Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Reexamination Certificate
1998-07-06
2004-05-11
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
C424S621000, C424S623000
Reexamination Certificate
active
06733792
ABSTRACT:
FIELD OF INVENTION
The present invention relates to arsenic sulfide compounds. The present invention also relates to pharmaceutical compositions useful for treating cancer, preferably hematological cancer and more preferably leukemia or lymphoma, which comprise an arsenic sulfide compound. The present invention further relates to methods for treating cancer, preferably hematological cancer and more preferably leukemia or lymphoma, using an arsenic sulfide compound. Finally, the present invention relates to processes for producing arsenic disulfide (As
4
S
4
).
BACKGROUND OF THE INVENTION
Cancer
Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia.
Leukemia refers to malignant neoplasms of the blood-forming tissues. Transformation to malignancy typically occurs in a single cell through two or more steps with subsequent proliferation and clonal expansion. In some leukemias, specific chromosomal translocations have been identified with consistent leukemic cell morphology and special clinical features (e.g., translocations of 9 and 22 in chronic myelocytic leukemia, and of 15 and 17 in acute promyelocytic leukemia). Acute leukemias are predominantly undifferentiated cell populations and chronic leukemias more mature cell forms.
Acute leukemias are divided into lymphoblastic (ALL) and non-lymphoblastic (ANLL or AML) types. They may be further subdivided by their morphologic and cytochemical appearance according to the French-American-British (FAB) classification or according to their type and degree of differentiation. The use of specific B- and T-cell and myeloid-antigen monoclonal antibodies are most helpful for classification. ALL is predominantly a childhood disease which is established by laboratory findings and bone marrow examination. ANLL or AML occurs at all ages and is the more common acute leukemia among adults; it is the form usually associated with irradiation as a causative agent.
One type of acute leukemias, acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, which generates a PML/RAR&agr; fusion protein between PML, a growth suppressor localized on nuclear matrix-associated bodies, and RAR&agr;, a nuclear receptor for retinoic acid (RA). PML/RAR&agr; was proposed to block myeloid differentiation through inhibition of nuclear receptor response, as does a dominant negative RAR&agr; mutant. In addition, in APL cells, PML/RAR&agr; displaces PML and other nuclear body (NB) antigens onto nuclear microspeckles, likely resulting in the loss of PML and/or NB functions. Diagnosis of acute promyelocytic leukemia (APL) is indicated most importantly on the morphological feature of APL cells in blood and bone marrow. A chromosomal translocation, t(15;17) is also typical of APL and is shown by banding or fluorescence in situ hybridization (FISH) staining techniques. The translocation can often be discovered in patients with APL, especially prior to complete remission. Polymerase chain reaction (PCR) of the patient's marrow also shows PML/RAR&agr; mRNA. Additionally, certain immunological markers, such as CD33
+
, CD13
+
, CD9
+
CD34
−
and HLA-DR
−
, are predominantly present in marrow cells.
Chronic leukemias are described as being lymphocytic (CLL) or myelocytic (CML). CLL is characterized by the appearance of mature lymphocytes in blood, bone marrow, and lymphoid organs. The hallmark of CLL is sustained, absolute lymphocytosis (>5,000/&mgr;L) and an increase of lymphocytes in the bone marrow. Most CLL patients also have clonal expansion of lymphocytes with B-cell characteristics. CLL is a disease of older persons. In CML (chronic myelocytic leukemia or chronic myeloid leukemia), the characteristic feature is the predominance of granulocytic cells of all stages of differentiation in blood, bone marrow, liver, spleen, and other organs. In the symptomatic patient at diagnosis the total WBC count is usually about 200,000/&mgr;L, but may reach 1,000,000/&mgr;L. CML is relatively easy to diagnose because of the presence of the Philadelphia chromosome.
With an incidence of 59,000 cases a year, the malignant lymphomas collectively represent the sixth most common causes of cancer in the United States. They are a heterogeneous group of disorders; about 15% of patients with malignant lymphomas have Hodgkin's disease, and the remainder have one of the non-Hodgkin's lymphomas. The etiology, epidemiology, pathology, clinical features, diagnostic evaluation and staging, treatment and management of lymphomas are disclosed in Malignant Lymphomas, the content of which is incorporated herein by reference. CML has been classified according to clinical courses such as, high grade, intermediate grade or low grade CML. Alternatively, CML has been classified according to immunological phenotyping such as T-cell, B-cell, or cytogenetic (chromosomal) aberrations. Histo-pathological changes and morphological changes are very important in the classification of CML. According to the current classification system, the non-Hodgkin's lymphomas are further subdivided into follicular, small cleaved cell and follicular, mixed small cleaved and large cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, mucosa-associated lymphoid tissue lymphoma, monocytoid B cell lymphomas, follicular, large cell lymphoma, diffuse, small cleaved cell lymphoma, diffuse, mixed small cleaved and large cell lymphoma, diffuse, large cell lymphoma, immunoblastic lymphoma, thymic B cell lymphoma, diffuse, small noncleaved cell lymphoma, lymphoblastic lymphoma, peripheral T cell lymphoma, large cell anaplastic lymphoma and non-Hodgkin's lymphomas in acquired immunodeficiency syndrome.
The very nature of hematopoietic cancer necessitates using systemic chemotherapy as the primary treatment modality. Drugs selected according to sensitivities of specific leukemias and lymphomas are usually given in combination. Radiation therapy may be used as an adjunct to treat local accumulations of leukemic cells. Surgery is rarely indicated as a primary treatment modality, but may be used in managing some complications. Bone marrow transplantation from an HLA-matched sibling is sometimes indicated.
Arsenic and Its Medical Uses
Arsenic has been considered to be both a poison and a drug for a long time in both Western and Chinese medical practices. In the latter part of the nineteenth century, arsenic was used frequently in attempts to treat diseases of the blood in the West. In 1878, it was reported that treatment of a leukemic patient with Fowler's solution (a solution containing potassium arsenite, valence +5) reduced markedly the count of white blood cells (Cutler and Bradford,
Am. J. Med. Sci.,
January 1878, 81-84). Further interests in the use of Fowler's solution as a palliative agent to treat chronic myelogenous leukemia (CML) was described by Forkner and Scott in 1931 (
J. Am. Med. Assoc.,
1931, iii, 97), and later confirmed by Stephens and Lawrence in 1936 (
Ann. Intern. Med.
9, 1488-1502). However, while the active chemical ingredient(s) of Fowler's solution was not determined, its toxicity was well recognized. Fowler's solution was administered strictly as an oral composition, and was given to leukemic patients as a solution until the level of white blood cells was depressed to an acceptable level or until toxicities (such as skin keratoses and hyperpigmentation) developed, while the patients enjoyed varying periods of remission. In the 1960's, Fowler's solution was still used occasionally in attempts to treat CML, however, most patients with CML were treated with other chemotherapeutic agen
Foley & Lardner
Owens, Jr. Howard V.
Wilson James O.
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