Thursday, May 14, 2009

Bryostatin Cancer Drugs

Bryostatin cancer drugs are currently undergoing Phase L and Phase II cancer trials according to the U. S. National Institute of Health Clinical Trials program.

Brysostatin-1 is a naturally occurring class of chemical compound that is toxic to cells (cytotoxic). Bryostatin cancer drugs are produced by the bacterium Candidatus endobugula sertula and are found in the marine bryozoan Bugula neritina. The rod-like bacterium C. endobugula sertula produces the chemical bryostatin during the larval stage of the bryozoan’s development. The young larvae bryozoans are coated with this compound allowing the young larvae to be distasteful and unpalatable to predators.

Bryozoan Bugula neritina is a tiny aquatic animal less than 1 mm in length that forms colonies similar to coral and sponges. Bryozoan colonies can be of various plant-like types similar to moss, branch or tree style, to gelatinous masses. Bryozoans are water filter-feeders. There are over 5,000 species of bryozoans in the world with only about 50 freshwater species. The more notable 130 species of bryozoans tend to be a nuisance animal fouling ship hulls, moorings, piers, and docks. Some freshwater species form large jelly-like masses that tend to clog industrial water intakes. The bryozoan’s Bugula neritina are found in the Pacific Ocean off the coast of California, in the Gulf of Mexico, and in the Gulf of Aomori in Japan.

The best source of the cytotoxic chemical bryostatin I was found in host bryozoans Bugula neritina in 1968. Bryostatin was found to contain potent anti-leukemic activity. It has shown promise against lung cancer, prostate cancer, Non-Hodgkin’s lymphoma, and possibly pancreatic cancer. Bryostatin cancer drugs act synergistically with other cancer drugs and are potent activators of Protein Kinase C.

Currently, over 20 types of bryostatins have been identified from the bryozoan Bugula neritina host. It currently takes about 14 tons of the bryozoan Bugula neritina to produce 1 ounce of bryostatin. To synthesize bryostatin, chemical formula C47H68O17 with a molecular weight of 905.033, it takes over 50 steps in the laboratory.

The effective mechanism of bryostatin is its unique ability to activate the cell-signaling enzyme Protein Kinase C (PKC) resulting in the inhibition of tumor cell growth and causing tumor cell death. PKC is an enzyme that is important for controlling biochemical reactions in the cell. Bryostatin cancer drugs have been associated with initiating immune response, regulating cell growth activity, and in learning and memory. Cancerous cells undergo rapid growth and need a controlled growth to keep the cells from causing damage to the body.

Since it is a promoter of PKC, bryostatin is being looked into assisting in memory enhancement and in particular to combat Alzheimer’s disease. Bryostatin has shown to increase rates of learning in rats. There are currently about 40 Phase 1 and Phase 2 clinical trials ongoing for the use of bryostatin cancer drugs for numerous cancers and in Alzheimer’s patients. The clinical trials thus far have been for cancers such as: kidney, stomach, breast, prostate, lung, esophageal, head and neck, ovarian, fallopian tube, cervical, multiple myeloma, and leukemia to name a few.

Currently, the Albert Einstein College of Medicine of Yeshiva University has been undergoing Phase II metastatic pancreatic cancer studies with Bryostatin-1 and Paclitaxel. Results for this study and other cancer studies can be found at the U.S. National Institute of Health Clinical Trials program.

Pancreatic Cancer HSP Trials

Pancreatic Cancer HSP trials began in 1997 for a Phase I study to involve fifteen patients through the Memorial Sloan-Kettering Cancer Center. HSP or heat-shock proteins are a of group proteins that are present in all cells. HSP are often identified during stressful situations such as extreme cold and hot conditions, and during deprivation of oxygen or glucose. Heat-shock proteins are often referred as the stress proteins.
Heat-shock proteins are the protein assistants of the cell. They have a library of every protein ever coded in the body. HSP understand the shape and the function of every amino acid sequence. If one amino acid sequence is not correct and a protein is not folded correctly the HSP is there to make sure that “neat and tidy” for the cell so the proteins are functioning at optimal level.
Heat-shock proteins are normally found inside the cell to help with protein functioning. If heat-shock proteins are found on the outside of the cell it means that the cell is not healthy.
When proteins are no longer useful the heat-shock proteins escort them to be dismantled by the cell into small amino acid pieces called peptides. The HSP then load the peptides onto another protein called major histocompatability complex (MHC). The fully loaded MHC takes the amino acid fragments (peptides) to the surface of the cell where the immune system is ready and waiting to react to the unfamiliar proteins.
When the cell dies it discharges the HSP and the peptide fragments of the extraneous protein. Circulating immune system dendritic cells or macrophages, referred to as antigen-presenting cells (APC), detect the HSP-peptide fragments. The HSP assist with loading the peptide fragments onto the CD91 receptor of the APC cell surface. The APC then swallow-up the HSP-peptide complexes. Once fully engulfed, the APC travel to the lymph nodes, the foundation of the immune system, where specialized immune cells called T- cells read the amino acid peptides sequences. The T-cells are able to code for a defense against that specific amino acid sequence. The T-cells are subsequently programmed to go through the body to seek out the specific foreign proteins and destroy the alien amino acid sequences. The T-cells are specific, being programmed to destroy the exact amino acid sequence that it was coded for and no other protein sequence.
When the body receives immunization with a sterile disease (vaccine) the body will recognize the disease-coded vaccine with the help of HSPs and the T-cells are activated and ready to fight off the disease. If the body is not immunized then the body has not built up a defensive system that is ready to combat the disorder.
Heat shock protein vaccines focus on individual vaccines specifically developed for each patient. Everybody has a detailed amino acid sequence in their cells that are explicitly coded for them. The HSP vaccine thus are “tailor-made” designer-drug style of vaccine to meet the specific requirements for each individual person.
Heat-shock proteins appear to work similar with cancer cells as with other diseases. Cancer can be removed from an individual and clinically weakened. The weakened cells can be injected back into the same patient. Heat-shock proteins keep track of every protein that is ever in the cell including abnormal proteins. If the weakened cells are injected into the body the heat-shock proteins will recognize that they are abnormal, bind against the abnormal proteins and bring to the surface of the cell. By bringing them to the surface the body’s immune systems recognizes an abnormal cell and builds up the defense. When a more powerful cancer occurs of that type the body’s immune systems is ready and quickly creates antibodies to counteract the abnormal proteins and removes the ailing cells.
With pancreatic cancer, the average survival rate is only 6 months by the time it is typically detected with only one in five patients surviving past one year.
During the 1997 pancreatic cancer HSP trials, the pancreatic enzymes began to degrade the HSPs. Only five of the 15 patients slated for the pancreatic cancer HSP trial could get the pancreatic cancer HSP vaccine. Due to the pancreatic enzymatic activity and the destruction of the heat-shock proteins, the trial was suspended. Of those five patients that were treated with the heat-shock protein procedure their survival rate was 8, 17, 30, 33, and 36 months after the procedure. The patient living for 36 months after the procedure did not have any signs of pancreatic cancer at the time. These five patients in the 1997 pancreatic cancer HSP study show very promising results in the heat-shock protein treatment technique. Since then, scientists have discovered a method to prevent pancreatic enzyme destruction of the heat-shock proteins. Study for Phase II pancreatic cancer HSP trials have been filled and are currently underway.

Improvement to cancer treatment is a continued challenge. Understanding the complexities of cancer and the treatment models are very critical. At pancreatic cancer is a major focus.

Monday, March 30, 2009

Cancer Mortality


Breast, prostate, and lung cancer are the most common types of cancer identified. Yearly, approximately 182,000 women will be diagnosed with breast cancer. The lifetime risk for American women in contracting breast cancer is approximately 13%, but the risk from dying from this disease is 3.3%. For every woman that is diagnosed with this disease, another 5 or 10 will have biopsy that shows benign disease.

Prostate cancer yields approximately 180,000 new cases yearly in the United States, and yields an approximate 18% mortality rate. Prostate cancer is generally considered a disease of the elderly, with a median age at diagnosis of 65 years. Prostate cancer is most common in western European nations and the United States. Blacks have a higher predisposition to prostate cancer at all ages compared to whites of similar socioeconomic class and education.

Lung cancer yields approximately 170,000 new cases yearly, and the mortality rate is 88%. Cigarette smoking constitutes the greatest risk factor in developing lung cancer. Approximately 90% of lung cancer in men and 80% of lung cancer in women are attributed to smoking. The lifetime risk of developing lung cancer to non-smokers is 1%.

Mortality rates from other types of cancer are: colon/rectum (39%), pancreatic (98%), leukemia (70%), ovarian (63%), and bladder (21%).

Pancreas - Islets of Langerhans

Insulin, the hormone that lowers the amount of glucose (sugar) in the blood is produced in the Beta cells that are located in the Islets of Langerhans. The Islets of Langerhans are where the endocrine (hormone-releasing) cells in the pancreas are located. The Islets are patchy and irregular shaped in the human pancreas. The Islets contain alpha, beta, delta, gamma, epsilon, and F-cells that surround the enzyme-secreting acinar cells. The Islets are evenly distributed around the pancreas and normal human pancreas contains about one million of these Islets.

Alpha cells in the Islets of Langerhans produce the hormone glucagon. Glucagon is released when glucose levels in the blood are low and glucagon stimulates the liver to convert glycogen to glucose.

Beta cells produce the hormones insulin and amylin. Beta cells make up about 70 percent of the Islets. Insulin is manufactured, stored, and secreted by the beta cells. Glucose moves from the blood into the body’s cells by the hormone insulin. Insulin assists in the metabolism of the glucose. Amylin is very similar to insulin in that it helps to reduce glucose in the blood. Amylin decreases the secretion of glucagon and moderates the emptying of the stomach,

Delta cells in the Islets produce the hormone somatostatin. The endocrine system is regulated by the peptide hormone somatostatin. Pancreatic somatostatin inhibits the release of glucagon and insulin.

Epsilon cells (ε-cells) produce the hormone ghrelin. Ghrelin stimulates appetite. Ghrelin hormones are increased before meals and are decreased after meals. The ghrelin hormone signals the hypothalamus in the brain. Body temperature, hunger, thirst, fatigue, anger, and sleep are controlled by the hypothalamus.

F Cells (PP cells) are pancreatic polypeptide producing cells. The PP cells are mainly found in the Islets of Langerhans at the head of the pancreas. The pancreatic polypeptide hormone is expressed at times when glucose levels in the blood are low. This can be created from fasting, exercising, eating protein meals, or from being hypoglycemic (low blood sugar). The increase of somatostatin and glucose in the blood decrease the PP levels. Having too little PP hormones appears to stimulate appetite, lessens the ability to resist the temptation of food, and increases the chances of a person becoming overweight.

Antarctic Ice

Ice sheets first appeared on Antarctica about 30 million years ago. Ice sheets continually flow from the Antarctic interior outwardly like a gently flowing river toward the ocean. As the glacial ice sheets reach the coast they tend to break off due to gravity, waves, current, and tides. Along the coast a portion of the glacier begins to crack, slowly, like time stood still and finally with a loud thunder a portion of the ice sheet (“calve”) falls into the seas.

During the winter months sea ice is formed from the freezing ocean water surrounding Antarctica. The seas around Antarctica begin to freeze in March (autumn). The sea ice forms quickly reaching half of its maximum thickness within a month. During the Antarctic Spring and summer (October through January) the sea ice breaks apart. The sea ice is extremely important to the ecosystem. The green algae need it as a habitat. The krill eat the algae, and a lot of animals in the Antarctic eat the krill. During the Antarctic spring the algae’s green pigment absorbs the solar radiation warming up the ice faster and breaking up the ice much quicker than it had formed. Build up of sea ice over successive seasons leach the salt brine from the ice creating fresh drinkable ice.

Seawater does not freeze at 32 F (0 C). The salt content in the sea water lowers the freezing temperature of the saltwater to 28oF (-1.8 C). Ice that appears to have an oily-sheen is called “Grease ice”. The grease ice is created when the surface water begins to freeze and crystallize on the salty brine. Within an hour the once ice free water can turn into a slushy icy-water mixture known as “Frazil-ice”. As the Frazil-ice thickens the water below begins to freeze. When the sea water begins to thicken more than four-inches then the ice is in the Nilas stage of ice berg formation.

Ocean swells and wind break the sea ice into large pieces called pack ice. Wind and currents provide the ability for the pack ice to move. Pack ice can change direction as it packs up against other ice. These conditions can be very dangerous as pack ice can make the journey impassable in a matter of hours. In some areas around the Antarctic, sea ice never forms. These areas have been identified as good navigational routes. These large ice-free open areas surrounded by pack ice are called “Polynyas” and they can be more than 60 miles across.

During the Antarctic summer the icebergs melt and change in shape. The majority of the iceberg is below the water. During the shifting of weight, sometimes an iceberg will “Turtle” as pieces break off and the iceberg can turn partially or completely over.

Antarctica has much larger icebergs than the Arctic. A large iceberg may weigh more than 400 million tons, and be more than 100 feet (30 m) above the surface. Icebergs do eventually melt. Sometimes a large iceberg can melt for years or decades. Most icebergs are less than 400 feet (123 m) across the waterline. The large icebergs are tabular and break off the ice sheets. They are generally 650 feet (200 m) to 1000 feet (308 m) thick. Icebergs break up into pieces named “growler” (< 15 ft), “bergy bits” (15-46 ft), small (47-200 ft), medium 201-400 ft), large 401-670 ft) and very large > 670 ft), depending on their size. Ice berg age can be rounded, irregular, or tabular in form. In 2000, an ice sheet broke off the Ross Ice Shelf in the Antarctic creating a 6,875 mi2 (11,000 km2) iceberg called B-15. In 2002, B-15 broke and created B-15A an 1875 mi2 (3000 km2) iceberg that finally in 2005 broke up.

Currently, the sea ice around the Antarctic is becoming less. The algae is not able to find suitable habitat, the krill is unable to find enough algae, which is causing a shift in penguin colonies.