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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