Cancer Development

 

Cancers develop at the cellular level.  As the building blocks of organs, cells are the body's smallest structures capable of performing all of the processes that define life such as transporting oxygen, digesting nutrients, reproducing, thinking, and moving.  Cells also have a programmed death known as apoptosis.

 

Cell Reproduction

 

Worn out, dying, or injured cells are replaced with new cells.  The rate in which cells reproduce depends on various factors including disease and injury.  For instance, white blood cells proliferate at a faster rate during infections, and endocrine organs respond to injury by regenerating damaged cells.  Cells reproduce when they receive signals from the growth factors or from contact with other cells.

 

Cell Cycles and Cancer

 

Cells reproduce through a series of steps known as growth cycles.  If any of these processes goes awry, a cell may become cancerous.  Cancer cells ignore signals that normally tell them to stop dividing, or to specialize, or to die and leave the circulation.  Growing rapidly and unable to recognize their boundaries, cancer cells can spread to other areas of the body.

 

Cyclin-Dependent Kinases

 

Several different proteins normally control the timing of events in cell cycles.  These regulations are necessary for normal cell division.  The loss of this growth regulation defines cancer.

 

Growth cycles in cells are controlled by the protein enzymes known as cyclin-dependent kinases.  Each of these kinases forms a complex with a particular cyclin protein.  This complex then binds and reacts with the cyclin-dependent kinase.  In the process, the kinase enzyme add phosphate groups to various proteins.  The phosphate molecules change the structure of the affected proteins, which can activate or inactivate the protein, depending on its function.

 

P53 is an important cell cycle protein with the properties of a transcription factor.  Transcription is a step in cell replication.  P53 binds to DNA and activates transcription of the protein P21.  In a subsequent step P21 blocks the activity of a cyclin-dependent kinase required for progression through the G1 step of the growth cycle.  This block allows the cell time to repair any defective DNA before it is replicated.  If the DNA damage is too severe, P53 orders the cell to commit suicide.  These steps of the cell growth cycle are blocked in various cancer cell therapies, including opiate antagonists.

 

The P53 mutation is the most common gene mutation leading to cancer.  Mutations in genes such as P53 that normally suppress tumor growth lead to cancer.

 

Dominant Mutations.  In cancer cells, several gene mutations occur that ultimately cause the cell to become defective.  In dominant mutations one gene in the pair is abnormal.  For instance, if a genetic mutation causes production of a protein that constantly activates the growth factor receptor, the cell must constantly divide.  When the dominant function of the cell is affected by a gene mutation, for example, when the mutation causes the growth factor receptor to be continuously activated, the dominant gene is called an oncogene.  This means it's capable of inducing cancer.

 

Recessive Mutations.  In recessive mutations, both genes in the pair are damaged.  For example, a normal gene called P53 produces a protein that turns off the cell cycle, thereby controlling cell growth.  The p53 gene primarily functions to repair or destroy defective genes, which helps reduce cancer cell growth.

 

If only one P53 in the pair is mutated, the other gene can still control the cell cycle.  If both genes are mutated, the off switch malfunctions and cell division is no longer under control. 

 

Normal vs Abnormal Cell Division.  Normal cell division requires external growth factors.  When growth factor production is impaired, cells can't divide.  Cancer cells don't require positive growth factors.  They divide in the absence of growth factors.

 

When in contact with other cells (contact inhibition), normal cells stop dividing.  That is, normal cells divide to fill in gaps in tissue.  When gaps are filled, normal cells stop dividing.  This property is lost in cancer cells.  Cancer cells continue to grow even when large masses of cells form.

 

Normal cells age and die through a process of apoptosis and are then replaced by new cells in an orderly fashion.  Most normal cells can divide about fifty times before they're programmed to die, which is related to their limited ability to replicate their DNA.  When cells replicate, the ends or telomers of their DNA shorten.  In growing cells. the enzyme telomerase repair these lost ends.  In cancerous cells, telomerase is activated continuously, allowing for unlimited cell divisions.

 

Normal cell stop dividing and go on to die when DNA is damaged or cell division is abnormal.  Cancer cells keep dividing even when the DNA is severely damaged.  These progeny cancer cells contain the abnormal DNA, and as they divide they accumulate even more damaged DNA.

 

Abnormal Cell Division.  When active oncogenes are expressed or when genes that normally suppress tumor formation are lost, abnormal cell division can occur.  This happens: when part of a gene is lost or deleted, when part of a chromosome is rearranged and transposed to the wrong place (translocation), or when an extremely small defect occurs in the cell's DNA, causing an abnormal DNA blueprint and production of a defective protein.

 

Cells Gone Wild

 

Cancer cells behave independently.  That is, cancer cells can be regarded as "cells gone wild".  In their haste for uncontrollable growth, cancer cells form tumors through a series of steps.  The first step is hyperplasia.  Hyperplasia is characterized by an increased number of cells caused by uncontrolled cell division.  The cell in hyperplasia, although increased in number, usually appear normal.

 

In the second step of cancer cell growth, cells appear abnormal, causing a condition of dysplasia.  In the third step, cells become markedly abnormal and begin to lose their functional properties.  These cells are called anaplasic.

 

In the third step, if anaplastic cells remain in their usually location the tumor is referred to as in situ.  In situ cells aren't invasive and are considered potentially malignant.

 

In the last step of cancer cell growth, the cells in the tumor metastasize or spread out of their areas and have the ability to invade other tissues.  Cancer that do not move on to other locations are considered noninvasive or benign.

 

Types of Tumors

 

Tumors are classified by the type of cells from which they arise.

 

1. Carcinoms, the most common cancers, stem from altered epithelial cells.

2. Sarcomas, stem from malignant white blood cells

3. Lymphomas, cancers of the B-lymphocyte white blood cells, derive from bone marrow.

4. Myelomas are cancers of immunoglobulin-producing white blood cells.

 

Angiogenesis

 

Tissues contain blood vessels that transport nutrients and oxygen to their cells.  Both cancerous and normal tissue cells need nutrients to grow.  As tumors grow and enlarge, the cells in their central area can't receive nutrients from the tissue's blood vessels.  These tumors must form their own blood vessels.

 

Angiogenesis refers to the creation of new blood vessels.  Professor Judah Folkman of Harvard Medical School found that tumors have the ability to produce new vessels.  Through the process angiogenesis, tumor cells make angiogenic growth factors that induce the formation of new capillary blood vessels.  Although the cells that form these new blood vessel cells are inactive in normal tissue, the tumor's angiogenic growth factors activate these blood vessels and order them to divide.  The new capillary blood vessels that grow in tumors allow for tumor growth and metastasis.

 

Both cells from tumor tissue and cells from tumor's blood vessels can cross into other blood vessels and spread into lymphatic tissue and other organs.  Tumor tissue cells give rise to dominant tumors that take up residence in other locations.  In contrast, the angiogenic tumor cells produce new blood vessels in the new location, which causes rapid tumor growth.

 

Ian Zagon and Cancer Research

 

Ian Zagon is the director of the Program on Education in Human Structure in the Department of Neural and Behavioral Sciences at Pennsylvania State University's College of Medicine.  With additional titles of Distinguished Professor and Distinguished Educator, Zagon is also a professor in neuroscience and anatomy and a member of the Specialized Cancer Research Center.

 

Areas of Research

 

Zagon's primary areas of research include the role of opioid peptides and opioid receptors in development, cancer, cell renewal, wound healing, angiogenesis, corneal renewal, neurodegeneration, and Crohn's disease.  Working with specialists in the Departments of Medicine, Health Evaluation, Surgery, Ophthalmology, and Pathology, Zagon focuses on translating scientific discoveries from the laboratory to the bedside.

 

Discovery of OGF

 

During the course of their research, Zagon and Dr. Patricia McLaughlin discovered that opioids can act as growth factors in neural and non-neural cells and tissues.  Zagon found that one native opioid, methionine-5-enkephalin, exerted a negative influence on growth at low doses and a stimulatory effect when used in high doses.  Zagon named this factor opioid growth factor (OGF) to signify its role as a growth factor, in addition to its ability to act as a neurotransmitter.

 

Unlike chemotherapy, OGF doesn't destroy cancer or other cells.  Therefore, it is not cytotoxic.  However, OGF halts cell growth and is thought to allow immunological mechanisms, for instance macrophages and natural killer (NK) lymphocytes, to accomplish the task of destroying cancerous cells.

 

LDN vs OGF

 

In his early studies of opiate antagonists on cell growth, Zagon discovered that low doses of opiate antagonists such as naloxone and naltrexone blocked opiate receptors for approximately four to six hours.  This resulted in increased production of endogenous opiates once the blockade ended.  In subsequent studies Zagon determined that the primary importance of this blockade is the increased production of opioid growth factor (OGF).  Administering OGF has an effect similar to that caused by administering LDN.  However, the concentrations of OGF derived from the direct administration of OGF are much higher than the concentration induced by LDN.

 

In some instances, LDN may be unable to induce sufficient OGF production.  This may be due to peptide deficiencies, loss of the OGF receptor or other metabolic changes associated with cancer development.  And in some cases, such as squamous cell head and neck cancers, a displacement of the OGF-OGFr complex contributes to cancer cell development and provides a growth advantage.  In these circumstances and in cancers where OGF production is typically low, Zagon and his team use pure OGF or naltrexone metabolite derivatives rather than low doses of naltrexone or naloxone.

 

The Role of Opioid Growth Factor

 

Opioid growth factor protein interacts with the opioid growth factor receptor (OGFr) found on the cell nucleus.  The OGFr is a nuclear-associated receptor for OGF that Zagon and his team have successfully clone and sequenced.  Bound to its receptor, OGF affects the growth and differentiation of cells and tissues.  Many cancer cells have been found to have OGF receptors.  In humans, the OGF receptor is highly expressed in the heart and liver, moderately expressed in skeletal muscle and kidney tissue and to a lesser extent in brain and pancreas.  The OGF is also expressed in tetal tissues including liver and kidney.

 

When LDN or OGF is administered, OGF reacts with the OGFr on cell nuclei and forms a complex.  The OGF-OGFr complex influences cell-growth pathways and arrests cell growth.  The National Cancer Institute defines OGF as an endogenous pentapeptide with potential antineoplastic and anti-angiogenic activities.  The NCI drug dictionary defines OGF as binding to and activating the OGFr present on some tumor cells and vascular cells, thereby inhibiting tumor cell proliferation and angiogenesis.

 

Zagon has found that the native complex of OGF and OGFr reduces cell growth in certain types of cancer, and it contributes to the maintenance of cell replication equilibrium.  In summary, the complex of OGF and OGFr serves as a tonically active system that maintain cellular homeostasis and targets the cyclin-dependent inhibitory kinase pathway.

 

OGF's Effect on Cell Pathways

 

OGF inhibits cell growth in cancer by targeting specific cyclin-dependent inhibitory kinase pathways.  In their research laboratory at Penn State, Zagon and his colleagues have demonstrated that the OGF-OGF receptor axis uses the P16 pathway to inhibit head and neck cancer cell growth.  Shortly after making this discovery, Zagon and his team determined that the OGF-OGF receptor axis uses the P21 pathway to inhibit pancreatic cell growth.

 

Effects of OGF on Cancer Cells

 

In the December 2007 issue of Neuropeptides, Zagon and his team reported the results of a study designed to determine the role of OGF and naltrexone on the migration, chemotaxis, invasion, and adhesion of human cancer cells.  The study involved cultured human pancreatic and colon cancer cells derived from squamous cell carcinoma of the head and neck.

 

Using high concentrations of naltrexone and related opiate antagonists to stimulate cell growth and low concentrations to inhibit cell growth, Dr. Zagon and his team showed that these effects are independent of cell migration, chemotaxis, invasion, and adhesive properties.  Furthermore, neither naltrexone nor OGF affected these biological properties of cancer cells.Zagon also tested a variety of endogenous and exogenous opioid compounds and showed that these compounds also had no effect on the biological properties of cancer cells.

 

Modulation of Angiogenesis

 

Zagon and his team have also determined, in animal studies using chick eggs, that opioid growth factor has a significant inhibitory effect on angiogenesis.  Their studies showed that both the number of blood vessels and the blood vessel length were decreased in vivo.  The study concluded that opioid factor is a tonically active peptide with a receptor-mediated action in regulating angiogenesis in developing endothelial and mesenchymal vascular cells.

 

Pancreatic Cancer

 

Pancreatic cancer is the fourth leading cause of cancer mortality in the United States.  Zagon and his team have been studying the effects of OGF in pancreatic cancer for the past decade.  In their laboratory, they found that OGF controls cell growth in pancreatic cancer.  Pancreatic cancer cells have OGF receptors that, when bound with OGF, inhibit additional cancer cell growth.  Because cancer cell growth is unregulated and cancer cells grow so quickly, the body can't produce enough OGF on its own to bind all the OGF receptors.  When OGF binds to the OGF receptors on cancer cells, cancer cell proliferation is inhibited.  Increasing OGF levels with LDN or OGF accelerates this process.

 

In a study published in the April 2007 International Journal of Oncology, Zagon and his team described a study in which they demonstrated that over expression of opioid growth factor receptor induced by low dose naltrexone also enhances growth inhibition in pancreatic cancer.  That is, LDN, by increasing both OGF and the number and density of OGF receptors, increases the number of OGF-OGFr complexes available to inhibit cancer cell growth.

 

Phase 1 Trials

 

Phase 1 trials of OGF conducted in Zagon's laboratory using human pancreatic cancer cells and xenografts of nude mice demonstrated that opioid growth factor inhibited pancreatic cell growth.  In additiona, in his trial, which was funded by the National Institute of Health, the safety of OGF and its maximum tolerated dose based on hypotension were determined in twenty one patients with unresectable pancreatic adenocarcinoma.  In this part of the trial, OGF was administered either subcutaneously or intravenously.  During the intravenous phase of the study, two patients had resolution of associated liver metastasis, and one patient showed regression of the pancreatic tumor.

 

INNO-105

 

OGF is a natural-occurring molecule also known as (Met-5)-enkephalin with potential as an anticancer compound.  Following the Phase 1 trial at Penn State University, Innovive Pharmaceuticals, a privately held biopharmaceutical company headquartered in New York, licensed OGF as an anticancer agent with the code name INNO-105.  In November 2005 Innovive began its own Phase 1 clinical trials on a variety of different cancers but discontinued development of INNO-105 in late September 2006.

 

Phase 2 Trials and Combination Therapies

 

In February 2008, Zagon's team was still recruiting patients for phase 2 clinical trials of OGF in people with advanced pancreatic cancer that cannot be removed by surgery.  Zagon's team also conducted a trial of combination chemotherapy with gemcitabine and OGF.  Gemcitabine exerts its effects through inhibition of DNA synthesis and has drawback of limited survival benefits.  Preclinical evidence from this trial showed that OGF enhances growth inhibition when used together with gemcitabine, which is the standard of care for advanced pancreatic neoplasia.

 

Lipoic Acid / OGF Protocol

 

Dr. Burton Berkson of Las Cruces, New Mexico, describes the long-term survival of a patient with pancreatic cancer treated with a combination of intravenous alpha-lipoic acid and low dose naltrexone.  In this respect, Berkson indicates that although the pancreatic tumor did not decrease in size it showed no disease progression, and the patient reported having an improved quality of life.

 

Head and Neck Cancer

 

Head and neck squamous cell carcinoma represents 5.5 percent of malignancies worldwide.  Approximately 30,000 new cases and 11,000 deaths are reported in the United States annually.  Studies performed by Zagon and his team show that the complex formed by the OGF=OGF receptor inhibits cell growth in these cancers, and that deficiencies of OGF receptor in head and neck squamous cell carcinoma are responsible for its rapid rate of tumor progression.  Related studies at Penn State using OGF alone and in combination with paclitaxel resulted in a significant reduction in tumor weight and increased survival.

 

Lymphoma

 

In a report presented at the April 2007 conference on opiate antagonists, Berkson presented a report of a case of follicular lymphoma he reversed in a sixty-one-year-old male patient using LDN and nine intravenous treatments with alpha-lipoic acid.  The patient refused standard medical treatments and declined further treatment wiith alpha-lipoic acid but continued on a six-month course of naltrexone alone.  Follow-up studies showed improvement up to one year following the end of treatment.

 

In his report Berkson described using the protocol for LDN taken at night originally recommended by Bernard Bihari in his anecdotal accounts, described on his web site, of successfully treating several patients with lymphoma.

 

Restoring Homeostasis

 

When asked what he considered the common link in all of the disorders that respond to LDN, Zagon stated that these are all disorders that benefit from LDN's influences on cell proliferation, for instance tumor cell growth.  Zagon also stated that LDN restores homeostasis.  That is, it allows the body to heal itself.

 

Dr. Nicholas Plotnikoff, a professor in the College of Pharmacy in the College of Medicine at the University of Illinois at Chicago describes metenkephalins as having immunological properties similar to those of the cytokines interleukin-s (IL-2) and interferon gamma (IFN) in that metenkephalins have potent antiviral and antitumor properties.  Specifically, Dr. Plotnikoff reports that metenkephalins increase levels of CD8 T lymphocytes, CD4 T lymphocytes, IL-2, and natural killer (NK) lymphocytes.  In addition, metenkephalins have been shown to cause increased blastogenic responses to mitogens.  These properties allow the body to fight cancers, viral infections, and inflammatory disorders, thereby helping the body heal itself.

 

Neuroblastoma

 

In an animal study published in 1983, Zagon and McLaughlin demonstrated that naltrexone modulates the tumor response in neuroblastoma inoculated mice.  In a series of studies conducted in the late 1980s, Zagon confirmed the presence of opioid receptors on neuroblastoma cells and demonstrated growth inhibition of neuroblastoma in mice with low dose naltrexone.  In this study, Zagon found that very small doses of naltrexone (0.1 mg/kg/day) inhibited tumor growth, prolonged survival in the mice that developed tumors, and protected some mice from developing tumors altogether.

 

In a study published in 2005, Zagon and McLaughlin demonstrated significant tumor cell growth inhibition by OGF in human cell cultures of pancreatic cancer, head and neck cancer, and neuroblastoma.  In each experiment, metenkephalin acted as a negative regulator of tumor development and significantly suppressed tumor appearance and growth.

 

Colon Cancer

 

In animal studies of mice, including nude mice inoculated with human colon cancer cells, OGF was shown to inhibit tumor cell growth, and it delayed and prevented growth of human colon cancer xenografts.  In the nude mice study published in 1996, mice were administered daily doses of 0.5, 5, or 25 mg/kg opioid growth factor, [Met5]enkephalin.  More than 80 percent of the mice receiving opioid growth factor beginning at the time of tumor cell inoculation did not exhibit neoplasias within three weeks, in comparison with a tumor incidence of 93 percent in control subjects.

 

Seven weeks after cancer inoculation 57 percent of the mice given OGF did not display a tumor.  OGF delayed tumor appearance and growth in animals developing colon cancer with respect to the control group.  The suppressive effects of OGF on oncogenicity were opioid receptor mediated.  In addition, OGF and its receptor were detected in transplanted HT-29 colon tumors.  Surgical specimens of human colon cancers also showed evidence of OGF.  The study concluded that naturally occurring opioid peptides act as a potent negative regulator of human gastrointestinal cancer and may suggest pathways for tumor etiology, progression, treatment and prophylaxis.

 

Metastatic Solid Tumors

 

A team of researchers located in Milan, Novosibirsk, Tel-Aviv, and Locarno, have applied principles rooted in psychoneuroimmunology in a collaborative study in which the researchers treated metastatic solid tumors with melatonin, with and without naltrexone, in combination with interleukin-2.

 

The rationale for the study was that naltrexone and melatonin, by activating Th1 lymphocytes and suppressing Th2 lymphocytes, should enhance the increase in total lymphocyte count induced by IL-2.  This preliminary study showed that the addition of naltrexone further amplifies the absolute lymphocyte count, which in turn, enhances the anticancer efficacy of IL-2.  The increase in lymphocyte count attributed to the addition of naltrexone was significantly higher than that achieved with melatonin and IL-2 alone.  In contrast, patients treated with IL-2 and melatonin without naltrexone showed primarily an increase in eosinophils.

 

Renal Cancer

 

Working with a team of oncologists and urologists at Penn State, Ian Zagon has demonstrated that OGF interacts with OGF receptor to directly inhibit proliferation of renal cell carcinoma in tissue culture.  In this study human renal cancer cells (CAKI-2) were grown using routine tissue culture techniques.  A variety of natural and synthetic opioids including OGF, opioid antagonists, and opioid antibodies were added to renal cancer cell cultures to determine the role of these peptides in renal cell carcinoma.

 

The experiments were repeated in serum-free media and with four other renal cancer cell lines.  Immunocytochemistry methods were used to examine the presence of OGF and its receptor.  The study results demonstrated that OGF was the most potent opioid peptide to influence human renal cell carcinoma.  OGF depressed growth within twelve hours of treatment, with cell numbers reduced by up to 48 percent of control levels.

 

In addition, OGF action was shown to be receptor mediated, reversible, not cytoxic, neutralized by antibodies to the peptide, and detected in the human renal cell carcinoma lines examined.  OGF appeared to be autocrine produced and secreted, and was constitutively expressed.  The researchers concluded tha OGF tonically inhibits renal cancer cell proliferation in tissue culture, and may play a role in the pathogenesis and management of human renal cell cancer.

 

Other Cancers

 

According to a report by the MedLiSight Research Institute, a nonprofit research institution in Baltimore, the following cancers have either been shown to have OGF receptors and/or have been anecdotally reported to respond to OGF and/or OGF-boosting mechanisms such as LDN: breast cancer, cervical cancer, colon and rectal cancer, gastric cancer, glioblastoma, head and neck cancer, Kaposi's sarcoma, lymphocytic leukemia, liver cancer, B cell lymphoma, T cell lymphoma, malignant melanoma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell and non-small cell lung cancer, throat cancer, tongue cancer, and uterine cancer.

 

Each week, Ian Zagon hears from physicians, including veterinarians, and patients from all over the world.  They seek advice regarding the use of LDN and OGF or they write to express their gratitude as they describe their --- or their patient's ---success in using LDN.  Zagon has shared some of this correspondence in confidence.  He admits that these anecdotal patient accounts are the most gratifying aspect of his work.