RU96122787A - METHODS AND COMPOSITIONS CONTAINING DNA-INFECTING AGENTS AND P53 - Google Patents

METHODS AND COMPOSITIONS CONTAINING DNA-INFECTING AGENTS AND P53

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RU96122787A
RU96122787A RU96122787/14A RU96122787A RU96122787A RU 96122787 A RU96122787 A RU 96122787A RU 96122787/14 A RU96122787/14 A RU 96122787/14A RU 96122787 A RU96122787 A RU 96122787A RU 96122787 A RU96122787 A RU 96122787A
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dna damaging
damaging agent
cell
tumor
protein
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RU96122787/14A
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Russian (ru)
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RU2146149C1 (en
Inventor
Джек А. Рот
Тосийоси Фудзивара
Элизабет А. Гримм
Тапас Мухопадьяй
Вей-Вей Шанг
Лори Б. Оувен-Шоб
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Борд Оф Риджентс, Зе Юниверсити Оф Техас Систем
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Priority claimed from US08/233,002 external-priority patent/US5747469A/en
Application filed by Борд Оф Риджентс, Зе Юниверсити Оф Техас Систем filed Critical Борд Оф Риджентс, Зе Юниверсити Оф Техас Систем
Publication of RU96122787A publication Critical patent/RU96122787A/en
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Publication of RU2146149C1 publication Critical patent/RU2146149C1/en

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Claims (74)

1. Способ умерщвления клетки, включающий обеспечение контакта клетки с протеином p53 или геном и поражающим DNA агентом в объединенном количестве, достаточном для умерщвления данной клетки.1. A method of killing a cell, comprising contacting the cell with the p53 protein or gene and a DNA damaging agent in a combined amount sufficient to kill the cell. 2. Способ по п. 1, в котором обеспечивают контакт клетки с протеином p-53 или геном в сочетании с рентгеновским облучением, ультрафиолетовым облучением, γ-облучением, микроволновым излучением, адриамицином, 5-флуороурацилом, этопозидом, камптотецином, актимомицином-D, митомицином C или цисплатином. 2. The method of claim 1, wherein the cell is contacted with the p-53 protein or gene in combination with x-ray, ultraviolet, gamma, microwave, adriamycin, 5-fluorouracil, etoposide, camptothecin, actimomycin-D, mitomycin C or cisplatin. 3. Способ по п. 1, в котором обеспечивают контакт клетки с протеином p-53 или геном в сочетании с цисплатином. 3. The method of claim 1, wherein the cell is contacted with the p-53 protein or gene in combination with cisplatin. 4. Способ по п. 1, в котором обеспечивают контакт клетки с рекомбинантным вектором, который возбуждает экспрессию протеина p-53 в данной клетке в сочетании с поражающим DNA агентом. 4. The method of claim 1, wherein the cell is contacted with a recombinant vector that excites the expression of p-53 protein in the cell in combination with a DNA damaging agent. 5. Способ по п. 4, в котором в качестве рекомбинантного вектора, вызывающего экспрессию p53, используют голый плазмид DNA, плазмид в пределах липосомы, ретровирусный вектор, вектор аденоассоциированного вируса (AAV) или вектор аденовируса-рекомбинанта. 5. The method of claim 4, wherein the naked plasmids DNA, plasmids within the liposome, the retroviral vector, the adeno-associated virus (AAV) vector, or the recombinant adenovirus vector are used as the recombinant vector causing p53 expression. 6. Способ по п. 5, в котором в качестве рекомбинантного вектора, вызывающего экспрессию p53, используют вектор аденовируса-рекомбинанта. 6. The method of claim 5, wherein the recombinant adenovirus vector is used as the recombinant vector causing p53 expression. 7. Способ по п. 6, в котором в качестве рекомбинантного вектора, вызывающего экспрессию p53, используют вектор аденовируса-рекомбинанта, включающий зону экспрессии p53, размещенную при контролирующем воздействии промотора вируса цитомегелии 1E. 7. The method of claim 6, wherein the recombinant vector inducing p53 expression is a recombinant adenovirus vector comprising the p53 expression zone, which is placed under the control of the cytomegelia 1E virus promoter. 8. Способ по п. 6, в котором используют вектор аденовируса-рекомбинанта, включающий зону экспрессии p53, промотор вируса цитомегелии 1E и ранний сигнал полиаденилации SV40. 8. The method of claim 6, wherein a recombinant adenovirus vector is used comprising a p53 expression zone, a cytomegelia virus 1E promoter, and an SV40 early polyadenylation signal. 9. Способ по п. 6, в котором по крайней мере один ген, ответственный за репликацию аденовируса, удаляют из структуры вектора указанного аденовируса, а зону экспрессии p53 внедряют на его место. 9. The method according to claim 6, in which at least one gene responsible for the replication of adenovirus is removed from the vector structure of the specified adenovirus, and the p53 expression zone is introduced in its place. 10. Способ по п. 9, в котором зоны E1A и E1B аденовирусного вектора удаляют, а зону экспрессии p53 внедряют на его место. 10. The method of claim 9, wherein the E1A and E1B zones of the adenoviral vector are removed and the p53 expression zone is inserted in its place. 11. Способ по п. 6, в котором используют вектор аденовируса-рекомбинанта, который присутствует в пределах аденовируса-рекомбинанта. 11. The method of claim 6, wherein a recombinant adenovirus vector that is present within the recombinant adenovirus is used. 12. Способ по п. 1, в котором сначала обеспечивают контакт клетки с протеином p53 или геном, а затем обеспечивают ее контакт с повреждающим DNA агентом. 12. The method of claim 1, wherein the cell is first contacted with the p53 protein or gene, and then contacted with the DNA damaging agent. 13. Способ по п. 1, в котором сначала обеспечивают контакт клетки с повреждающим DNA агентом, а затем обеспечивают ее контакт с протеином p53 или геном. 13. The method of claim 1, wherein the cell is first contacted with the DNA damaging agent and then contacted with the p53 protein or gene. 14. Способ по п. 1, в котором одновременно обеспечивают контакт клетки с протеином p53 или геном и с повреждающим DNA агентом. 14. The method of claim 1, wherein the cell is simultaneously contacted with the p53 protein or gene and the DNA damaging agent. 15. Способ по п. 1, в котором обеспечивают контакт клетки с первой композицией, содержащей протеин p53 или ген, и со второй композицией, содержащей повреждающий DNA агентом. 15. The method of claim 1, wherein the cell is contacted with a first composition containing a p53 protein or gene, and with a second composition containing a DNA damaging agent. 16. Способ по п. 15, в котором первую и вторую композицию диспергируют в фармакологически приемлемом виде. 16. The method according to p. 15, in which the first and second composition are dispersed in a pharmacologically acceptable form. 17. Способ по п. 1, в котором обеспечивают контакт клетки с единственной композицией, содержащей протеин p53 или ген в сочетании с повреждающим DNA агентом. 17. The method of claim 1, wherein the cell is contacted with a single composition containing the p53 protein or gene in combination with a DNA damaging agent. 18. Способ по п. 17, в котором композицию диспергируют в фармакологически приемлемом виде. 18. The method according to p. 17, in which the composition is dispersed in a pharmacologically acceptable form. 19. Способ по п. 17, в котором обеспечивают контакт клетки с единственной композицией, содержащей рекомбинантный вектор, который возбуждает экспрессию p53 в клетке в сочетании с повреждающим DNA агентом. 19. The method of claim 17, wherein the cell is contacted with a single composition comprising a recombinant vector that excites p53 expression in the cell in combination with a DNA damaging agent. 20. Способ по п. 19, в котором обеспечивают контакт клетки с единственной композицией, содержащей аденовирус-рекомбинант, включающий рекомбинантный вектор, который возбуждает экспрессии p53 в клетке в сочетании с повреждающим DNA агентом. 20. The method of claim 19, wherein the cell is contacted with a single composition comprising a recombinant adenovirus comprising a recombinant vector that excites p53 expression in the cell in combination with a DNA damaging agent. 21. Способ по п. 1, в котором в качестве клетки используют человеческую клетку. 21. The method of claim 1, wherein the human cell is used as a cell. 22. Способ по п. 1, в котором в качестве указанной клетки используют клетку злокачественного новообразования. 22. The method according to p. 1, in which the cell is used as a malignant tumor cell. 23. Способ по п. 22, в котором в качестве указанной клетки используют клетку рака легких. 23. The method of claim 22, wherein a lung cancer cell is used as said cell. 24. Способ по п. 22, в котором в качестве указанной клетки используют клетку рака груди. 24. The method of claim 22, wherein the breast cancer cell is used as said cell. 25. Способ по п. 22, в котором в качестве указанной клетки используют клетку, имеющую мутацию в гене p53. 25. The method according to p. 22, in which as the specified cell using a cell having a mutation in the p53 gene. 26. Способ по п. 1, в котором указанную клетку помещают в организм животного, протеин p53 или ген и поражающий DNA агент вводят в этот организм животного в фармакологически приемлемом виде. 26. The method according to p. 1, in which the specified cell is placed in the body of the animal, the p53 protein or gene and the DNA damaging agent is introduced into this body of the animal in a pharmacologically acceptable form. 27. Способ лечения рака, включающий введение в организм животного, больного раком, терапевтически эффективного сочетания протеина p53 или гена с повреждающим DNA агентом. 27. A method of treating cancer, comprising administering to the animal an cancer patient a therapeutically effective combination of a p53 protein or gene with a DNA damaging agent. 28. Способ по п. 27, включающий впрыскивание в место, поврежденное опухолью, терапевтически эффективного количества фармацевтического соединения, содержащего аденовирус-рекомбинант, включающий рекомбинантный вектор, который вызывает экспрессию p53 в пораженной опухолью клетке, и обеспечение контакта опухоли с поражающим DNA агентом. 28. The method according to p. 27, comprising injecting into a site damaged by a tumor, a therapeutically effective amount of a pharmaceutical compound containing an adenovirus recombinant comprising a recombinant vector that causes expression of p53 in the tumor-affected cell and contacting the tumor with the DNA damaging agent. 29. Способ по п. 28, который обеспечивает контакт опухоли с поражающим DNA агентом путем облучения поврежденного опухолью места рентгеновскими лучами, ультрафиолетовыми лучами γ- лучами или путем микроволнового облучения. 29. The method according to p. 28, which provides contact of the tumor with a DNA damaging agent by irradiating the damaged site with x-rays, ultraviolet rays, γ-rays or by microwave irradiation. 30. Способ по 28, который обеспечивает контакт опухоли с поражающим DNA агентом путем ввода в организм животного терапевтически эффективного количества фармацевтического соединения, содержащего поражающий DNA агент. 30. The method according to 28, which provides contact of the tumor with a DNA damaging agent by introducing into the animal's body a therapeutically effective amount of a pharmaceutical compound containing a DNA damaging agent. 31. Способ по п. 28, в котором в качестве поражающего DNA агента используют цисплатин. 31. The method of claim 28, wherein cisplatin is used as the DNA damaging agent. 32. Композиция, содержащая протеин p53 или ген в сочетании с повреждающим DNA агентом. 32. A composition comprising a p53 protein or gene in combination with a DNA damaging agent. 33. Композиция по п. 32, содержащая протеин p53 или ген в сочетании с адриамицином, 5-флуороурацилом, этопозидом, камптотецином, актимомицином-D, митомицином C или цисплатином. 33. The composition of claim 32, containing the p53 protein or gene in combination with adriamycin, 5-fluorouracil, etoposide, camptothecin, actimomycin-D, mitomycin C, or cisplatin. 34. Композиция по п. 33, содержащая протеин p53 или ген в сочетании с цисплатином. 34. The composition according to p. 33, containing the p53 protein or gene in combination with cisplatin. 35. Композиция по п. 32, содержащая рекомбинантный вектор, который обеспечивает экспрессию протеина p53 в клетке животного в сочетании с поражающим DNA агентом. 35. The composition according to p. 32, containing a recombinant vector that provides expression of p53 protein in an animal cell in combination with a DNA damaging agent. 36. Композиция по п. 35, в которой в качестве рекомбинантного вектора используют голый плазмид DNA, плазмид в пределах липосомы, ретровирусный вектор, вектор аденоассоциированного вируса (AAV) или вектор аденовируса-рекомбинанта. 36. The composition of claim 35, wherein the naked plasmids DNA, plasmids within the liposome, a retroviral vector, an adeno-associated virus (AAV) vector, or a recombinant adenovirus vector are used as a recombinant vector. 37. Композиция по п. 36, в которой в качестве рекомбинантного вектора используют вектор аденовируса-рекомбинанта. 37. The composition of claim 36, wherein the recombinant adenovirus vector is used as the recombinant vector. 38. Композиция по п. 37, в которой в качестве рекомбинантного вектора используют вектор аденовируса-рекомбинанта, присутствующий в пределах аденовирусной рекомбинантной частицы. 38. The composition of claim 37, wherein the recombinant vector is a recombinant adenovirus vector present within the adenovirus recombinant particle. 39. Композиция по п. 32, содержащая вектор аденовируса-рекомбинанта, присутствующего в пределах аденовирусной рекомбинантной частицы в сочетании с цисплатином. 39. The composition of claim 32, comprising the recombinant adenovirus vector present within the adenovirus recombinant particle in combination with cisplatin. 40. Композиция по п. 32, диспергированная в фармакологически приемлемой форме. 40. The composition according to p. 32, dispersed in a pharmacologically acceptable form. 41. Композиция по п. 40, составленная для введения внутрь пораженного места. 41. The composition according to p. 40, formulated for administration into the affected area. 42. Терапевтический набор, содержащий внутри соответствующей оболочки приготовленное фармацевтическое средство рекомбинантного вектора, которое вызывает экспрессию протеина p53 в клетке живого организма, и приготовленное фармакологическое средство поражающего DNA агента. 42. A therapeutic kit comprising, within an appropriate envelope, a prepared recombinant vector pharmaceutical agent that induces the expression of p53 protein in a living organism cell and a prepared pharmacological agent for a DNA damaging agent. 43. Терапевтический набор по п. 42, в котором рекомбинантный вектор и поражающий DNA агент присутствуют в пределах одной единственной оболочки. 43. The therapeutic kit according to claim 42, wherein the recombinant vector and the DNA damaging agent are present within one single envelope. 44. Терапевтический набор по п. 42, в котором рекомбинантный вектор и поражающий DNA агент присутствуют в пределах различных отдельных оболочек. 44. The therapeutic kit according to claim 42, wherein the recombinant vector and the DNA damaging agent are present within various distinct envelopes. 45. Терапевтический набор по п. 42, содержащий фармацевтическое средство аденовируса-рекомбинанта, включающего рекомбинантный вектор, который вызывает экспрессию протеина p53 в клетке живого организма, и фармацевтическое средство - цисплатин. 45. The therapeutic kit according to claim 42, comprising a recombinant adenovirus pharmaceutical agent comprising a recombinant vector that induces expression of p53 protein in a living organism cell and a cisplatin pharmaceutical agent. 46. Способ по п. 26, включающий впрыскивание в пораженное опухолью место терапевтически эффективного количества фармацевтической композиции, включающей аденовирус-рекомбинант, содержащий рекомбинантный вектор, вызывающий экспрессиию p53 в опухолевой клетке, и обеспечение контакта опухоли с поражающим DNA агентом. 46. The method according to p. 26, comprising injecting into the tumor site a therapeutically effective amount of a pharmaceutical composition comprising an adenovirus recombinant containing a recombinant vector that expresses p53 in the tumor cell and contacting the tumor with the DNA damaging agent. 47. Способ по п. 46, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем радиоактивного облучения, ультрафиолетового облучения, γ-облучения или микроволнового облучения. 47. The method according to p. 46, in which the contact of the tumor with the DNA damaging agent by radiation, ultraviolet radiation, γ-radiation or microwave radiation. 48. Способ по п. 47, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем радиоактивного облучения места расположения опухоли. 48. The method according to p. 47, in which the contact of the tumor with a DNA damaging agent by radiation exposure of the location of the tumor. 49. Способ по п. 47, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем ультрафиолетового облучения места расположения опухоли. 49. The method according to p. 47, in which the contact of the tumor with a DNA damaging agent by ultraviolet irradiation of the location of the tumor. 50. Способ по п. 47, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем γ-облучения места расположения опухоли. 50. The method of claim 47, wherein the tumor is contacted with the DNA damaging agent by γ-irradiating the location of the tumor. 51. Способ по п. 47, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем микроволнового облучения места расположения опухоли. 51. The method according to p. 47, in which the contact of the tumor with a DNA damaging agent by microwave irradiation of the location of the tumor. 52. Способ по п. 46, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем введения в организм животного терапевтически эффективного количества фармацевтической композиции, содержащей поражающее DNA соединение. 52. The method of claim 46, wherein the tumor is contacted with the DNA damaging agent by administering to the animal an therapeutically effective amount of a pharmaceutical composition comprising the DNA damaging compound. 53. Способ по п. 52, в котором в качестве поражающего DNA агента используют цисплатин. 53. The method of claim 52, wherein cisplatin is used as the DNA damaging agent. 54. Способ по п. 52, в котором в качестве поражающего DNA агента используют доксорубицин. 54. The method of claim 52, wherein doxorubicin is used as the DNA damaging agent. 55. Способ по п. 52, в котором в качестве поражающего DNA агента используют этопозид. 55. The method of claim 52, wherein etoposide is used as the DNA damaging agent. 56. Способ по п. 52, в котором в качестве поражающего DNA агента используют верапамил. 56. The method of claim 52, wherein verapamil is used as the DNA damaging agent. 57. Способ по п. 52, в котором в качестве поражающего DNA агента используют подофиллотоксин. 57. The method of claim 52, wherein podophyllotoxin is used as the DNA damaging agent. 58. Способ по п. 52, в котором в качестве поражающего DNA агента используют 5-FU. 58. The method of claim 52, wherein 5-FU is used as the DNA damaging agent. 59. Способ по п. 29, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем радиоактивного облучения места расположения опухоли. 59. The method according to p. 29, in which the contact of the tumor with a DNA damaging agent by radioactive irradiation of the location of the tumor. 60. Способ по п. 29, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем ультрафиолетового облучения места расположения опухоли. 60. The method according to p. 29, in which the contact of the tumor with a DNA damaging agent by ultraviolet irradiation of the location of the tumor. 61. Способ по п. 29, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем γ-облучения места расположения опухоли. 61. The method according to p. 29, in which the contact of the tumor with a DNA damaging agent by γ-irradiation of the location of the tumor. 62. Способ по п. 29, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем микроволнового облучения места расположения опухоли. 62. The method according to p. 29, in which the contact of the tumor with a DNA damaging agent by microwave irradiation of the location of the tumor. 63. Способ по п. 26, в котором обеспечивают контакт опухоли с поражающим DNA агентом путем введения в организм животного терапевтически эффективного количества фармацевтической композиции, содержащей поражающее DNA соединение. 63. The method of claim 26, wherein the tumor is contacted with the DNA damaging agent by administering to the animal an therapeutically effective amount of a pharmaceutical composition comprising the DNA damaging compound. 64. Способ по п. 28, в котором в качестве поражающего DNA агента используют доксорубицин. 64. The method of claim 28, wherein doxorubicin is used as the DNA damaging agent. 65. Способ по п. 28, в котором в качестве поражающего DNA агента используют этопозид. 65. The method of claim 28, wherein etoposide is used as the DNA damaging agent. 66. Способ по п. 28, в котором в качестве поражающего DNA агента используют верапамил. 66. The method of claim 28, wherein verapamil is used as the DNA damaging agent. 67. Способ по п. 28, в котором в качестве поражающего DNA агента используют подофиллотоксин. 67. The method of claim 28, wherein podophyllotoxin is used as the DNA damaging agent. 68. Способ по п. 28, в котором в качестве поражающего DNA агента используют 5-FU. 68. The method of claim 28, wherein 5-FU is used as the DNA damaging agent. 69. Способ по п. 26, в котором ген p53 или протеин вводят перед поражающим DNA агентом. 69. The method of claim 26, wherein the p53 gene or protein is introduced before the DNA damaging agent. 70. Способ по п. 26, в котором ген p53 или протеин вводят после поражающего DNA агентом. 70. The method of claim 26, wherein the p53 gene or protein is introduced after the DNA damaging agent. 71. Способ по п. 26, в котором ген p53 или протеин вводят одновременно с поражающим DNA агентом. 71. The method of claim 26, wherein the p53 gene or protein is administered simultaneously with a DNA damaging agent. 72. Способ по п. 27, в котором ген p53 или протеин вводят перед поражающим DNA агентом. 72. The method of claim 27, wherein the p53 gene or protein is introduced before the DNA damaging agent. 73. Способ по п. 27, в котором ген p53 или протеин вводят после поражающего DNA агентом. 73. The method of claim 27, wherein the p53 gene or protein is introduced after the DNA damaging agent. 74. Способ по п. 27, в котором ген p53 или протеин вводят одновременно с поражающим DNA агентом. 74. The method of claim 27, wherein the p53 gene or protein is administered simultaneously with a DNA damaging agent.
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