Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-06
2002-12-24
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S142100
Reexamination Certificate
active
06498181
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of treating cancer in which histamine is administered in conjunction with other cancer therapies. The cancer therapy includes surgery, radiation, immunotherapy, the administration of an agent which enhances the humoral immune response of the patient or any combination thereof.
BACKGROUND OF THE INVENTION
Despite tremendous advances over the past several years, current cancer therapies fail to cure many forms of cancer. The problems faced by investigators and clinicians are numerous. Some tumors are not resectable or do not respond to radiation or chemotherapy or combinations of these procedures. Furthermore, the severe morbidity often associated with these treatments has led many to look for entirely new approaches to tumor therapy that are more specifically lethal for cancer cells and less toxic for normal cells. Attempts to promote an immune response to the tumor by immunizing the cancer patient with killed cancer cells or antigens specific for cancer cells have been largely unsuccessful and the use of monoclonal antibodies (mAbs) as the “magic bullet” to specifically destroy cancer cells without harming normal cells remains clinically limited. Methods that enhance the effectivity of known cancer therapies are desperately needed.
Surgery is touted by many to be the only potentially curative therapy for patients suffering from stomach, pancreatic, carcinoid and ovarian tumors. (Norton,
Digestion
55(suppl 3):98-103 (1994)). Although surgery is often the indicated treatment for malignant disease, this form of cancer therapy has two major shortcomings. First, many tumors are not resectable because they are located in or have spread into vital structures. (Dvorak et al.,
Cancer Cells
3: 77-85 (1991)). While debulking of tumors in vital areas has been presented as an alternative, such procedures are felt by many to inadequately treat the disease and only improve the quality of life of the patient. (Norton,
Digestion
55(suppl 3):98-103 (1994)). Second, by the time of diagnosis and removal of the primary tumor, many tumors have already metastasized. (Dvorak et al.,
Cancer Cells
3: 77-85 (1991)) and (Norton,
Digestion
55(suppl 3):98-103 (1994)). Metastases, which tend to be multiple and wide spread, do not easily lend themselves to surgical excision and, consequently, many patients undergo major surgical procedures only to have rapid disease progression found soon after surgery. (Dvorak et al.,
Cancer Cells
3: 77-85 (1991)). While surgery remains a good first line of defense against cancer, oncologists are now also combining other treatment methods including radiation, chemotherapy and immunotherapy to obtain better patient survival. (Hacker and van der Burg,
Annals of Oncology
4 (suppl. 4): S17-S22 (1993)).
External beam radiation has replaced surgery for the long-term control of many tumors of the head and neck, cervix, bladder, prostate and skin, in which it often achieves a reasonable probability of tumor control with good cosmetic result. (
Basic Clinical Radiobiology
2nd edition. Steel ed., Arnold Publishers, pp. 1-13 (1997)). External beam radiation is generally helpful for the treatment of localized tumors but this approach is also problematic because it causes considerable damage to surrounding cells and compromises the patient's immune system. The use of radioactive “seed implants” has provided more focus on tumor cells and less damage to surrounding tissue but a more specific means to deliver radiation to the tumor is needed. While radiation therapy is a good alternative to surgery, it is unable to treat a large percentage of cancers that are radiation-insensitive and, because of the high morbidity associated with high doses of external beam radiation, the use of radiation to treat metastastic disease is not desirable. (Dvorak et al.,
Cancer Cells
3: 77-85 (1991)).
Many forms of antibody therapy to treat cancer have also been reported. Early antibody therapy treatments relied almost entirely on complement fixation to kill tumor cells. (
Cellular and Molecular Immunology
. Eds. Abul K Abbas, Andrew H. Lichtman, and Jordan S. Pober, W. B. Saunders Co., Philadelphia (1991)). Recently, greater success has been achieved using antibodies which block cancer cell growth factor receptors. (
Wong, Genetic Engineering News
pp.23 and 49 (July 1998) and Ashley et al.,
J of Neuro-Oncology
35:259-273 (1997)). The use of antibody conjugates which bind tumor cells with cytotoxic substances such as toxic molecules or radioisotopes has also seen promising results. (Larson et al.,
ACTA Oncologica
32:709-715 (1993); Quack and van Dongen,
Eur Arch Otorhinolaryngol
251:1-5 (1994); Frankel et al.,
Cancer Biology
6:307-317 (1995); Mach et al.,
Curr Op in Immunol
3:685-693 (1191) and
Recent Results in Cancer Research vol
141
:Systemic Radiotherapy with Monoclonal Antibodies
. edited by M. L. Sautter-Bihl and M Wannenmacher, Springer-Verlag publishers, (1996)). Another innovative antibody treatment for cancer uses antibody heteroconjugates—dual purpose antibodies which direct bound cancer cells to phagocytic cells of the immune system. (Wong,
Genetic Engineering News
pp.23 and 49 (July 1998)). Preliminary clinical trials with mAb heteroconjugates have shown promise in the treatment of renal and prostate cancer. (Id.).
Although a variety of tumor cells can be lysed in vitro by antibody-dependent mechanisms such as complement activation or antibody-dependent cell-mediated cytotoxicity, few therapies based on enhancing the humoral response of a subject have been clinically successful. (Sedlacek,
Critical Reviews in Oncogenesis
5(6):555-587 (1994)). In one study, patients suffering from melanoma were administered a vaccine containing a mixture of three allogenic melanoma cell lines and showed a 71% 10-year actuarial survival as opposed to the 40% 10-year actuarial survival demonstrated by melanomic patients who received a single cell line vaccine. (Slingluff and Seigler,
Ann Plast Surg
28:104-107 (1992)). In another study, however, leukemic patients immunized with killed leukemia cells failed to demonstrate any significant improvement. (
Cellular and Molecular Immunology
. Eds. Abul K Abbas, Andrew H. Lichtman, and Jordan S. Pober, W. B. Saunders Co., Philadelphia (1191)).
In an attempt to improve cancer vaccines, researchers have tried numerous strategies to make the cancer cell vaccines more antigenic. (Sedlacek,
Critical Reviews in Oncogenesis
5(6):555-587 (1994)). Studies on immunization with plasmid DNA encoding defined tumor antigens or with a complex comprising hydrophobized polysaccharides attached to an oncogenic receptor protein, for example, may show greater clinical success. (Tuting et al.,
J Mol Med
75:478-491 (1997) and Gu et al.
Cancer Research
58:3385-3390 (1998)). At present investigators have had limited success with treating cancer by administering agents which enhance the humoral response of the patient and approaches to improve the effectivity of this form of treatment are needed.
Despite recent progress in cancer therapy, many problems persist. Tumors often metastasize, grow in sensitive areas and are not treatable by surgery or radiation. (Dvorak et al.,
Cancer Cells
3: 77-85 (1191)). Tumor cells also generally avoid immunosurveillance in the cancer patient and most current vaccines poorly trigger a cancer patient's immune system to overcome this immunotolerant state. (Sedlacek;
Critical Reviews in Oncogenesis
5(6):555-587 (1994)). Further, the use of antibody therapies such as immunotoxins, immunoradionuclides, immunoheteroconjugates, and receptor specific antibodies has been limited by low-level expression of the targeted tumor associated antigen, low-affinity mAbs, inefficient radionuclides, non-specific toxicity of the antibody conjugate and poor tumor uptake of the therapeutic agent. (Ashley et al.,
J of Neuro-Oncology
35:259-273 (1997); Frankel et al.,
Cancer Biology
6:307-317 (1995); Mach et al.,
Curr Op in Immunol
. 3:685-693 (1191) and Sedlacek,
C
Gehlsen Kurt R.
Hellstrand Kristoffer
Hermodsson Svante
Goldberg Jerome D.
Knobbe Martens Olson & Bear LLP
Maxim Pharmaceuticals
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