Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-09-12
2003-06-17
McGarry, Sean (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S375000, C435S377000
Reexamination Certificate
active
06579856
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates generally to molecular medicine and cancer therapy and more specifically to compositions that inhibit the stress activated protein kinase pathway and methods of using such compositions to sensitize cancer cells to a cancer therapy.
Background Information
In renewing tissues such as bone marrow, the intestine and the skin, a steady state is maintained between the rate of cell growth and the rate of cell death. In particular, the rate of cell death in renewing tissue occurs through programmed cell death pathways and are characterized by the process of apoptosis. Disruption of this steady state often is associated with the development of cancer. For example, where the rate of programmed cell death is lower than normal, an increased number of cells occurs in a tissue, resulting in the formation of a tumor.
Cancer cells are characterized by an ability to proliferate indefinitely and to invade into normal tissue surrounding the tumor. In addition, many types of cancer cells can metastasize throughout the body such that the tumor is disseminated in the cancer patient.
Conventional methods for treating cancer have increased the survival and quality of life of cancer patients. Such conventional methods include surgery, radiotherapy and chemotherapy. In addition, bone marrow transplantation is becoming useful in treating patients with certain types of cancers.
Surgery generally is the first choice for treating patients having a tumor that is localized to a specific area of the human body. Tumor excision is quick and quite effective, accounting for the majority of cures. However, surgery has several disadvantages. One major obstacle to this form of treatment occurs when the tumor is in an inoperable location such that resection of the tumor is not possible. In addition, the cancer already may have spread to other parts of the body, but is not yet detectable at the time of surgery. While surgical removal of the localized tumor can improve the quality of the patient's life, the cancer is destined to recur in the other locations. Similarly, even when a tumor is localized and has not yet spread, failure to remove all of the cancer cells can result in recurrence of the tumor. Finally, surgery is, by nature, an invasive procedure and can cause loss of function of a normal tissue or organ or affect the patient's appearance.
Radiotherapy often is used in combination with, or as an alternative, to surgery. Radiation primarily causes damage to the tumor cell DNA, thus inducing apoptosis and death of the cells. Of course, normal cells in the radiation field also are damaged, but normal cells generally have a greater ability than cancer cells to recover from radiation damage and, therefore, a therapeutic benefit can be obtained. However, radiation therapy, like surgery, is a localized treatment and suffers from the same inadequacies, for example, failure to kill tumor cells that are outside of the treatment field, particularly metastatic lesions. In addition, radiation damage occurs to particularly susceptible tissues such as bone marrow, skin and intestine, thus causing patient morbidity.
In contrast to surgery and radiotherapy, chemotherapy provides a systemic method of treating cancer. Chemotherapy utilizes various classes of chemotherapeutic agents that have different modes of action. For example, anti-metabolite chemotherapeutic agents generally share structural similarities with normal cellular components and exert their toxic effect by inhibiting a normal cellular process. For example, methotrexate is a chemical analogue of folic acid, which is a vitamin required for DNA synthesis. Methotrexate functions by competing with folic acid for binding to an enzyme normally involved in the conversion of folic acid into adenine and guanine, which are two building blocks of DNA. As a result of the competition, methotrexate prevents cells from dividing by inhibiting their ability to synthesize DNA.
Other chemotherapeutic agents, such as topoisomerase analogs or inhibitors and alkylating agents, also function by disrupting normal DNA synthesis in cells, resulting in death of the cells. Since tumor cells generally divide more rapidly than normal tissues, tumor cells are somewhat preferentially killed by such chemotherapeutic agents. However, as discussed above, cells such as bone marrow cells, intestinal epithelial cells and skin cells also are rapidly dividing and, therefore, susceptible to the toxic effects of such chemotherapeutic agents. In fact, it is the toxicity to normal cells that generally limits the dose of chemotherapeutic agent that can be administered to a patient. In addition, tumor cells have a propensity to acquire resistance to certain chemotherapeutic agents, further limiting the usefulness of such agents for treating cancer.
More recently, biochemical agents that are expressed normally in individuals and act as natural defense agents or as agents that induce natural immunity against diseased cells have been used as cancer therapeutic agents. In particular, the cytokines are a class of naturally occurring biochemicals that are involved in stimulation and activation of the immune response system. Such cytokines, including, for example, the interferons and interleukins can kill cells directly and provide the additional advantage that they can stimulate the patient's immune response. However, the normal expression of such biochemicals in the body is tightly regulated and the usefulness of agents is limited by the toxic effects that occur when higher than physiological amounts of these agents are administered to an individual.
In order to improve the therapeutic advantage of the various conventional cancer therapeutic modalities, the therapies often are used in combination. Thus, as toxicity to normal cells or tissues begins to occur due to the use of one modality, that modality is terminated and an second treatment using a different type of modality is initiated. Such first and second modalities can be, for example, surgery or radiotherapy, followed by chemotherapy, or a first type of chemotherapy followed by a second type of chemotherapy or a biochemical agent therapy.
In addition, a therapeutic advantage can be obtained by combining a therapeutic modality with treatment using an agent that modifies the effectiveness of the modality to a greater extent against cancer cells than normal cells. Such chemical modifiers generally are not toxic at the doses used, but act to modify or enhance the responsiveness of cancer cells to a conventional therapy. The effectiveness of a such chemical modifiers to sensitize tumor cells to a cytotoxic therapy generally is expressed as the sensitizer enhancement ratio, which is a ratio of the dose of a therapy required to produce a defined level of killing in the absence of the sensitizer to the dose required to produce the same level of cell killing in the presence of the sensitizer.
The use of chemical sensitizers is exemplified by the use of oxygen mimetics to increase the sensitivity of tumor cells to radiotherapy. Generally, the cancer cells forming a tumor grow faster than the cells that produce blood vessels in the tumor. As a result, as the tumor increases in size, it develops regions that are relatively deficient in oxygen. Such hypoxic tumor cells are relatively resistant to radiation damage and, therefore, limit the effectiveness of radiotherapy. However, chemical sensitizers have been developed that act as oxygen mimetics. The administration of such sensitizers to a cancer patient increases the “oxygenation” of the otherwise hypoxic tumor cells, thus rendering them more sensitive to a given dose of radiation. Since normal tissue generally is normally oxygenated, the use of such chemical sensitizers essentially has no effect on the normal cells. Of course, as discussed above, the use of radiotherapy nevertheless remains limited to treatment of patients having relatively localized tumors. Thus, while methods for treating cancer continue to improve, a nee
David B. Waller & Associates
McGarry Sean
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