Antisense oligonucleotides directed to ribonucleotide reductase R2 and uses thereof in the treatment of cancer
The present invention provides antisense oligonucleotides directed to a mammalian ribonucleotide reductase R2 gene and combinations of the antisense oligonucleotides with one or more chemotherapeutic agents for use in the treatment of cancer.
1. A method of treating acute myeloid leukemia in a human patient comprising administering to said patient an antisense oligonucleotide consisting of the sequence as set forth in SEQ ID NO:1 at a dose of between about 3 mg/kg/day and about 5 mg/kg/day, in combination with cytarabine.
2. The method according to claim 1 , wherein said antisense oligonucleotide is a modified or substituted oligonucleotide.
3. The method according to claim 1 , wherein said antisense oligonucleotide is a phosphorothioated oligonucleotide.
4. The method according to claim 1 , wherein said antisense oligonucleotide is administered to said patient at a dose of about 3.5 mg/kg/day.
5. The method according to claim 1 , wherein said antisense oligonucleotide is administered to said patient at a dose of about 5 mg/kg/day.
6. The method according to claim 1 , wherein said antisense oligonucleotide is administered systemically.
7. The method according to claim 1 , wherein said antisense oligonucleotide is administered intravenously.
8. The method according to claim 7 , wherein said antisense oligonucleotide is administered by continuous intravenous infusion.
9. The method according to claim 1 , wherein said cytarabine is administered to said patient at a dose of between about 1500 mg/m 2 /12 hours and 3000 mg/m 2 /12 hours.
10. The method according to claim 1 , wherein said cytarabine is administered to said patient at a dose of between about 1500 mg/m 2 /12 hours and 2000 mg/m 2 /12 hours.
11. The method according to claim 1 , wherein said cytarabine is administered to said patient at a dose of between about 2000 mg/m 2 /12 hours and 3000 mg/m 2 /12 hours.
12. The method according to claim 1 , wherein said cytarabine is administered intravenously.
13. The method according to claim 1 , wherein said antisense oligonucleotide is administered prior to said cytarabine.
14. The method according to claim 1 , wherein said antisense oligonucleotide is administered concurrently with said cytarabine.
15. The method according to claim 1 , wherein said antisense oligonucleotide is administered after said cytarabine.
16. The method according to claim 1 , where said acute myeloid leukemia is a refractory acute myeloid leukemia.
17. The method according to claim 1 , where said acute myeloid leukemia is a relapsed acute myeloid leukemia.
18. The method according to claim 1 , wherein said patient has undergone prior chemotherapy.
19. The method according to claim 1 , wherein said patient has undergone prior autologous or allogeneic stem cell transplantation.