Reagents and methods for treating cancer
This invention describes a genetic system for targeting the EVI1 gene in mammalian cells. The EVI1 gene is an oncogenic transcription factor that, when expressed, accelerates cell division and inhibits death of cells. Nucleotide sequences that block the expression of EVI1 and drug delivery systems for them are described. These nucleotide sequences cause a block in cell growth and division and trigger death of mammalian cells, including lung and ovarian cancer cells.
1. A pharmaceutical composition for specifically reducing expression of the human Ecotropic Virus Integration site 1 (EVI1) gene in a tumor cell, the pharmaceutical composition comprising:
an isolated polynucleotide comprising a sequence that is a contiguous portion of nucleotide sequence of SEQ ID NO: 1, wherein said contiguous portion of the nucleotide sequence of SEQ ID NO: 1 is from nucleotide 2900 through 2930, and comprises a length of 19 to 30 nucleotides,
the pharmaceutical composition further comprising a chemotherapeutic drug or agent; and
a pharmaceutically acceptable carrier, excipient or adjuvant.
2. The pharmaceutical composition of claim 1 , wherein
the isolated polynucleotide is an oligoribonucleotide comprising a RNA sequence that hybridizes to mRNA transcribed from said contiguous portion of the nucleotide sequence of SEQ ID NO: 1.
3. The pharmaceutical composition of claim 1 , wherein the isolated polynucleotide is double-stranded, and wherein the isolated polynucleotide comprises a combination of SEQ ID NOS: 13 and 14.
4. A method for inhibiting Ecotropic Virus Integration site 1 (EVI1) in a tumor cell, comprising the step of contacting a tumor cell with an effective amount of the pharmaceutical composition of claim 1 .
5. The method of claim 4 wherein the tumor cell is from:
a tumor of lung, breast, prostate, or ovarian tissue or organ; or
a melanoma; or
acute myelocytic leukemia.
6. The pharmaceutical composition of claim 1 , further comprising a liposome.
7. The pharmaceutical composition of claim 6 , wherein the liposome is PEGylated.
8. The pharmaceutical composition of claim 6 , wherein the liposome comprises a cell-targeting moiety.
9. The pharmaceutical composition of claim 8 , wherein the cell-targeting moiety is a protein, a peptide or an aptamer.
10. The pharmaceutical composition of claim 1 , further comprising a nanoparticle.
11. The pharmaceutical composition of claim 10 , wherein the nanoparticle comprises lipids, cyclodextrin, chitosan, carbohydrate polymers, elastin-like polymers (ELP), calcium phosphate polymers or combinations thereof.
12. The pharmaceutical composition of claim 10 , wherein the nanoparticle is PEGylated.
13. The pharmaceutical composition of claim 10 , wherein the nanoparticle comprises a cell-targeting moiety.
14. The pharmaceutical composition of claim 13 , wherein the cell-targeting moiety is a protein, a peptide or an aptamer.
15. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is encapsulated in the liposome.
16. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is encapsulated in the liposome.