Definitions

• the invention relates generally to a device and method for preventing and
• present invention relates to devices and methods for preventing or treating cancers and other
• cell proliferative diseases such as arteriosclerosis, in mammals, by inducing or stimulating
• methods of the invention are useful in the stimulation of cell death and/or the inhibition of
• Cancer is characterized primarily by an increase
• a primary initiating factor in the formation of the atheromatous plaques is the proliferation of
• target cells include vascular and fibrotic proliferative diseases, retinopathies, eczema or
• Target cells include, but are not limited to, precancerous cells,
• cancerous cells cells having specific growth receptors and surrounding stromal cells in
• the receptors for growth factors may include, but are not limited to, the
• EGF epidermal growth factor
• TGF alpha and beta transforming growth factors
• NGF growth factor
• FGF fibroblast growth factor
• IGF insulin-like growth factors
• PDGF platelet-derived growth factor
• Apoptosis is a mechanism by which cells are programmed to die under a wide range of conditions.
• apoptosis is both a mechanism which suppresses tumorigenesis and is a predominant
• Apoptosis is also an important cellular response to a large variety of stress
• signals including, but not limited to, ionizing radiation, UN radiation, heat, growth factor
• T ⁇ F tumor necrosis factor
• IF ⁇ interferon
• the device can include
• a probe to be inserted into a site within the body or a transducer for focusing ultrasound at a
• the preventive and/or treatment method can be any suitable preventive and/or treatment method.
• the present invention can provide a method of preventing cancer by applying
• the method can include subjecting the
• the present invention can also provide a therapeutic method for the treatment
• ultrasonic energy source coupled to a transmitter which transmits the ultrasonic
• antioxidant therapy including the administration of an effective amount of an antioxidant such as vitamin E, N-acetylcysteine, glutathione, vitamin C, cysteine, methionine, 2-
• the present invention also provides devices and methods for inducing
• apoptosis of cells undergoing abnormal proliferation for example, in conditions including
• arteriosclerosis vascular and fibrotic proliferative diseases, retinopathies, eczema or
• antioxidants including vitamin E, N-acetylcysteine, reduced glutathione, vitamin,
• precancerous, cancerous and other target cells which includes an ultrasonic
• control unit which controls the amount of ultrasonic energy transmitted to the blood vessel
• the present invention is based on the unexpected discovery that ultrasonic
• apoptosis in target cells having one or more growth factors including, but not limited to EGF,
• TGF TGF, NGF, FGF, IGF, PDGF.
• the invention accordingly comprises the several steps and the relation of one
• Fig. 1 is a diagram illustrating the change in side scatter versus the forward
• quadrant (4) represents the early apoptotic cells with Annexin V-FITC positive
• the upper right quadrant (2) contains the non-viable, late apoptotic
• necrotic cells which are positive for Annexin V-FITC binding and for PI uptake.
• Figs. 2a, 2b, 2c and 2d are scattergrams representing the apoptotic cells as the
• lymphocytes taken from a chronic lymphocytic leukemia (CLL) patient
• lymphocytes from a patient suffering from CLL (after 48 hours) and lymphocytes from a patient suffering from CLL (after 8 hours) and HL-60
• Figs. 3a, 3b and 3c are photographs of cells showing the morphology of PHA-
• Fig. 4 is a schematic illustration of an invasive ultrasonic device in accordance
• the present invention generally pertains to novel devices and methods for
• the cancer prevention and therapy methods of the invention are fundamentally based upon a newly-discovered effect of
• invention also provides a method for inducing apoptosis in aging cells and/or tissues that
• Cancer is a disease of inappropriate tissue accumulation. This derangement is
• combination of agents is complex and is likely to include more than one process.
• cytotoxic drugs can be most effective against cycling cells.
• Flourouracil 5'-Flouro-deoxyuridine, Camptothecin, Hydroxyurea, Ara-C, 5-Azacytidine, Nitrogen Mustard, Methotrexate, Chlorambucil, Bleomycin, BCNU, Actinomycin D or
• Apoptosis is a general property of most cells, being fundamental for the
• apoptosis or programmed cell death is both apoptosis and a programmed cell death
• Apoptosis is an important cellular response to a variety of signals including
• ionizing radiation UV radiation, heat, cytokines (TNF and IFN ⁇ ) as well as
• Apoptosis is a distinct morphological form of cell death which can be
• a striking characteristic of apoptosis is the formation of
• the proto-oncogene Bcl-2 suppresses apoptosis through the regulation of an antioxidant
• methods of the present invention are directed to inhibit Bcl-2 induced antiapoptotic activity
• Suitable antioxidants include, but are not limited to, one or more of N-
• antioxidant formulations or pharmaceutical compositions may be any antioxidant formulations or pharmaceutical compositions.
• Formulations may be administered in a variety of routes and routes of delivery.
• forms including for example, solid (tablets, pills, powders), semi-solid and liquid dosage
• compositions may be
• proliferative diseases retinopathies, eczema or psoriasis.
• Patient dosages for oral administration would vary according to the oxidant
• the adult dose for vitamin E would range from 200 LU. to 1000 LU per
• epithelial cells in prostate cancer is influenced by EGF, TGF-alpha, TGF-beta, NGF and
• methods of the present invention include, but are not limited to, human sarcomas and
• carcinomas e.g., colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate
• fibrosarcoma myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma,
• chondroma angiosarcoma, endotheliosarcoma, lymphangiosarcoma,
• lymphangioendotheliosarcoma synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,
• rhabdomyosarcoma squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat
• gland carcinoma sebaceous gland carcinoma, papillary carcinoma, papillary
• adenocarcinomas adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal
• carcinoma Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung
• carcinoma bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,
• craniopharyngioma ependymoma, pinealoma, hemangioblastoma, acoustic neuroma
• oligodendroglioma meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias, e.g.,
• acute lymphocytic leukemia and acute myelocytic leukemia myeloblastic, promyelocytic,
• myelomonocytic, monocytic and erythroleukemia myelomonocytic, monocytic and erythroleukemia
• chronic leukemia chronic myelocytic
• lymphoma Hodgkin's disease and non-Hodgkin's disease
• multiple myeloma Waldenstrom's
• the invention is illustrated, by way of protocols for ultrasound therapy alone
• cancer radiation therapy, hormonal therapy or chemotherapy in treatment of prostate cancer.
• Cytoxtoxic chemotherapy is largely ineffective in treating
• prostate cancer Accordingly, there is a great demand for improved prostate cancer
• the present invention provides a method of preventing and treating prostate
• cancer comprising ultrasound therapy alone or in combination with a conventional therapy
• preoperatively i.e., to the tumor in situ or postoperatively, in the region of the tumor after
• An invasive ultrasonic device can include the following elements shown in the
• a power generator 20 supplies an apoptosis inducing system with
• a handpiece 40 in a handpiece 40, includes piezoelectric elements (not shown) that convert electrical energy
• An ultrasonic transmission wire 50 is connected at its proximal end to
• the transducer and has an ultrasound tip 60 at the other end.
• the ultrasonic energy can be any suitable ultrasonic energy.
• the frequency level of ultrasound energy used is in the range of 1 kHz to 3
• Power is supplied by power generator 20. Tumor cell irradiation is performed
• Tumor cell are irradiated with a power, for example
• ultrasound system being used as well as on the target tissue.
• Non-invasive ultrasound technology enables delivery of ultrasonic energy
• the energy of the treatment should be high enough to create acoustic transient cavitation at the
• the energy is preferably
• Either continuous wave or pulsed wave ULS can be used.
• a target tissue such as a soild tumor.
• the device can be made compatible with ultrasound imaging systems by the
• the combined system can serve as both
• a software package can add the capability to
• diseases in accordance with the present invention may typically include a therapeutic agent
• ultrasound probe preferably containing therapeutic and imaging capabilities.
• ultrasound element can be based on any method for focusing ultrasound (e.g., geometric, annular array, phase array).
• the system will typically also include a control unit for
• controlling the ultrasonic energy output which may preferably include a monitor, similar to
• Peripheral blood mononuclear cells were obtained from healthy adult
• CLL chronic lymphatic leukemia
• the blood mononuclear cells were isolated by density gradient
• RPMI-1640 containing 10% fetal calf serum (FCS).
• FCS fetal calf serum
• PHA phytohemaglutinin
• the blood MNC and the HL-60 leukemic cells were treated with ultrasonic
• a sonicator which consists of a resonant length (90mm) of a vertically suspended thin
• titanium probe (diameter 2mm) and which resonates at a frequency of 20 kHz and variable power levels.
• the temperature was measured using a
• thermocoupler which was placed in the test tube.
• Controls consisted of the same number of unsonicated cells.
• the LD50 of the therapeutic ultrasound was found to be 1.5 watts for 15 sec
• the plasma membrane integrity was analyzed by an assay for detection of
• Annexin V which has a high affinity for PS
• lymphocytes after 48 hours. The percentage of total blood MNC in early apoptosis after
• the second method employed to detect apoptotic cells was by measuring the
• hypo-diploid cell population cells indicative of degraded DNA in
• the third method used to study apoptosis was to monitor morphological
• Figs. 3a, 3b and 3c indicate the morphological changes of MNC undergoing
• apoptosis including the condensation of nuclear chromatin and nuclear fragmentation (shown
• PHA-activated M ⁇ C cells and CLL M ⁇ C cells contain degraded D ⁇ A and show a

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• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

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• 1998
  • 1998-12-18 EP EP98964087A patent/EP1140289A1/de not_active Withdrawn
  • 1998-12-18 AU AU19283/99A patent/AU1928399A/en not_active Abandoned
  • 1998-12-18 JP JP2000589247A patent/JP2002532210A/ja active Pending
  • 1998-12-18 CA CA002333626A patent/CA2333626A1/en not_active Abandoned

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