History of the Growth Inhibitory Peptide

Alpha-fetoprotein (AFP) has long been known as a transport protein in the fetus, and has served as a serum marker in the clinical laboratory for both cancer (especially hepatomas) and fetal defects [1]. Of-late, a multitude of studies have shown that the AFP molecule acts as a growth regulator during both ontogenic and tumor progression [2], and it is this regulatory role that distinguishes the AFP molecule from other transport proteins such as albumin. It was shown that the AFP molecule is largely a growth enhancing agent.

However growth is a process that requires fine-tuning for both up-regulation and down-regulation to operate correctly over a defined period or event such as pregnancy or cancer. During pregnancy, for example, the fetus may encounter several situations which require periods of growth cessation, such as differentiation and prevention of organ/tissue overgrowth [3]. The fetus may also experience temporary stress or shock conditions in the microenvironment thus requiring a temporary halt for homeostasis to recover. Administration of AFP however has showed growth enhancing properties regardless of whether the tissue is of fetal or cancer origin.

So why are we talking so much about Alpha-fetoproteins (AFP)? Well, it was reported later that a 34-amino acid peptide segment, located in the third domain of AFP can temporarily bestow growth suppressive properties upon the full-length AFP molecule, in contradiction to its growth enhancing properties [4]. This 34- amino acid peptide generally lies buried in a molecular cleft within the AFP molecule and thus does not show its pharmacological action. The hidden peptide sequence on the AFP molecule can expose itself by a proposed rotational hinge on the parent AFP molecule by either extreme ligand concentrations or possibly by stress/shock conditions during fetal growth. [5]

The 34 amino-acid sequence was synthesized and isolated and was then labeled the Growth Inhibitory Peptide or the GIP. It has now been demonstrated that the GIP is capable of growth suppression in a multitude of human tumors, both in vitro and in vivo. [6]

Dr. Gerald J. Mizejewski (presently at the Division of Molecular Medicine, Wadsworth Center, New York State Department of Health) is one of the leading researchers of the AFP molecule and he and his team are the discoverers of the GIP. He has been working on these molecules for over 30 years now, and is currently involved in pre-clinical trials of the GIP molecule.

References:
1. Mizejewski, G. J. New insights into AFP structure and function: potential biomedical applications. In: G. J. Mizejewski and I. H. Porter (eds.). a-Fetoprotein and Congenital Disorders, pp. 5-34. Orlando: Academic Press, 1985.
2. Toder, V., Blank, M., Gold-Gefter, L., and Nebel, J. The effect of afetoprotein on the growth of placental cells in vitro. Placenta, 4: 79-86, 1983.
3. Everman, D. B., Shuman, C., and Dzolganovski, B. Serum AFP levels in Beckwith-Wiedeman syndrome. J. Pediatr., 137: 123-127, 2000.
4. Mizejewski GJ, Dias JA, Hauer CR, Henrikson KP, Gierthy J: Alpha-fetoprotein derived synthetic peptides: assay of an estrogen-modifying regulatory segment. Mol Cell Endocrinol 118: 15-23, 1996.
5. Mizejewski, G. J. a Fetoprotein structure and function: relevance to isoform, epitopes, and conformation variants. Exp. Biol. Med., 226: 377- 408, 2001.
6. Mizejewski GJ, MacColl R: Alpha-fetoprotein growth inhibitory peptides: Potential leads for cancer therapeutics. Mol Cancer Ther 2: 1243-1255, 2003.