growth regulatory activity. Chemical modifications of the cysteine residues also have little influence on the antigrowth activity of the GIP. Fragments of the 34-mer possess variable growth activities of their own, with an octamer from near the carboxyl terminus displaying estrogen-dependent antigrowth activity similar to that of the 34-mer. It was further observed that the GIP can bind both Zn(2+) and Co(2+); the Co(2+) peptide complex was shown to have a distorted tetrahedral symmetry, involving coordination of two cysteine and two histidine residues. The Zn(2+)-GIP complex had antigrowth activity and did not form the intrapeptide disulfide bond characteristic of the free GIP in aqueous solution. The GIP was tested in vitro for anticancer activity and was found to suppress the growth in 38 of 60 human cancer cell lines, representing nine different cancer types. In vivo studies of the GIP, certain analogues, and its fragments revealed anticancer activities in both isograft and xenograft animal tumor transplants. Furthermore, the 2C --> 2A replacement analogue was active against a breast tumor in vivo and in vitro and a prostate cancer in vitro. Thus, it is proposed that the GIP, its analogues, and its fragment peptides can potentially serve as lead compounds for cancer therapeutics.
Mizejewski
Gerald J
GJ
Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA. Mizejew@wadsworth.org
MacColl
Robert
R
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000509:alpha-Fetoproteins / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D010455:Peptides; D000509:alpha-Fetoproteins