Monday, 2 June 2014

Epithalon.

Introduction.
Epithalon (Epitalon®) is a peptide drug used to regulate the cell cycle through up-regulation of telomerase activity. The sequence of amino acids in the peptide is Alanine-Glutamate-Asparagine-Glycine. Animal studies have been done on the effects of Epithalon on suppression of spontaneous mammary tumors and spontaneous carcinogenesis. Studies have shown that the mode of action of Epithalon involves suppression of oncogene expression and modification of telomerase activity. A summary of the studies and research on telomerase is provided below.
Telomerase.
It is a specific RNA (ribonucleic acid)-dependent polymerase that elongates and maintains the length of telomeres by adding tandem repeats on the chromosomal 3' end. The enzyme is composed of two parts: an RNA component which supplies the telomere template for elongation, and the catalytic subunit which possesses reverse transcriptase activity. These two parts work in tandem to avert telomere attrition especially in somatic cells. In vitro experiments have shown that telomere elongation promotes indefinite cellular proliferation and that suppression of telomerase activity promotes apoptosis of neoplastic cells. However, these studies have also shown that maintenance of telomere length within a range of 15-20 kilobase pairs does prevent tumorigenesis. All the research and studies done concerning telomerase do show that telomerase activity is limited to cell division through its action of stabilizing the telomere length.
Telomeres are located at either ends of a chromosome, and they do protect the adjacent gene sequence from shortening due to repeated replication cycles. Elongation of telomeres enables senescent cells to stabilize their telomeric length. However, excess elongation would enable such cells to exceed their Hayflick limit via evasion of apoptosis or the post-mitotic phase; and therefore, such cells have the potential of becoming immortal and this predisposes them to neoplastic transformation.
Human telomeres are made up of tandem repeats of the nucleotide sequence TTAGGG that form a T loop structure when associated with telomere-binding proteins. The T loop structure ensures the integrity of the telomeres by protecting them from constitutive degradation. These tandem repeats do shorten as a consequence of repeated chromosomal replication cycles. Such shortening is due to the inability of DNA polymerase to repeatedly replicate the nucleotides located in the T loop region. This leads to senescence or growth arrest, and a critically shortened telomere does induce a p53-mediated DNA checkpoint reaction. Some cells do evade senescence if they have nonfunctional p53 and/or pRb, but cell death still occurs due to either lethal DNA rearrangements or chromosomal fusion. Thus, evasion of telomere-mediated senescence is the main way that cells use to avert premature senescence and apoptosis. This occurs only when telomerase activity is up-regulated. Telomerase elongation leads to stabilization of the genotype as the rate of gene mutation is maintained within normal limits. However, an increase in the rate of apoptosis leads to a proportionate increase in cellular regeneration rate, and this causes an increase in the number of sporadic gene mutations that occur thus predisposing the person to pro-neoplastic mutations.
Current studies show that telomere shortening is associated with chronic diseases such as pulmonary fibrosis, coronary artery disease, diabetes mellitus and Alzheimer’s disease, though their findings are still considered inconclusive. Based on the findings of these studies, it can be theorized that Epithalon could prevent the development of these diseases. 
Specific studies.
The studies considered below are conclusive and their findings are considered to have a clinical bearing on the use of Epithalon as a cancer chemotherapeutic agent.
1.      Does Epithalon suppress spontaneous mammary tumors?
In 2002, Anisimov et al did a study titled “Inhibitory effect of the peptide Epitalon® on the development of spontaneous mammary tumors in HER-2/neu transgenic mice” in which the anti-neoplastic efficacy and potency of Epitalon® were evaluated. The total number of subjects was 80 and the subjects used were 2 months old FVB/N HER-2/neu female transgenic mice. HER-2/neu is a human oncogene which encodes for EGF (epidermal growth factor) receptor in human breast tissue, and as such the suppression of this oncogene in the transgenic mice would indicate its probable suppression in human breast tissue.
The mice were divided into three separate groups which were treated as follows: The first group (28 mice) received subcutaneous injection of saline (0.1 ml), the second group (25 mice) was subcutaneously injected with single-dose Epitalon® (1 μg per mouse) and the third group (27 mice) received a subcutaneous injection of single-dose Vilon® (1 μg per mouse). The duration of treatment was 5 consecutive days per month for three months. The first group was the control group. Vilon® is a dipeptide drug which up-regulates telomerase activity.
The results of the experiment showed that Epitalon® treatment did decrease the overall number and size of mammary tumors (p < 0.05). As compared to the control group, it did increase the population of mice with a single mammary tumor while it concurrently decreased the population with 2 or more mammary tumors. It also decreased the size of lung metastases but it had no effect on the number of such metastases. Moreover, Epitalon® suppressed the expression of HER-2/neu oncogene by a factor of 3.7 as evidenced by a reduction in the number of the corresponding mRNA (messenger RNA). On the other hand, Vilon® treatment as compared to the control group had overwhelmingly negative results. Vilon® treatment increased the incidence of spontaneous mammary cancer and shortened the tumor latency period thus leading to a cumulative increase in the number of mammary tumors. However, it suppressed the expression of HER-2/neu oncogene by a factor of 1.9. No suppression of HER-2/neu oncogene occurred in the control group.
The results of this study thus show that Epitalon® does inhibit spontaneous mammary tumor development in HER-2/neu mice by down-regulating the expression of the HER-2/neu oncogene.
2.      1.   Does Epithalon suppress the incidence of spontaneous carcinogenesis?
In 2005, Popovich et al did a study titled “Effect of Epitalon® and melatonin on life span and spontaneous carcinogenesis in senescence accelerated mice (SAM)” to evaluate the effect of Epithalon on senescence and carcinogenesis. The subjects were female mice divided into three groups SAM-prone (SAMP), SAM-Resistant (SAMR) and the control group. The SAMP group was divided into two groups which were treated with subcutaneous melatonin (1ml/kg/mouse) and Epitalon® (1ml/kg/mouse) respectively. The same was done for the SAMP group.  The control group was treated subcutaneous injection of normal saline (0.1ml per day). The duration of treatment was 5 consecutive days. The following parameters were monitored: temperature, food consumption, body weight, tumor incidence, estrous function and lifespan.
The results showed that with advancement of age, the body weight increased whereas temperature and food consumption were unaffected. These parameters showed no sub-strain differences, and they were also unaffected by melatonin or Epitalon® treatment. Age advancement also increased the frequency of irregular estrous cycles in the control groups, and its incidence rate reduced upon treatment with either melatonin or Epitalon®. The rate of accelerated aging was higher in the SAMP group than in the SAMR. Also, the overall mean lifespan of the SAMR group was longer than that in the SAMP group. There was also a positive correlation between body mass and the duration of the lifespan. In both groups, Epitalon® treatment lengthened the lifespan more than melatonin. Malignant lymphoma predominated in melatonin-treated SAM groups as compared to the Epithalon-treated SAM groups, without any sub-strain differences. Epithalon reduced the tumor incidence in the SAM groups while melatonin had no effect on tumor incidence. Epithalon reduced the incidence of carcinogenesis in the SAMP group, but it had no effect on carcinogenesis in the SAMR group.
The results of this study thus show that Epitalon® does suppress the rate of senescence in senescence-sensitive subjects. It also shows that Epitalon® suppresses the incidence of spontaneous carcinogenesis.


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