2.1 Brain Cancer
Brain tumor contributes significantly to morbidity and mortality in every age group. In infants and young children, brain tumors are the second most common form of cancer, after leukemia. In adults, primary brain tumors rank thirteenth in frequency of all adult cancers and is the second and fifth leading cause of cancer-related deaths in men and women, respectively, ages 20–39 (Jemal et al., 2002, Cancer Statistics 52(1):23–45). The annual incidence rate, depending on the age group, is between 4.8 and 19.6 per 100,000 population (Boring et al., 1994, CA Cancer J Clin. 44:7–26). It is expected that over 186,000 brain tumors will be diagnosed in the United States during 2002. Of those people, about 36,600 will be diagnosed with a primary brain tumor, which is any tumor that originates in the brain; about 150,000 will be found to have a metastatic brain tumor, which is any tumor that began as a cancer elsewhere in the body and spread to the brain (7th ed. Primer of Brain Tumors, Chapter 3: Facts and Statistics).
The exact cause of brain tumors is unknown. However, several genetic and environmental factors have been identified as increasing the risk of brain cancer. Only about 5% of primary brain tumors are known to be associated with hereditary factors such as Li-Fraumeni syndrome (LFS), p53 defects (usually associated with LFS), tuberous sclerosis, neurofibromatosis 1 and 2, von Hippel-Lindau disease, Turcot syndrome, and familial polyposis. Families with higher-than-average cancer incidence may have an increased genetic pre-disposition. Pregnant women who took vitamin supplements containing C, A, E and/or folate during the entire period of their pregnancy were half as likely to have their child develop a brain tumor before age 5, as compared to those who didn't take vitamins (McNeil C., 1997, J of Natl Cancer Inst. 89:1481–82). Studies also show that brain cancer occurs more frequently in people regularly exposed to acrylonitrile, vinyl chloride, formaldehyde, lubricating oils, N-nitroso compounds, phenols, pesticides, polycyclic aromatic hydrocarbons, and organic solvents.
Specific symptoms, treatment, and prognosis (probable outcome) vary according to the site and type of the tumor and the age and general health of the person. For adults, common symptoms include recent onset or persistent headache, vomiting, personality and behavior changes, emotional instability, intellectual decline (e.g., confusion, loss of memory, impaired calculating abilities, and impaired judgment), seizures, reduced level of consciousness, neurologic changes (e.g., vision changes, hearing loss, decreased sensation of a body area, weakness of a body area, speech difficulties, and decreased coordination), fever, weakness, general ill feeling, positive Babinski's reflex, and decerebrate or decorticate posture. Common symptoms in infants include bulging fontanelles, separated sutures, opisthotonos, increased head circumference, no red reflex in the eye. Additional symptoms include tongue problems, difficulty swallowing, impaired smell, obesity, uncontrollable movement, absent menstruation, hiccups, hand tremor, facial paralysis, different pupil sizes, eyelid drooping, and breathing problem.
Examination often shows focal (isolated location) or general neurologic changes that are specific to the location of the tumor. While some tumors may not show symptoms until they are very large and cause rapid neurologic decline, others are characterized by slowly progressive symptoms. Most brain tumors will include signs typical of space-occupying masses (aggregations of cells) which cause increased intracranial pressure and compression of brain tissue. The diagnosis is usually confirmed, and the tumor localized by CT scan, MRI, angiography, and EEG of the head, CSF (cerebral spinal fluid), or a CPK isoenzymes test.
Brain tumors are classified on the basis of both cellular origin and histologic grade. Interestingly, neurons, although having an overall importance to brain function (numbering about 100 billion in the adult brain), have no significant reproductive capabilities and are therefore rarely the site of neoplastic transformation. Instead, half of all primary brain tumors are found at the glial cells (e.g., astocytomas, oligodendrogliomas, ependymomas, and glioglastoma multiforme). The remaining brain tumors take origin from a variety of other supporting elements of the CNS (central nervous system): meninges (meningiomas), choroid plexus (choroid plexus papillomas), nerve sheath tumors (neurinomas), and blood vessels (hemangioblastoma). Specifically, the following types of pediatric brain tumors are commonly diagnosed in infants and children: medulloblastoma (20%), cerebellar astrocytoma (10% to 30%), ependymoma (10%), brainstem glioma (10% to 15%), and craniopharyngioma (5%).
The staging of brain cancer is based on the revised criteria of TNM staging by the American Joint Committee for Cancer (AJCC) published in 1988. Staging is the process of describing the extent to which cancer has spread from the site of its origin. It is used to assess a patient's prognosis and to determine the choice of therapy. The stage of a cancer is determined by the size and location in the body of the primary tumor, and whether it has spread to other areas of the body. Staging involves using the letters T, N and M to assess tumors by the size of the primary tumor (T); the degree to which regional lymph nodes (N) are involved; and the absence or presence of distant metastases (M)—cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Each of these categories is further classified with a number 1 through 4 to give the total stage. Once the T, N and M are determined, a “stage” of I, II, III or IV is assigned. Stage I cancers are small, localized and usually curable. Stage II and III cancers typically are locally advanced and/or have spread to local lymph nodes. Stage IV cancers usually are metastatic (have spread to distant parts of the body) and generally are considered inoperable.
Brain cancer can be treated with surgery, radiation therapy, chemotherapy, surveillance, adjuvant (additional), or a combination of these treatments. Treatment of brain cancer depends on the type of cancer, the stage, the size and shape of the tumor, the age and general health of the patient.
Surgery is the primary treatment for accessible brain tumors. There are many different types of surgery for brain cancer. The most commonly performed surgery for removal of a brain tumor is called a craniotomy. Some patients with brain tumors develop increased intracranial pressure (IICP). To relieve the pressure, a shunt procedure to drain excess or blocked fluid is sometimes required. However, in certain situations, the tumor is too great in numbers, inaccessible and aggressive to cure.
Radiation therapy is a common treatment for brain tumors. It is often used following surgery, for inoperable tumor, to relieve symptoms, and to prevent a cancer in another part of the body from developing in the brain, at a dose of 40 to 60 Gy. Even though no survival advantage was shown, radiation therapy appeared to reduce the incidence of pelvic recurrences. Radiation is also used to shrink an especially large tumor prior to surgery or to slow the growth of inoperable tumors using either external beam (similar to an x-ray) or brachytherapy (internal radiation delivered with implanted radioactive seeds). Fatigue is a possible side effect of radiation therapy, but it gradually ceases after treatment is completed. More importantly, the brains of young children are very susceptible to radiation damages, deterring the use of radiation therapy.
Short-term chemotherapy, such as hydroxyurea and cisplatin, is used primarily in cases where the disease has spread outside the brain. Potential side effects include nausea and vomiting, loss of hair, low blood cell counts, and fatigue. Many chemotherapeutic drugs have been tried in the past as single agents for the palliation of brain cancer, but the results were generally disappointing. Nevertheless, the role of chemotherapy in the management of brain cancer is continually evolving. Oftentimes, chemotherapy with radiation in adjunct to surgery is used. In general, chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease (Ali et al., 2000, Oncology 14(8):1223–30). Unfortunately, the high initial response rates to first line chemotherapy does not appear to translate into a survival benefit (Kohno and Kitahara, 2001, Gan To Kagaku Ryoho 28(4):448–53). Moreover, there are many undesirable side effects associated with chemotherapy such as temporary hair loss, mouth sores, anemia (decreased numbers of red blood cells that may cause fatigue, dizziness, and shortness of breath), leukopenia (decreased numbers of white blood cells that may lower resistance to infection), thrombocytopenia (decreased numbers of platelets that may lead to easy bleeding or bruising), and gastrointestinal symptoms like nausea, vomiting, and diarrhea. Active chemotherapeutic agents include procarbazine, platinum analogs (cisplatin, carboplatin), the nitrosureas, and an oral medication called Temodar® (temozolomide). One chemotherapeutic agent that has proved to be effective is BCNU (Gliadel®, BiCNU®), which is placed into the surgical cavity after the tumor has been removed. Other chemotherapeutic agents for the treatment of recurrent gliomas include interferon and retinoic acid.
The identification of active chemotherapeutic agents against cancers traditionally involved the use of various animal models of cancer. The mouse has been one of the most informative and productive experimental system for studying carcinogenesis (Sills et al., 2001, Toxicol Letters 120:187–198), cancer therapy (Malkinson, 2001, Lung Cancer 32(3):265–279; Hoffman R M., 1999, Invest New Drugs 17(4):343–359), and cancer chemoprevention (Yun, 1999, Annals NY Acad Sci. 889:157–192). Cancer research started with transplanted tumors in animals which provided reproducible and controllable materials for investigation. Pieces of primary animal tumors, cell suspensions made from these tumors, and immortal cell lines established from these tumor cells propagate when transplanted to animals of the same species.
To transplant human cancer to an animal and to prevent its destruction by rejection, the immune system of the animal are compromised. While originally accomplished by irradiation, thymectomy, and application of steroids to eliminate acquired immunity, nude mice that are athymic congenitally have been used as recipients of a variety of human tumors (Rygaard, 1983, in 13th International Cancer Congress Part C, Biology of Cancer (2), pp37–44, Alan R. Liss, Inc., NY; Fergusson and Smith, 1987, Thorax, 42:753–758). While the athymic nude mouse model provides useful models to study a large number of human tumors in vivo, it does not develop spontaneous metastases and are not suitable for all types of tumors. Next, the severe combined immunodeficient (SCID) mice is developed in which the acquired immune system is completely disabled by a genetic mutation. Human lung cancer was first used to demonstrate the successful engraftment of a human cancer in the SCID mouse model (Reddy S., 1987, Cancer Res. 47(9):2456–2460). Subsequently, the SCID mouse model have been shown to allow disseminated metastatic growths for a number of human tumors, particularly hematologic disorders and malignant melanoma (Mueller and Reisfeld, 1991, Cancer Metastasis Rev. 10(3): 193–200; Bankert et al., 2001, Trends Immunol. 22:386–393). With the recent advent of transgenic technology, the mouse genome has become the primary mammalian genetic model for the study of cancer (Resor et aL, 2001, Human Molec Genet. 10:669–675).
While surgery, chemotherapeutic agents and radiation are useful in the treatment of brain cancer, there is a continued need to find better treatment modalities and approaches to manage the disease that are more effective and less toxic, especially when clinical oncologists are giving increased attention to the quality of life of cancer patients. The present invention provides an alternative approach to cancer therapy and management of the disease by using an oral composition comprising yeasts.
2.2 Yeast-Based Compositions
Yeasts and components thereof have been developed to be used as dietary supplement or pharmaceuticals. However, none of the prior methods uses yeast cells which have been cultured in an electromagnetic field to produce a product that has an anti-cancer effect. The following are some examples of prior uses of yeast cells and components thereof:
U.S. Pat. No. 6,197,295 discloses a selenium-enriched dried yeast product which can be used as dietary supplement. The yeast strain Saccharomyces boulardii sequela PY 31 (ATCC 74366) is cultured in the presence of selenium salts and contains 300 to about 6,000 ppm intracellular selenium. Methods for reducing tumor cell growth by administration of the selenium yeast product in combination with chemotherapeutic agents is also disclosed.
U.S. Pat. No. 6,143,731 discloses a dietary additive containing whole β-glucans derived from yeast, which when administered to animals and humans, provide a source of fiber in the diet, a fecal bulking agent, a source of short chain fatty acids, reduce cholesterol and LDL, and raises HDL levels.
U.S. Pat. No. 5,504,079 discloses a method of stimulating an immune response in a subject utilizing modified yeast glucans which have enhanced immunobiologic activity. The modified glucans are prepared from the cell wall of Saccharomyces yeasts, and can be administered in a variety of routes including, for example, the oral, intravenous, subcutaneous, topical, and intranasal route.
U.S. Pat. No. 4,348,483 discloses a process for preparing a chromium yeast product which has a high intracellular chromium content. The process comprises allowing the yeast cells to absorb chromium under a controlled acidic pH and, thereafter inducing the yeast cells to grow by adding nutrients. The yeast cells are dried and used as a dietary supplement.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents are considered material to the patentability of the claims of the present application. All statements as to the date or representations as to the contents of these documents are based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.