Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-02-28
2003-11-11
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S314000, C514S357000, C514S367000, C514S375000, C514S400000, C514S359000, C514S427000, C546S172000, C546S331000, C548S179000, C548S217000, C548S267200, C548S323500, C548S561000, C564S082000, C564S091000, C564S092000
Reexamination Certificate
active
06646009
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to compositions and methods for the treatment of proliferative disorders, including but not limited to cancer. The invention relates to the field of protecting normal cells and tissues from anticipated, planned or inadvertent exposure to ionizing radiation.
BACKGROUND OF THE INVENTION
&agr;-&bgr;-Unsaturated Sulfonamides
Cancer remains a leading cause of mortality in the United States and in the world. To be useful, a new chemotherapeutic agent should have a wide spectrum of activity and significant therapeutic index. Styrene-&ohgr;-sulfonanilide has been prepared by reacting styrylsulfonyl chloride with aniline (Bordwell et al.,
J. Amer. Chem. Soc.
68:139, 1946). This and certain other styrene-&ohgr;-sulfonanilides have been prepared by Knoevenagel-type synthesis as possible chemosterilants against the common house fly
Musca domestica
L. (Oliver et al,
Synthesis
321-322, 1975).
U.S. Pat. No. 4,035,421 to Snyder, Jr. describes the preparation of N-(3,4-dichlorophenyl)-2-phenylethenesulfonamide and its use as an antibacterial agent.
The styrene-&ohgr;-sulfonanilides 3′-hydroxy-4-nitrostyrene-&bgr;-sulfonanilide, 3′-hydroxy-2-nitrostyrene-&bgr;-sulfonanilide and 5′-hydroxy-2′-methyl-4-nitrostyrene-&bgr;-sulfonanilide were utilized as intermediates in the preparation of certain stilbenes by Waldau et al.
Angew. Chem., Int. Ed. Engl.
11(9):826-818 (1972). The styrene-&ohgr;-sulfonanilides 3′-hydroxy-3-nitrostyrene-&bgr;-sulfonanilide and 5′-hydroxy-2′-methyl-4-nitrostyrene-&bgr;-sulfonanilide have been utilized in the preparation of stilbenes used as dyes (DE 2118493—Farbenfab AG).
Aswarthamma et al.,
Chimica Acta Turcica
24:7-10 (1996) disclose the preparation of certain trans-(1-aryl-(2-anilinesulphonyl)ethylenes. No biological activity is set forth for the compounds. Touarti et al.,
J. Soc. Alger. Chim.
6(1):39-52 (1996) disclose the preparation of certain &agr;,&bgr;-unsaturated sulfonamides for inhibition of coniferyl alcohol dehydrogenase (CADH).
Except for the isolated teaching of antibacterial activity of N-(3,4-dichlorophenyl)-2-phenylethenesulfonamide, no useful pharmaceutical activity has been proposed for the limited numbers of &agr;,&bgr;-unsaturated sulfonamides known to the prior art. In particular, no anti-cell proliferation or anticancer utility has been proposed for this class of compounds.
New cell antiproliferative agents, and anticancer therapeutics in particular, are needed which are useful in inhibiting proliferation of and/or killing cancer cells. In particular, such agents are needed which are selective in the killing of proliferating cells such as tumor cells, but not normal cells. Antineoplasitc agents are needed which are effective against a broad range of tumor types.
Ionizing Radiation Health Risks
Ionizing radiation has an adverse effect on cells and tissues, primarily through cytotoxic effects. In humans, exposure to ionizing radiation occurs primarily through therapeutic techniques (such as anticancer radiotherapy) or through occupational and environmental exposure.
A major source of exposure to ionizing radiation is the administration of therapeutic radiation in the treatment of cancer or other proliferative disorders. Depending on the course of treatment prescribed by the treating physician, multiple doses may be received by a subject over the course of several weeks to several months.
Therapeutic radiation is generally applied to a defined area of the subject's body which contains abnormal proliferative tissue, in order to maximize the dose absorbed by the abnormal tissue and minimize the dose absorbed by the nearby normal tissue. However, it is difficult (if not impossible) to selectively administer therapeutic ionizing radiation to the abnormal tissue. Thus, normal tissue proximate to the abnormal tissue is also exposed to potentially damaging doses of ionizing radiation throughout the course of treatment. There are also some treatments that require exposure of the subject's entire body to the radiation, in a procedure called “total body irradiation”, or “TBI.” The efficacy of radiotherapeutic techniques in destroying abnormal proliferative cells is therefore balanced by associated cytotoxic effects on nearby normal cells. Because of this, radiotherapy techniques have an inherently narrow therapeutic index which results in the inadequate treatment of most tumors. Even the best radiotherapeutic techniques may result in incomplete tumor reduction, tumor recurrence, increasing tumor burden, and induction of radiation resistant tumors.
Numerous methods have been designed to reduce normal tissue damage while still delivering effective therapeutic doses of ionizing radiation. These techniques include brachytherapy, fractionated and hyperfractionated dosing, complicated dose scheduling and delivery systems, and high voltage therapy with a linear accelerator. However, such techniques only attempt to strike a balance between the therapeutic and undesirable effects of the radiation, and full efficacy has not been achieved.
For example, one treatment for subjects with metastatic tumors involves harvesting their hematopoietic stem cells and then treating the subject with high doses of ionizing radiation. This treatment is designed to destroy the subject's tumor cells, but has the side effect of also destroying their normal hematopoietic cells. Thus, a portion of the subject's bone marrow (containing the hematopoietic stem cells), is removed prior to radiation therapy. Once the subject has been treated, the autologous hematopoietic stem cells are returned to their body.
However, if tumor cells have metastasized away from the tumor's primary site, there is a high probability that some tumor cells will contaminate the harvested hematopoietic cell population. The harvested hematopoietic cell population may also contain neoplastic cells if the subject suffers from a cancers of the bone marrow such as the various French-American-British (FAB) subtypes of acute myelogenous leukemias (AML), chronic myeloid leukemia (CML), or acute lymphocytic leukemia (ALL). Thus, the metastasized tumor cells or resident neoplastic cells must be removed or killed prior to reintroducing the stem cells to the subject. If any living tumorigenic or neoplastic cells are reintroduced into the subject, they can lead to a relapse.
Prior art methods of removing tumorigenic or neoplastic cells from harvested bone marrow are based on a whole-population tumor cell separation or killing strategy, which typically does not kill or remove all of the contaminating malignant cells. Such methods include leukopheresis of mobilized peripheral blood cells, immunoaffinity-based selection or killing of tumor cells, or the use of cytotoxic or photosensitizing agents to selectively kill tumor cells. In the best case, the malignant cell burden may still be at 1 to 10 tumor cells for every 100,000 cells present in the initial harvest (Lazarus et al. J. of Hematotherapy, 2(4):457-66, 1993).
Thus, there is needed a purging method designed to selectively destroy the malignant cells present in the bone marrow, while preserving the normal hematopoietic stem cells needed for hematopoietic reconstitution in the transplantation subject.
Exposure to ionizing radiation can also occur in the occupational setting. Occupational doses of ionizing radiation may be received by persons whose job involves exposure (or potential exposure) to radiation, for example in the nuclear power and nuclear weapons industries. Military personnel stationed on vessels powered by nuclear reactors, or soldiers required to operate in areas contaminated by radioactive fallout, risk similar exposure to ionizing radiation. Occupational exposure may also occur in rescue and emergency personnel called in to deal with catastrophic events involving a nuclear reactor or radioactive material. Other sources of occupational exposure may be from machine parts, plastics, and solvents left over from the manufacture of radioactive me
Bell Stanley C.
Reddy E. Premkumar
Reddy M.V. Ramana
O'Sullivan Peter
Temple University — Of Commonwealth System of Higher Education
LandOfFree
N-(aryl)-2-arylethenesulfonamides and therapeutic uses thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with N-(aryl)-2-arylethenesulfonamides and therapeutic uses thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and N-(aryl)-2-arylethenesulfonamides and therapeutic uses thereof will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3136080