# US 7,405,205 B2 · Antitumor antisense sequences directed against R1 and R2 components of ribonucleotide reductase > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,405,205 B2 - Document ID: US7405205B2 - Status: Granted - Kind: B2 - Application number: 10/447,136 - Filed: 2003-05-29 - Published: 2004-01-15 - Granted: 2008-07-29 - Earliest claimed: 1996-08-02 - Assignees: Lorus Therapeutics Inc. - Inventors: Jim A. Wright; Aiping H. Young - Web page: https://patentgrep.com/patent/US7405205B2 ## CPC - C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)} - A61P 35/00: Antineoplastic agents - C12N 9/0093: {acting on CH or CH2 groups (1.17)} - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - C07K 2319/00: Fusion polypeptide - C12N 2310/111: spanning the whole gene, or a large part of it - C12N 2310/315: Phosphorothioates - C12N 2799/027: where the vector is derived from a retrovirus - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract Compounds and methods for modulating cell proliferation, preferably inhibiting the proliferation of tumor cells are described. Compounds that may be used to modulate cell proliferation include antisense oligonucleotides complementary to regions of the mammalian ribonucleotide reductase genes. ## Claims ### Claim 1 A method of increasing sensitivity of leukemia cells to a chemotherapeutic drug in a mammal, said method comprising contacting the leukemia cells with an effective amount of an antisense oligonucleotide of between 12 and 100 nucleotides in length comprising a sequence as set forth in any one of SEQ ID NOs: 3 to 102, wherein said sequence is complementary to a mRNA sequence of a mammalian ribonucleotide reductase protein component R2. ### Claim 2 (depends on 1) The method according to claim 1, wherein the amount of the antisense oligonucleotide in the absence of the chemotherapeutic drug is insufficient to inhibit leukemia cell growth. ### Claim 3 (depends on 1) The method according to claim 1, wherein the amount of the antisense oligonucleotide in the absence of the chemotherapeutic drug is sufficient to inhibit leukemia cell growth. ### Claim 4 (depends on 1) The method according to claim 1, wherein said antisense oligonucleotide is between 12 and 50 nucleotides in length. ### Claim 5 (depends on 1) The method according to claim 1, wherein said antisense oligonucleotide is between 12 and 35 nucleotides in length. ### Claim 6 (depends on 1) The method according to claim 1, wherein said antisense oligonucleotide comprises a sequence as set forth in SEQ ID NO: 42. ### Claim 7 (depends on 1) The method according to claim 1, wherein said antisense oligonucleotide consists of a sequence as set forth in SEQ ID NO: 42. ### Claim 8 (depends on 1) The method according to claim 1, wherein said antisense oligonucleotide is a modified or substituted antisense oligonucleotide. ### Claim 9 (depends on 1) The method according to claim 1, wherein said antisense oligonucleotide is a phosphorothioated antisense oligonucleotide. ### Claim 10 (depends on 1) The method according to claim 1, wherein said antisense oligonucleotide is administered to said mammal intravenously. ### Claim 11 (depends on 1) The method according to claim 1, wherein said mammal is a human. ### Claim 12 A method for inhibiting the proliferation of leukemia cells in a mammal, said method comprising contacting leukemia cells with an effective amount of an antisense oligonucleotide of between 12 and 100 nucleotides in length comprising a sequence as set forth in any one of SEQ ID NOs: 3 to 102, wherein said sequence is complementary to a mRNA sequence of a mammalian ribonucteotide reductase protein component R2. ### Claim 13 (depends on 12) The method according to claim 12, wherein said antisense oligonucleotide is between 12 and 50 nucleotides in length. ### Claim 14 (depends on 12) The method according to claim 12, wherein said antisense oligonucleotide is between 12 and 35 nucleotides in length. ### Claim 15 (depends on 12) The method according to claim 12, wherein said antisense oligonucleotide comprises a sequence as set forth in SEQ ID NO: 42. ### Claim 16 (depends on 12) The method according to claim 12, wherein said antisense oligonucleotide consists of a sequence as set forth in SEQ ID NO: 42. ### Claim 17 (depends on 12) The method according to claim 12, wherein said antisense oligonucleotide is a modified or substituted antisense oligonucleotide. ### Claim 18 (depends on 12) The method according to claim 12, wherein said antisense oligonucleotide is a phosphorothioated antisense oligonucleotide. ### Claim 19 (depends on 12) The method according to claim 12, wherein said antisense oligonucleotide is administered to said mammal intravenously. ### Claim 20 (depends on 12) The method according to claim 12, wherein said mammal is a human. ### Claim 21 A method of treating leukemia in a mammal comprising administering to said mammal an effective amount of an antisense oligonucleotide of between 12 and 100 nucleotides in length comprising a sequence as set forth in any one of SEQ ID NOs: 3 to 102, wherein said sequence is complementary to a mRNA sequence of a mammalian ribonucleotide reductase protein component R2. ### Claim 22 (depends on 21) The method according to claim 21, wherein said antisense oligonucleotide is between 12 and 50 nucleotides in length. ### Claim 23 (depends on 21) The method according to claim 21, wherein said antisense oligonucleotide is between 12 and 35 nucleotides in length. ### Claim 24 (depends on 21) The method according to claim 21, wherein said antisense oligonucleotide comprises a sequence as set forth in SEQ ID NO: 42. ### Claim 25 (depends on 21) The method according to claim 21, wherein said antisense oligonucleotide consists of a sequence as set forth in SEQ ID NO: 42. ### Claim 26 (depends on 21) The method according to claim 21, wherein said antisense oligonucleotide is a modified or substituted antisense oligonucleotide. ### Claim 27 (depends on 21) The antisense oligonucleotide according to claim 21, wherein said antisense oligonucleotide is a phosphorothioated antisense oligonucleotide. ### Claim 28 (depends on 21) The method according to claim 21, wherein said antisense oligonucleotide is administered to said mammal intravenously. ### Claim 29 (depends on 21) The method according to claim 21, wherein said mammal is a human. ### Claim 30 A method of treating leukemia in a human comprising administering to said human an effective amount of an antisense oligonucleotide of between 12 and 100 nucleotides in length comprising at least 7 consecutive nucleotides from SEQ ID NO: 42. ### Claim 31 A method for inhibiting the proliferation of leukemia cells in a mammal, said method comprising contacting leukemia cells with an effective amount of an antisense oligonucleotide of between 12 and 100 nucleotides in length comprising a sequence as set forth in any one of SEQ ID NOs: 3 to 102, wherein said sequence is complementary to a mRNA sequence of a mammalian ribonucleotide reductase protein component R2 in combination with one or more chemotherapeutic agents. ### Claim 32 (depends on 31) The method according to claim 31, wherein said antisense oligonucleotide is between 12 and 50 nucleotides in length. ### Claim 33 (depends on 31) The method according to claim 31, wherein said antisense oligonucleotide is between 12 and 35 nucleotides in length. ### Claim 34 (depends on 31) The method according to claim 31, wherein said antisense oligonucleotide comprises a sequence as set forth in SEQ ID NO: 42. ### Claim 35 (depends on 31) The method according to claim 31, wherein said antisense oligonucleotide consists of a sequence as set forth in SEQ ID NO: 42. ### Claim 36 (depends on 31) The method according to claim 31, wherein said antisense oligonucleotide is a modified or substituted antisense oligonucleotide. ### Claim 37 (depends on 31) The method according to claim 31, wherein said antisense oligonucleotide is a phosphorothioated antisense oligonucleotide. ### Claim 38 (depends on 31) The method according to claim 31, wherein said antisense oligonucleotide is administered to said mammal intravenously. ### Claim 39 (depends on 31) The method according to claim 31, wherein said mammal is a human. ### Claim 40 A method of treating leukemia in a mammal comprising administering to said mammal an effective amount of an antisense oligonucleotide of between 12 and 100 nucleotides in length comprising a sequence as set forth in any one of SEQ ID NOs: 3 to 102, wherein said sequence is complementary to a mRNA sequence of a mammalian ribonucleotide reductase protein component R2 in combination with one or more chemotherapeutic agents. ### Claim 41 (depends on 40) The method according to claim 40, wherein said antisense oligonucleotide is between 12 and 50 nucleotides in length. ### Claim 42 (depends on 40) The method according to claim 40, wherein said antisense oligonucleotide is between 12 and 35 nucleotides in length. ### Claim 43 (depends on 40) The method according to claim 40, wherein said antisense oligonucleotide comprises a sequence as set forth in SEQ ID NO: 42. ### Claim 44 (depends on 40) The method according to claim 40, wherein said antisense oligonucleotide consists of a sequence as set forth in SEQ ID NO: 42. ### Claim 45 (depends on 40) The method according to claim 40, wherein said antisense oligonucleotide is a modified or substituted antisense oligonucleotide. ### Claim 46 (depends on 40) The antisense oligonucleotide according to claim 40, wherein said antisense oligonnucleotide is a phosphorothioated antisense oligonucleotide. ### Claim 47 (depends on 40) The method according to claim 40, wherein said antisense oligonucleotide is administered to said mammal intravenously. ### Claim 48 (depends on 40) The method according to claim 40, wherein said mammal is a human. ### Claim 49 (depends on 40) The method according to claim 40, wherein said one or more chemotherapeutic agents is methotrexate or hydroxyurea. ### Claim 50 (depends on 31) The method according to claim 31, wherein said one or more chemotherapeutic agents is methotrexate or hydroxyurea. ### Claim 51 A method of treating leukemia in a human comprising administering to said human an effective amount of an antisense oligonucleotide of between 12 and 100 nucleotides in length comprising at least 7 consecutive nucleotides from SEQ ID NO: 42 in combination with one or more chemotherapeutic agents. ### Claim 52 A method of treating a solid cancer in a mammal comprising administering to said mammal an effective amount of an antisense oligonucleotide of between 12 and 100 nucleotides in length comprising at least 7 consecutive nucleotides of a sequence as set forth in SEQ ID NO: 42, wherein said solid cancer is a bladder cancer, a colon cancer, a lung cancer, a breast cancer, a pancreatic cancer, a prostate cancer, a liver cancer, a cervical cancer or a melanoma. ### Claim 53 (depends on 52) The method according to claim 52, wherein said antisense oligonucleotide is between 12 and 50 nucleotides in length. ### Claim 54 (depends on 52) The method according to claim 52, wherein said antisense oligonucleotide is between 12 and 35 nucleotides in length. ### Claim 55 (depends on 52) The method according to claim 52, wherein said antisense oligonucleotide comprises the sequence as set forth in SEQ ID NO: 42. ### Claim 56 (depends on 52) The method according to claim 52, wherein said antisense oligonucleotide consists of the sequence as set forth in SEQ ID NO: 42. ### Claim 57 (depends on 52) The method according to claim 52, wherein said antisense oligonucleotide is a modified or substituted antisense oligonucleotide. ### Claim 58 (depends on 52) The method according to claim 52, wherein said antisense oligonucleotide is a phosphorothioated antisense oligonucleotide. ### Claim 59 (depends on 52) The method according to claim 52, wherein said antisense oligonucleotide is administered to said mammal intravenously. ### Claim 60 (depends on 52) The method according to claim 52, wherein said mammal is a human. ### Claim 61 (depends on 52) The method according to claim 52, wherein said antisense oligonucleotide is administered to said mammal in combination with one or more chemotherapeutic agents. ### Claim 62 (depends on 61) The method according to claim 61, wherein said one or more chemotherapeutic agents is N-(phosphonacetyl)-L-aspartate, 5-fluorouracil, mitomycin C, methotrexate or hydroxyurea. ### Claim 63 A method of treating a proliferative disorder in a mammal comprising administering to said mammal an effective amount of an antisense oligonucleotide of between 12 and 100 nucleotides in length comprising at least 7 consecutive nucleotides of a sequence as set forth in SEQ ID NO: 42. ### Claim 64 (depends on 63) The method according to claim 63, wherein said antisense oligonucleotide is between 12 and 50 nucleotides in length. ### Claim 65 (depends on 63) The method according to claim 63, wherein said antisense oligonucleotide is between 12 and 35 nucleotides in length. ### Claim 66 (depends on 63) The method according to claim 63, wherein said antisense oligonucleotide comprises the sequence as set forth in SEQ ID NO: 42. ### Claim 67 (depends on 63) The method according to claim 63, wherein said antisense oligonucleotide consists of the sequence as set forth in SEQ ID NO: 42. ### Claim 68 (depends on 63) The method according to claim 63, wherein said antisense oligonucleotide is a modified or substituted antisense oligonucleotide. ### Claim 69 (depends on 63) The antisense oligonucleotide according to claim 63, wherein said antisense oligonucleotide is a phosphorothioated antisense oligonucleotide. ### Claim 70 (depends on 63) The method according to claim 63, wherein said antisense oligonucleotide is administered to said mammal intravenously. ### Claim 71 (depends on 63) The method according to claim 63, wherein said mammal is a human. ### Claim 72 (depends on 63) The method according to claim 63, wherein said antisense oligonucleotide is administered to said mammal in combination with one or more chemotherapeutic agents. ### Claim 73 (depends on 72) The method according to claim 72, wherein said one or more chemotherapeutic agents is N-(phosphonacetyl)-L-aspartate, 5-fluorouracil, mitomycin C, methotrexate or hydroxyurea.