WO2005112966A1 - Thérapie combinée extrait végétal plus un réovirus pour tuer les cellules néoplasiques chez un sujet - Google Patents

Thérapie combinée extrait végétal plus un réovirus pour tuer les cellules néoplasiques chez un sujet Download PDF

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Publication number
WO2005112966A1
WO2005112966A1 PCT/IB2004/001729 IB2004001729W WO2005112966A1 WO 2005112966 A1 WO2005112966 A1 WO 2005112966A1 IB 2004001729 W IB2004001729 W IB 2004001729W WO 2005112966 A1 WO2005112966 A1 WO 2005112966A1
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Prior art keywords
reovirus
herbal extract
administered
cells
subject
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PCT/IB2004/001729
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English (en)
Inventor
Danny Chiu Leung Cheung
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Orison Biotechnology Inc.
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Priority to PCT/IB2004/001729 priority Critical patent/WO2005112966A1/fr
Publication of WO2005112966A1 publication Critical patent/WO2005112966A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/074—Ganoderma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/765—Reovirus; Rotavirus

Definitions

  • the field of the invention is killing neoplastic cells in a subject.
  • Cancer remains one of the leading causes of morbidity and mortality of humans worldwide.
  • Current methods of treatment for neoplasia include surgery, radiation, chemotherapy and gene therapy.
  • Surgery is typically used as the primary treatment for early stages of cancer; however, many tumors cannot be completely removed by surgical means.
  • metastatic growth of neoplasms may prevent complete cure of cancer by surgery.
  • Radiation therapy relies on the greater ability of normal cells, in contrast with neoplastic cells, to repair themselves after treatment with radiation. Radiotherapy cannot be used to treat many neoplasms, however, because of the sensitivity of tissue surrounding the tumor.
  • certain tumors have demonstrated resistance to radiotherapy and such may be dependent on oncogene or anti-oncogene status of the cell.
  • Chemotherapy involves administration of compounds having anticancer activity, such as alkylating agents, antimetabolites, and antitumor antibiotics.
  • the efficacy of chemotherapy is often limited by severe side effects, including nausea and vomiting, bone marrow depression, renal damage, and central nervous system depression.
  • gene therapy anticancer strategies various shortcornings in virus vectors and other gene vectors have limited the efficacy of gene therapy methods for eradicating neoplastic cells from subjects such as humans afflicted with cancer.
  • the need still exists for improved methods for the treatment of most types of cancers.
  • Reovirus has recently been discovered as a selective anticancer agent which kills ras-activated neoplastic cells but not normal cells, due to selective replication of reovirus in cells with an activated ras pathway (U.S. Pat. No. 6,136,307; - U.S. Pat. No. 6,565,831; Lee, P.W.K. et al. (1999) "Reovirus for the Treatment of Neoplasia", PCT International Application No.
  • the present invention overcomes the shortcomings of prior art anticancer therapies involving reovirus and chemotherapeutic agent by improving the efficacy of reovirus anticancer therapy and by elirninating the severe side effects associated with the chemotherapeutic agent.
  • the present invention relates to a method of killing neoplastic cells in a subject having neoplastic cells.
  • the method comprises administering a herbal extract and a reovirus to the subject.
  • the herbal extract and reovirus exhibit anticancer activities that are at least additive, and that may be synergistic.
  • the herbal extract is an extract from a Ganoderma lucidum.
  • the Ganoderma lucidum includes a spore and/or a fruiting body.
  • Reovirus has recently been discovered as a selective anticancer agent which kills ras- activated neoplastic cells but not normal cells, due to selective replication of reovirus in cells with an activated ras pathway (U.S. Pat. No. 6,136,307; U.S. Pat. No. 6,565,831; Lee, P.W.K. et al. (1999) "Reovirus for the Treatment of Neoplasia", PCT International Application No. PCT/CA98/00774; Coffey M C et al., (1998) Science 282:1332; Strong J E et al., (1998) EMBO J 17: 3351).
  • reovirus is capable of sensitizing a neoplastic cell to a chemotherapeutic agent having anticancer activity.
  • the effects of the combination of both reovirus and chemotherapeutic agent are not only additive but also synergistic (Coffey et al. (2002) "Sensitization of chemotherapeutic agent resistant neoplastic cells with a virus" US Patent Application Publication No. US 2002/0168344 Al). Therefore, it is contemplated that reovirus may also be capable of sensitizing a neoplastic cell to a herbal extract having anticancer activity.
  • the present invention of using combination of a reovirus and a herbal extract may improve the efficacy of reovirus anticancer therapy and more importantly, may eliminate the severe side effects associated with a chemotherapeutic agent.
  • the methods and uses of the invention provide an effective means to kill neoplastic cells in a subject, without the side effects associated with other forms of cancer therapy.
  • reovirus and herbal extract are not known to be associated with disease, any safety concerns associated with deliberate administration of the reovirus and the herbal extract are minimized.
  • one aspect of the present invention provides a method of sensitizing a neoplastic cell to a herbal extract, comprising:
  • the cell is preferably a ras-activated neoplastic cell.
  • the reovirus is administered under conditions which result in infection of the neoplastic cell by the reovirus.
  • the cell may be susceptible to the herbal extract in the absence of reovirus.
  • reovirus can preferably be administered prior to administration of the herbal extract.
  • reovirus and the herbal extract can be administered concurrently with each other. Both the reovirus and herbal extract may individually be administered in a single dose or multiple doses.
  • the neoplastic cell is preferably located in a mammal, particularly a dog, cat, sheep, goat, cattle, horse, pig, human or non-human primates.
  • the cell is most preferably located in a human.
  • the present invention may be used to sensitize neoplastic cells to herbal extract.
  • the herbal extract is an extract from a Ganoderma lucidum.
  • the Ganoderma lucidum includes a spore and/or a fruiting body.
  • the reovirus may be any reovirus, including mammalian and avian reovirus.
  • the reovirus is a mammalian virus, particularly a human reovirus.
  • the human reovirus is preferably a serotype 3 reovirus and most preferably a Dealing strain serotype 3 reovirus.
  • Also provided by the present invention is a method of killing neoplastic cells in a subject having neoplastic cells, said method comprising:
  • the reovirus may be administered any time with respect to the herbal extract.
  • the reovirus is administered prior to or concurrently with administration of the herbal extract.
  • the reovirus is administered in multiple doses.
  • the herbal extract may also be a ⁇ rninistered in multiple doses. It is contemplated that the reovirus may be acLm sculpturestered in multiple doses prior to any administration of the herbal extract.
  • the subject is preferably a mammal, particularly a dog, cat, sheep, goat, cattle, horse, pig, human or non-human primates, and most preferably a human.
  • the method of the present invention may be used to kill neoplastic cells in a mammal such as human.
  • the neoplastic cells may be selected from the group consisting of lung cancer cells, prostate cancer cells, colorectal cancer cells, thyroid cancer cells, renal cancer cells, adrenal cancer cells, liver cancer cells, pancreatic cancer cells, breast cancer cells, lymphomas cells, leukemias cells and central and peripheral nervous system cancer cells.
  • the neoplastic cells may be an original neoplastic cell or a metastatic neoplastic cell.
  • the invention also relates to pharmaceutical composition
  • pharmaceutical composition comprising a herbal extract and a reovirus.
  • the invention further relates to a kit for killing neoplastic cells in a subject having neoplastic cells.
  • the kit comprises a herbal extract and a reovirus.
  • the kit may further comprise an instructional material.
  • the invention still further relates to use of a herbal extract and a reovirus for manufacture of a medicament for killing neoplastic cells in a subject having neoplastic cells.
  • the invention yet further relates to use of a herbal extract and a reovirus for manufacture of a kit for killing neoplastic cells in a subject having neoplastic cells.
  • the present invention relates to a method of killing neoplastic cells in a subject having neoplastic cells.
  • the method comprises administering a herbal extract and a reovirus to the subject.
  • the herbal extract and reovirus exhibit anticancer activities that are at least additive, and that may be synergistic.
  • the herbal extract is an extract from a
  • the Ganoderma lucidum includes a spore and/or a fruiting body.
  • Reovirus has recently been discovered as a selective anticancer agent which kills ras- activated neoplastic cells but not normal cells, due to selective replication of reovirus in cells with an activated ras pathway (U.S. Pat. No. 6,136,307; U.S. Pat. No. 6,565,831 ; Lee, P.W.K. et al. (1999) "Reovirus for the Treatment of Neoplasia", PCT International Application No. PCT/CA98/00774; Coffey M C et al., (1998) Science 282:1332; Strong J E et al., (1998) EMBO J 17: 3351).
  • reovirus is capable of sensitizing a neoplastic cell to a chemotherapeutic agent having anticancer activity.
  • the effects of the combination of both reovirus and chemotherapeutic agent are not only additive but also synergistic
  • reovirus may also be capable of sensitizing a neoplastic cell to a herbal extract having anticancer activity.
  • Ganoderma lucidum Although the molecular mechanisms involved in the biological actions of Ganoderma lucidum are not well understood, the dried powder of Ganoderma lucidum is commercially available as a food supplement. More importantly, Ganoderma lucidum is not known to be associated with disease. Most importantly, recent studies have indicated that Ganoderma lucidum demonstrates strong anticancer activity, and is suggested to be as a potential therapeutic tool for the treatment of cancers (Sliva D et al. (2003), " Biologic activity of spores and dried powder from Ganoderma lucidum for the inhibition of highly invasive human breast and prostate cancer cells" J Altern Complement Med., 9(4):491-7; Sliva D et al.
  • the cell surface recognition signal is sialic acid (Armstrong, G. D. et al. (1984), Virology 138:37; Gentsch, J. R. K. and Pacitti, A. F. (1985), J. Virol. 56:356; Paul R. W. et al. (1989) Virology 172:382-385). Due to the ubiquitous nature of sialic acid, reovirus binds efficiently to a multitude of cell lines and as such can potentially target many different tissues; however, there are significant differences in susceptibility to reovirus infection between cell lines. This is probably the reason why reovirus is not known to be associated with any particular disease.
  • the present invention of using combination of a reovirus and a herbal extract may improve the efficacy of reovirus anticancer therapy and more importantly, may eliminate the severe side effects, such as nausea and vomiting, bone marrow depression, renal damage, and central nervous system depression, associated with a chemotherapeutic agent.
  • an element means one element or more than one element.
  • a “subject” is an animal, preferably a mammal such as a human.
  • a neoplastic cell is "killed” if it is induced to lyse, if it is induced to undergo apoptosis, or if it is rendered incapable of growing or dividing.
  • Ganoderma lucidum refers to Ganoderma lucidum (Fr.) Karst or refers to any basidiomycete classified in the genus Ganoderma of Polyporaceae.
  • a "herbal extract” refers to a pharmaceutical preparation consisting essentially of an extract from a Ganoderma lucidum.
  • the Ganoderma lucidum includes a spore and/or a fruiting body.
  • “Sensitizing" a neoplastic cell to a herbal extract refers to the act of enhancing the sensitivity of a neoplastic cell to a herbal extract.
  • Sensitivity of a neoplastic cell to a herbal extract is the susceptibility of the neoplastic cell to the inhibitory effect of the herbal extract.
  • sensitivity of a neoplastic cell to a herbal extract is indicated by reduction in growth rate of the cell in response to the herbal extract. The sensitivity may also be demonstrated by a reduction of the symptoms caused by the neoplastic cells.
  • chemotherapeutic agent is any chemical compound having anticancer activity used in the treatment of cancers.
  • neoplasm refers to the entry and replication of reovirus in a neoplastic cell.
  • infection of a neoplasm by reovirus refers to the entry and replication of reovirus in the neoplastic cells of a neoplasm.
  • a new growth comprising neoplastic cells is a neoplasm, also known as a tumor.
  • a neoplasm is an abnormal tissue growth, generally forming a distinct mass, that grows by cellular proliferation more rapidly than normal tissue growth.
  • a neoplasm may show partial or total lack of structural organization and functional coordination with normal tissue.
  • a neoplasm is intended to encompass hematopoietic tumors as well as solid tumors.
  • a neoplasm may be benign (benign tumor) or malignant (malignant tumor or cancer).
  • Malignant tumors can be broadly classified into three major types. Malignant neoplasms arising from epithelial structures are called carcinomas, malignant neoplasms that originate from connective tissues such as muscle, cartilage, fat or bone are called sarcomas and malignant tumors affecting hematopoietic structures (structures pertaining to the formation of blood cells) including components of the immune system, are called leukemias and lymphomas. Other neoplasms include, but are not limited to neurofibromatosis.
  • proliferative disorder is a disease or condition caused by cells which grow more quickly than normal cells, i.e., neoplastic cells.
  • Proliferative disorders include benign tumors and malignant tumors. When classified by structure of the tumor, proliferative disorders include solid tumors and hematopoietic tumors.
  • Ras-activated neoplastic cells or “ras-mediated neoplastic cells” refer to cells which proliferate at an abnormally high rate due to, at least in part, activation of the ras pathway.
  • the ras pathway may be activated by way of ras gene structural mutation, elevated level of ras gene expression, elevated stability of the ras gene message, or any mutation or other mechanism which leads to the activation of ras or a factor or factors downstream or upstream from ras in the ras pathway, thereby increasing the ras pathway activity.
  • EGF receptor EGF receptor
  • PDGF receptor PDGF receptor
  • Ras-mediated neoplastic cells include, but are not limited to, ras-mediated cancer cells, which are cells proliferating in a malignant manner due to activation of the ras pathway.
  • Reovirus refers to any virus classified in the reovirus genus, whether naturally occiirring, modified or recombinant.
  • Reoviruses are viruses with a double-stranded, segmented RNA genome.
  • the virions measure 60-80 nrn in diameter and possess two concentric capsid shells, each of which is icosahedral.
  • the genome consists of double- stranded RNA in 10-12 discrete segments with a total genome size of 16-27 kbp. The individual RNA segments vary in size.
  • Three distinct but related types of reovirus have been recovered from many species. All three types share a common complement- fixing antigen.
  • the human reovirus consists of three serotypes: type 1 (strain Lang or TIL), type 2 (strain Jones, T2J) and type 3 (strain Dealing or strain Abney, T3D).
  • type 1 strain Lang or TIL
  • type 2 strain Jones, T2J
  • type 3 strain Dealing or strain Abney, T3D
  • the three serotypes are easily identifiable on the basis of neutralization and hemagglutinin- inhibition assays (Sabin, A. B. (1959), Science 130:966; Fields, B. N. et al. (1996), Fundamental Virology, 3rd Edition, Lippincott-Raven; Rosen, L. (1960) Am. J. Hyg.71:242; Stanley, N. F. (1967) Br. Med. Bull. 23:150).
  • the reovirus may be naturally occurring or modified.
  • the reovirus is "naturally- occurring" when it can be isolated from a source in nature and has not been intentionally modified by humans in the laboratory.
  • the reovirus can be from a "field source", that is, from a human who has been infected with the reovirus.
  • the reovirus may be modified but still capable of lyrically infecting a mammalian cell having an active ras pathway.
  • the reovirus may be chemically or biochemically pretreated (e.g., by treatment with a protease, such as chymotrypsin or trypsin) prior to administration to the neoplastic cells. Pretreatment with a protease removes the outer coat or capsid of the virus and may increase the infectivity of the virus.
  • the reovirus may be coated in a liposome or micelle (Chandron and Nibert, 1998).
  • the virion may be treated with chymotrypsin in the presence of micelle forming concentrations of alkyl sulfate detergents to generate a new infectious subvirion particle.
  • the reovirus may be a recombinant (i.e. reasserted) reovirus from two or more types of reoviruses with differing pathogenic phenotypes such that it contains different antigenic determinants, thereby reducing or preventing an immune response by a mammal previously exposed to a reovirus subtype.
  • recombinant virions can be generated by co-infection of mammalian cells with different subtypes of reovirus with the resulting resorting and incorporation of different subtype coat proteins into the resulting virion capsids.
  • the reovirus may be modified by incorporation of mutated coat proteins, such as for example .sigma.l, into the virion outer capsid.
  • the proteins may be mutated by replacement, insertion or deletion.
  • Replacement includes the insertion of different amino acids in place of the native amino acids
  • insertions include the insertion of additional amino acid residues into the protein at one or more locations.
  • Deletions include deletions of one or more amino acid residues in the protein.
  • Such mutations may be generated by methods known in the art. For example, oligonucleotide site directed mutagenesis of the gene encoding for one of the coat proteins could result in the generation of the desired mutant coat protein.
  • mutated protein infected mammalian cells in vitro such as COS1 cells will result in the incorporation of the mutated protein into the reovirus virion particle (Turner and Duncan, 1992; Duncan et al., 1991; Mah et al., 1990).
  • the reovirus is preferably a reovirus modified to reduce or eliminate an immune reaction to the reovirus.
  • modified reovirus are termed "immunoprotected reovirus".
  • Such modifications could include packaging of the reovirus in a liposome, a micelle or other vehicle to mask the reovirus from the mammals immune system.
  • the outer capsid of the reovirus virion particle may be removed since the proteins present in the outer capsid are the major determinant of the host humoral and cellular responses.
  • administering reovirus refers to the act of administering reovirus to a subject in a manner so that it contacts the target neoplastic cells.
  • the route by which the reovirus is administered, as well as the formulation, carrier or vehicle, will depend on the location as well as the type of the target cells. A wide variety of administration routes can be employed and is discussed below in further detail.
  • a "metastatic neoplastic cell” is a neoplastic cell that has metastasized from a tumor located at another place in the same animal.
  • An “effective amount” is an amount of a herbal extract or reovirus which is sufficient to result in the intended effect.
  • an efficient amount is an amount sufficient to alleviate or eliminate the symptoms of the disease, or to slow down the progress of the disease.
  • an efficient amount is an amount sufficient to increase sensitivity of the neoplastic cell to the herbal extract.
  • Reovirus is an effective therapeutic agent against ras-activated neoplasia because it selectively replicates in cells with an activated ras pathway (U.S. Pat. No. 6,136,307).
  • the ras pathway is not activated in normal cells, therefore reovirus kills neoplastic cells with high selectivity.
  • Recent studies have also demonstrated that reovirus is capable of sensitizing a neoplastic cell to a chemotherapeutic agent having anticancer activity.
  • the effects of the combination of both reovirus and chemotherapeutic agent are not only additive but also synergistic (Coffey et al.
  • reovirus may also be capable of sensitizing a neoplastic cell to a herbal extract having anticancer activity.
  • reovirus in the present invention, representative types of human reovirus that can be used include type 1 (e.g., strain Lang or TIL); type 2 (e.g., strain Jones or T2J); and type 3 (e.g., strain Dealing or strain Abney, T3D or T3A); other strains of reovirus can also be used.
  • the reovirus is human reovirus serotype 3, more preferably the reovirus is human reovirus serotype 3, strain Dealing.
  • the reovirus can be a non-human mammalian reovirus (e.g., non-human primate reovirus, such as baboon reovirus; equine; or canine reovirus), or a non-mammalian reovirus (e.g., avian reovirus).
  • non-human primate reovirus such as baboon reovirus; equine; or canine reovirus
  • a non-mammalian reovirus e.g., avian reovirus
  • a combination of different serotypes and/or different strains of reovirus, such as reovirus from different species of animal, can be used.
  • the reovirus may be naturally occurring or modified.
  • the reovirus is "naturally- occurring" when it can be isolated from a source in nature and has not been intentionally modified by humans in the laboratory.
  • the reovirus can be from a "field source", that is, from a human who has been infected with the reovirus.
  • the reovirus may be modified but still capable of lytically infecting a mammalian cell having an active ras pathway.
  • the reovirus may be chemically or biochemically pretreated (e.g., by treatment with a protease, such as chymotrypsin or trypsin) prior to administration to the neoplastic cells. Pretreatment with a protease removes the outer coat or capsid of the virus and may increase the infectivity of the virus.
  • the reovirus may be coated in a liposome or micelle (Chandron and Nibert, 1998).
  • the virion may be treated with chymotrypsin in the presence of micelle forming concentrations of alkyl sulfate detergents to generate a new infectious subvirion particle.
  • the reovirus may be a recombinant (i.e. reasserted) reovirus from two or more types of reoviruses with differing pathogenic phenotypes such that it contains different antigenic determinants, thereby reducing or preventing an immune response by a mammal previously exposed to a reovirus subtype.
  • recombinant virions can be generated by co-infection of mammalian cells with different subtypes of reovirus with the resulting resorting and incorporation of different subtype coat proteins into the resulting virion capsids.
  • the reovirus may be modified by incorporation of mutated coat proteins, such as for example .sigma.l, into the virion outer capsid.
  • the proteins may be mutated by replacement, insertion or deletion.
  • Replacement includes the insertion of different amino acids in place of the native amino acids.
  • Insertions include the insertion of additional arnino acid residues into the protein at one or more locations.
  • Deletions include deletions of one or more amino acid residues in the protein.
  • Such mutations may be generated by methods known in the art. For example, oligonucleotide site directed mutagenesis of the gene encoding for one of the coat proteins could result in the generation of the desired mutant coat protein.
  • mutated protein infected mammalian cells in vitro such as COS1 cells will result in the incorporation of the mutated protein into the reovirus virion particle (Turner and Duncan, 1992; Duncan et al., 1991; Mah et al., 1990).
  • the reovirus is preferably a reovirus modified to reduce or eliminate an immune reaction to the reovirus.
  • modified reovirus are termed "immunoprotected reovirus".
  • Such modifications could include packaging of the reovirus in a liposome, a micelle or other vehicle to mask the reovirus from the mammals immune system.
  • the outer capsid of the reovirus virion particle may be removed since the proteins present in the outer capsid are the major determinant of the host humoral and cellular responses.
  • the reovirus is administered in a manner so that it contacts the target neoplastic cells.
  • the route by which the reovirus is administered, as well as the formulation, carrier or vehicle, will depend on the location as well as the type of the target cells.
  • a wide variety of administration routes can be employed.
  • the reovirus can be administered by injection directly to the neoplasm.
  • the reovirus can be adniinistered intravenously or intravascularly.
  • the reovirus is administered in a manner such that it can be transported systemically through the body of the mammal and thereby reach the neoplasm (e.g., intravenously or intramuscularly).
  • the reovirus can be administered directly to a single solid neoplasm, where it then is carried systemically through the body to metastases.
  • the reovirus can also be administered subcutaneously, intraperitoneally, intrathecally (e.g., for brain tumor), topically (e.g., for melanoma), orally (e.g., for oral or esophageal neoplasm), rectally (e.g., for colorectal neoplasm), vaginally (e.g., for cervical or vaginal neoplasm), nasally or by inhalation spray (e.g., for lung neoplasm).
  • intrathecally e.g., for brain tumor
  • topically e.g., for melanoma
  • orally e.g., for oral or esophageal neoplasm
  • rectally e.g., for colorectal neoplasm
  • vaginally e.g., for cervical or vaginal neoplasm
  • nasally or by inhalation spray e.g., for lung neoplasm
  • the reovirus or herbal extract can be aclministered in a single dose, or multiple doses (i.e., more than one dose).
  • the multiple doses can be administered concurrently at different sites or by different routes, or consecutively (e.g., over a period of days or weeks).
  • the reovirus is preferably administered prior to or concurrently with administration of the herbal extract.
  • the effective amount is from about 10.sup.2 pfu/kg body weight to about 10.sup.13 pfu/kg body weight.
  • approximately 10.sup.2 to 10.sup.13 plaque forming units (PFU) of reovirus can be used.
  • the effective amount will be determined on an individual basis and may be based, at least in part, on consideration of the type of reovirus; the chosen route of administration; the individual's size, age, gender; and the like.
  • the reovirus is preferably formulated in a unit dosage form, each dosage containing from about 10.sup.2 pfus to about 10.sup.13 pfus of the reovirus.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of reovirus calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the method of the present invention may be used to kill neoplastic cells in a mammal such as human.
  • the neoplastic cells may be selected from the group consisting of lung cancer cells, prostate cancer cells, colorectal cancer cells, thyroid cancer cells, renal cancer cells, adrenal cancer cells, liver cancer cells, pancreatic cancer cells, breast cancer cells, lymphomas cells, leukemias cells and central and peripheral nervous system cancer cells.
  • the subject is preferably a mammal, particularly a dog, cat, sheep, goat, cattle, horse, pig, human or non-human primates, and most preferably a human.
  • the present invention may be combined with other tumor therapies such as radiation therapy or surgery.
  • the present invention can be used to increase the sensitivity of neoplastic cells to herbal extract.
  • the herbal extract is an extract from a Ganoderma lucidum.
  • the Ganoderma lucidum includes a spore and/or a fruiting body.
  • the extract of the present invention can be prepared from the Ganoderma lucidum by utilizing the procedures set forth below, or any organic extraction procedure.
  • the invention includes a pharmaceutical composition useful for killing neoplastic cells in a subject having neoplastic cells.
  • This composition comprises a herbal extract and a reovirus.
  • the composition may be supplied as an already-mixed composition or as two separate compositions which are mixed shortly before or during administration to the subject.
  • the invention also includes a kit comprising a herbal extract and a reovirus.
  • the kit differs from the pharmaceutical composition in that the herbal extract and reovirus in the kit need not be combined before or during administration to the subject, but may instead be administered to the subject at different times (e.g. within days, hours, or seconds).
  • the kit may further include an instructional material which describes use of the herbal extract and reovirus for killing neoplastic cells in a subject, appropriate dosages, appropriate routes of administration, appropriate dosing schedules, or the like.
  • each of the herbal extract and the reovirus may be supplied, together or separately, in a variety of forms.
  • each is provided in the form of an injectable or infusible solution or suspension, or in a form which may be easily reconstituted (e.g. by addition of sterile water, saline, or buffer) to generate an injectable or infusible solution or suspension.
  • a solution or suspension which may be injected directly into the tumor tissue or in a form which be easily reconstituted to generate an injectable solution or suspension.
  • the invention encompasses the preparation and use of medicaments and pharmaceutical compositions comprising a herbal extract and a reovirus as active ingredients.
  • a pharmaceutical composition may consist of the active ingredients alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the active ingredients and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. Administration of one of these pharmaceutical compositions to a subject is useful for killing neoplastic cells in the subject, as described elsewhere in the present disclosure.
  • the herbal extract may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
  • the term "pharmaceutically acceptable carrier” means a chemical composition with which one or more of the active ingredients may be combined and which, following the combination, can be used to administer the active ingredient(s) to a subject.
  • physiologically acceptable ester or salt means an ester or salt form of a herbal extract which is compatible with any other ingredients of the pharmaceutical composition and which is not deleterious to the subject to which the composition is to be administered.
  • compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient(s) into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
  • pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for a ⁇ rninistration to animals of all sorts.
  • compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.
  • Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other mammals such as primates, and laboratory animals such as mice, rats, guinea pigs, rabbits, and the like.
  • compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ophmahnic, or another route of a ⁇ rninistration, depending on the anticipated site at or to which the composition is to be administered.
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
  • a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient(s).
  • the amount of the active ingredient(s) is generally equal to the dosage of the active ingredient(s) which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • compositions of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
  • a formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared, packaged, or sold in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient.
  • Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion.
  • an "oily" liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water.
  • a tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent.
  • Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture.
  • compositions used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents.
  • Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate.
  • Known surface active agents include, but are not limited to, sodium lauryl sulphate.
  • Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate.
  • Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid.
  • binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.
  • Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.
  • Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient.
  • a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets.
  • tablets may be coated using methods described in
  • Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide pharmaceutically elegant and palatable preparation.
  • Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
  • an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
  • Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin.
  • Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.
  • Oral compositions may be made, using known technology, which specifically release orally-administered agents in the small or large intestines of a human patient.
  • formulations for delivery to the gastrointestinal system, including the colon include enteric coated systems, based, e.g., on methacrylate copolymers such as poly(methacrylic acid, methyl methacrylate), which are only soluble at pH 6 and above, so that the polymer only begins to dissolve on entry into the small intestine.
  • the site where such polymer formulations disintegrate is dependent on the rate of intestinal transit and the amount of polymer present.
  • a relatively thick polymer coating is used for delivery to the proximal colon (Hardy et al., 1987 Aliment. Pharmacol.
  • Polymers capable of providing site-specific colonic delivery can also be used, wherein the polymer relies on the bacterial flora of the large bowel to provide enzymatic degradation of the polymer coat and hence release of the drug.
  • azopolymers U.S. Pat. No. 4,663,308
  • glycosides Friend et al., 1984, J. Med. Chem. 27:261-268
  • Pulsed release technology such as that described in U.S. Pat. No. 4,777,049 may also be used to administer the active agent to a specific location vvithin the gastrointestinal tract.
  • Such systems permit drug delivery at a predetermined time and can be used to deliver the active agent, optionally together with other additives that my alter the local microenvironment to promote agent stability and uptake, directly to the colon, without relying on external conditions other than the presence of water to provide in vivo release.
  • Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.
  • Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle.
  • Aqueous vehicles include, for example, water and isotonic saline.
  • Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
  • Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents.
  • Oily suspensions may further comprise a tMckening agent.
  • suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose.
  • Known dispersing or wetting agents include, but are not limited to, natoally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g. polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively).
  • natoally-occurring phosphatides such as lecithin
  • condensation products of an alkylene oxide with a fatty acid with a long chain aliphatic alcohol
  • a partial ester derived from a fatty acid and a hexitol or with a partial ester derived from a fatty acid and
  • emulsifying agents include, but are not limited to, lecithin and acacia.
  • preservatives include, but are not limited to, methyl, ethyl, or n-propyl-para- hydroxybenzoates, ascorbic acid, and sorbic acid.
  • Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.
  • Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.
  • Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent.
  • Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent.
  • Aqueous solvents include, for example, water and isotonic saline.
  • Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
  • Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.
  • a pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion.
  • the oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these.
  • compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for rectal administration.
  • a composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or colomc irrigation.
  • Suppository formulations may be made by combining the active ingredient with a non- irritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i.e. about 20.degree. C.) and which is liquid at the rectal temperature of the subject (i.e. about 37.degree. C. in a healthy human).
  • Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various glycerides.
  • Suppository formulations may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives.
  • Retention enema preparations or solutions for rectal or colonic irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier.
  • enema preparations may be administered using, and may be packaged within, a delivery device adapted to the rectal anatomy of the subject.
  • Enema preparations may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives.
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for vaginal adniinistration.
  • a composition may be in the form of, for example, a suppository, an impregnated or coated vaginally-insertable material such as a tampon, a douche preparation, or a solution for vaginal irrigation.
  • Methods for impregnating or coating a material with a chemical composition include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e. such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.
  • Douche preparations or solutions for vaginal irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier.
  • douche preparations may be administered using, and may be packaged within, a delivery device adapted to the vaginal anatomy of the subject.
  • Douche preparations may further comprise various additional ingredients including, but not limited to, antioxidants, antibiotics, antifungal agents, and preservatives.
  • parenteral adn ⁇ inistration of a pharmaceutical composition includes any route of adudinistration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue.
  • Parenteral a ⁇ xriinistration thus includes, but is not limited to, admimstration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
  • parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intravenous, intraarterial, intramuscular, or intrasternal injection and intravenous, intraarterial, or kidney dialytic infusion techniques.
  • Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline.
  • a pharmaceutically acceptable carrier such as sterile water or sterile isotonic saline.
  • Such formulations may be prepared, packaged, or sold in a form suitable for bolus a ⁇ rninistration or for continuous administration.
  • injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules, in multi-dose containers containing a preservative, or in single-use devices for auto-injection or injection by a medical practitioner.
  • Formulations for parenteral adrninistration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained- release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
  • the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.
  • compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
  • This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
  • Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example.
  • Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
  • compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
  • Formulations suitable for topical adniinistration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in- water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, and preferably from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for adniinistration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling solvent/powder-dispensing container such as a device comprising the active ingredient dissolved or suspended in a low-boiling propellant in a sealed container.
  • such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. More preferably, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions preferably include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65.degree. F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient).
  • compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension.
  • Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration preferably have an average diameter in the range from about 0.1 to about 200 nanometers.
  • additional ingredients include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials.
  • excipients surface active agents
  • dispersing agents inert diluents
  • granulating and disintegrating agents binding agents
  • lubricating agents such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; e
  • the ordinarily skilled physician or veterinarian will readily determine and prescribe effective amounts of the herbal extract and reovirus of the invention to kill neoplastic cells in the subject. In so proceeding, the physician or veterinarian may, for example, prescribe relatively low doses at first, subsequently increasing the doses until an appropriate response is obtained. It is further understood, however, that the specific dose levels for any particular subject will depend upon a variety of factors including the activities of the specific herbal extract and reovirus employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the extent, density, location, and type of neoplastic cells to be killed.
  • kits comprising a pharmaceutical composition of the invention and an instructional material.
  • an "instructional material” includes a publication, a recording, a diagram, or any other medium of expression which is used to communicate the usefulness of the pharmaceutical composition of the invention for killing neoplastic cells in a subject.
  • the instructional material may also, for example, describe an appropriate dose of the pharmaceutical composition of the invention.
  • the instructional material of the kit of the invention may, for example, be affixed to a container which contains a pharmaceutical composition of the invention or be shipped together with a container which contains the pharmaceutical composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the pharmaceutical composition be used cooperatively by the recipient.
  • the invention also includes a kit comprising a pharmaceutical composition of the invention and a delivery device for delivering the composition to a subject.
  • the delivery device may be a squeezable spray bottle, a metered-dose spray bottle, an aerosol spray device, an atomizer, a dry powder delivery device, a self- propelling solvent/powder-dispensing device, a syringe, a needle, a tampon, or a dosage measuring container.
  • the kit may further comprise an instructional material as described herein.

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Abstract

L’invention inclut des méthodes, des compositions, et des trousses pour tuer des cellules néoplasiques chez un sujet, tel un patient humain. Les méthodes comprennent l’administration d’un extrait végétal et d'un réovirus sur un patient qui a des cellules néoplasiques. L’extrait végétal et le réovirus révèlent des activités anticancéreuses au minimum adjuvantes et éventuellement synergiques. L’extrait végétal vient du champignon Ganoderma lucidum. Ce champignon contient, de préférence, un spore ou un corps de fructification. Il est possible d’utiliser un réovirus humain, un réovirus de mammifère non humain, ou un réovirus aviaire. Dans le cas d’un réovirus humain, du type 1 (par exemple, une souche Lang), du type 2 (par exemple, une souche Jones), du type 3 (par exemple, une souche Dearing ou une souche Abney), il est possible d’utiliser tant d’autres sérotypes que des souches de réovirus. Il est possible d’utiliser une combinaison de différents sérotypes ou de différentes souches de réovirus, comme un réovirus de différentes espèces animales. Le réovirus peut être original ou modifié. Il est de préférence modifié. Les compositions et les trousses comprennent un extrait végétal et un réovirus dans un mélange ou à part.
PCT/IB2004/001729 2004-05-21 2004-05-21 Thérapie combinée extrait végétal plus un réovirus pour tuer les cellules néoplasiques chez un sujet WO2005112966A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050051A2 (fr) * 1999-02-24 2000-08-31 Oncolytics Biotech, Inc. Reovirus pour le traitement de troubles cellulaires proliferants
EP1092765A2 (fr) * 1999-10-12 2001-04-18 Xin Liu Spores de Ganoderma lucidum rouge qui sont activées pour germination, et leur procédé de production
WO2002066040A2 (fr) * 2001-02-20 2002-08-29 Oncolytics Biotech, Inc. Sensibilisation des cellules neoplasiques resistant aux agents chimiotherapeutiques avec un reovirus
WO2002096450A1 (fr) * 2001-05-30 2002-12-05 Wackvom Limited Compositions contenant une fraction active isolee a partir de ganoderma lucidum et utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050051A2 (fr) * 1999-02-24 2000-08-31 Oncolytics Biotech, Inc. Reovirus pour le traitement de troubles cellulaires proliferants
EP1092765A2 (fr) * 1999-10-12 2001-04-18 Xin Liu Spores de Ganoderma lucidum rouge qui sont activées pour germination, et leur procédé de production
WO2002066040A2 (fr) * 2001-02-20 2002-08-29 Oncolytics Biotech, Inc. Sensibilisation des cellules neoplasiques resistant aux agents chimiotherapeutiques avec un reovirus
WO2002096450A1 (fr) * 2001-05-30 2002-12-05 Wackvom Limited Compositions contenant une fraction active isolee a partir de ganoderma lucidum et utilisations

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