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.