Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
1998-12-08
2001-07-24
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S145100, C424S152100, C424S153100, C424S155100, C530S350000, C530S351000, C530S380000, C530S386000, C530S387100
Reexamination Certificate
active
06264948
ABSTRACT:
FIELD OF THE INVENTION
The invention relates in general to the field of cancer prevention and treatment.
BACKGROUND OF THE INVENTION
The inhibition of malignant cell induction and proliferation is the primary goal of cancer prevention and treatment. Physiological changes that are coincident with the occurrence of cancer may indicate phenomena that are either causative or protective with regard to the development and progression of the disease and are, therefore, of significant interest to clinical researchers.
Eosinophils are granulocytic leukocytes with bi-lobed nuclei, named for their property of staining red in eosin dye. Their production from bone marrow stem cells, maturation and activation occur specifically in response to signals mediated by interleukin-5 (Weller, 1991,
New England J. Med,
324: 1110-1118). These cells reside largely in epithelium-lined tissues that are in contact with the environment, such as the gastrointestinal- and lower genitourinary tracts, as well as the respiratory epithelium (Devos et al., 1995,
J. Leuk. Biol.,
57: 813-819; Weller, 1991, supra; Wong et al., 1990,
J. Exp. Med.,
172: 673-681).
Tissue eosinophilia in malignancies of epithelial origin has been reported since 1893 (Reinback, 1893,
Arch. Klin. Chir.,
46: 486-562); however, the role of the eosinophil in the cancer etiology remains unclear. Eosinophil influx has been shown to be associated with a number of human tumors, primarily carcinomas (Goldsmith et al., 1987,
Otolaryngology
-
Head and Neck Surgery,
96: 319-|
-324; Iwasaki et al., 1986,
Cancer,
58: 1321-1327; Kolb and Muller, 1979,
Br. J. Cancer,
40: 410-416; Lowe and Fletcher, 1984,
Histopathology,
8: 627-632; Loew et al., 1984,
Histopathology,
8: 619-625; McGinnis et al., 1989,
Cancer Res.,
49: 5989-5993; Pretlow et al., 1983,
Cancer Res.,
43: 2997-3000).
While eosinophils have been found not to suppress growth in interleukin-5 transfected tumor cells (Kuger-Krasagakes et al., 1993,
Eur. J. Immunol.,
23: 992-995), suppression of tumor development has been demonstrated in cells transfected with genes encoding either IL-4 (Tepper et al., 1989,
Cell,
57: 503-512) or monocyte chemoattractant MCP-1/JE (Rollins and Sunday, 1991,
Mol. Cell. Biol.,
11: 3125-3131) through a host-reactive inflammatory response that consists of significant tissue eosinophilia. Using antibodies that specifically block the accumulation of granulocytes at the site of inflammation, it further has been demonstrated that eosinophils are directly involved in the observed IL-4-mediated tumor cytotoxicity (Tepper et al., 1992,
Science,
257: 548-551).
Published clinical evidence supports both host-protective and tumor-inducing roles for eosinophils in cancer, thereby providing little or no therapeutic guidance. Stromal eosinophilia has been suggested as a favorable prognostic indicator in cases of human neoplasms, including head and neck cancers (Goldsmith et al., 1987, supra), which supports the hypothesis of a “protective” role of eosinophils in cancer. Increased survival and decreased metastasis correlate positively with the level of tumor associated tissue eosinophilia (TATE) in patients suffering colonic carcinoma (Pretlow et al., 1983, supra) and tumors of the uterine cervix (Kapp and Livolsi, 1983,
Gynecologic Oncology,
16: 19-30). Heavy eosinophilic infiltration has been suggested as indicating an unfavorable prognosis in well-differentiated squamous cell carcinomas of the oral cavity (Horiuchi et al., 1993,
J. Surg. Oncol.,
53: 92-96); however, this finding is contradicted by reports that massive tissue eosinophilia is associated with a favorable prognosis in cases of squamous cell carcinoma of the oral cavity, external genitalia, and anus (Lowe and Fletcher, 1984,
Histopathology,
8: 627-632) as well as tumors of the bladder (Lowe and Fletcher, 1984,
J. Clin. Pathol.,
37: 500-502). It has also been reported that interleukin-4 transfected tumor cells lose their ability to form tumors if eosinophils are present (Tepper et al., 1989,
Cell,
57: 503-512).
There is a need in the art for improved methods for the prevention and treatment of cancer.
SUMMARY OF THE INVENTION
The invention provides a method of suppressing tumor cell growth, comprising administration to a mammal in need thereof of an amount of an inhibitor of eosinophilia sufficient to result in a delay in the onset- or reduction in the rate of tumor cell growth.
As used herein, the term “suppressing” refers to reducing the frequency of tumor formation in individuals who are at risk of developing tumors. A 2- to 10-fold reduction in the percentage of at-risk individuals at who form tumors after treatment with an inhibitor of eosinophilia, relative to the percentage of at-risk individuals who form tumors when left untreated, is required for treatment to be considered effective according to the invention. Preferably, the reduction is in the range of 20- to 100-fold, or even to 200- to 1,000-fold. The term “suppressing” additionally refers to increasing the length of time required for tumor cells to arise after exposure to a tumorigenic substance (or, in the case of subjects with a genetic propensity to develop tumors, birth), reducing the rate of cell division in an existing tumor or causing regression (shrinkage in cell number) of an existing tumor. A prolongation of the onset of tumor cell growth that is indicative of effective treatment according to the invention is at least 4-fold, preferably from 5- to 10-fold, and even from 20- to 100-fold the average length of time until the first tumor cells are observed in control individuals in whom eosinophilia has not been blocked. In order to be judged effective, an inhibitor of eosiniophilia must mediate a reduction in the rate of cell division in an existing tumor of at least 2- to 10-fold, preferably 20- to 100-fold and even up to 200- to 1000-fold. A regression of at least 50% of tumor burden in treated individuals relative to untreated controls is indicative of effective treatment according to the invention; preferably, such a loss of tumor cell mass is up to 75% or even 100% of the total present.
A “tumor cell” is any cell that has undergone one or more rounds of cell division that take place outside the course of the growth of an organism to maturity, normal biological function (e.g. the production of hematopoietic cells or gametes from stem cells) or wound healing, characterized by a loss of contact inhibition or substrate dependence or changes in morphology and/or protein production.
As used herein, “malignant” refers to cancerous cell growth.
In contrast, “normal tissue” is defined as being one or more cells that are not tumor cells and/or that do not possess a malignant phenotype (that is, that do not display cancerous cell growth), as defined above.
As used herein to describe tumor cells, the term “growth” is defined as including induction (determination that a normal cell will become a tumor cell), transformation (differentiation of a normal cell to a tumor cell, whether or not such transformation is oncogenic) and proliferation.
As used herein, the term “mammal” refers to any member of the Class Mammalia, including a human.
Preferably, the mammal is a human.
As used herein, the term “inhibitor” is defined as any substance which blocks or reverses the influx of eosinophils into tumor tissue or an adjacent site, whether directly or by inhibiting a signalling pathway that results in such infiltration. Such blocking or reversal may occur at the level of synthesis of a substance that promotes the maturation or migration of eosinophils. Alternatively, it may be the native activity of such a substance which is blocked or reversed, either directly, or by inhibition of downstream target molecules, e.g. in a signalling cascade or biosynthetic pathway. An inhibitor may exert an opposing function (for example, activation of a receptor that is opposed by the substance being inhibited, or of a receptor that regulates a signalling cascade that results in an opposing function to that controlled by a receptor activated by
Weller Peter F.
Wong David T. W.
Beth Israel Deaconess Hospital, Inc.
Harris Alana M.
Huff Sheela
Palmer & Dodge LLP
Williams Kathleen M.
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