DNA damaging agents in combination with tyrosine kinase inhibitors
View Patent ↗The present invention relates to the signalling pathways connecting DNA damage, such as that induced by ionizing radiation or alkylating agents, and phosphorylation by tyrosine kinases.
1. A method of inhibiting an undesirable cell comprising contacting said cell with a low molecular weight inhibitor of a tyrosine kinase and a DNA-damaging agent.
2. The method of claim 1 , wherein said low molecular weight inhibitor of a tyrosine kinase inhibits a Src-like tyrosine kinase.
3. The method of claim 1 , wherein said low molecular weight inhibitor of a tyrosine kinase inhibits p56/p53 lyn .
4. The method of claim 1 , wherein low molecular weight inhibitor of tyrosine kinase is a tyrphostin, a chlorosulfoid, an isoflavonoid, or a flavonoid.
5. The method of claim 1 , wherein low molecular weight synthetic inhibitor of tyrosine kinase is genistein, herbimycin A, erbstatin, RG 14921, Lavendustin A, Piceatannol, emodin, desmal, malhamensilpin A, fetuin, AG17, AG18, T23, T47, RG-13022, RG-14620, AG879, RG-50864, 2,2′-dithiobis (1-methyl-N-phenyl-1H-indole-3-carboxamides, (Z)-alpha-[(3,5-dicholorphenyl)methylene]-3-pyridylacetonitrile (RG-14620), BE-23372M, 4,5-Dianilinophthalimide and hydroxylated 2-(5′-salicyl)napthalenes.
6. The method of claim 1 , wherein said DNA-damaging agent is a chemical.
7. The method of claim 6 , wherein said chemical DNA-damaging agent is a genotoxic alkylating agent, a DNA cross-linker, a DNA intercalator, a chromosomal segregation inhibitor, or a DNA replication inhibitor.
8. The method of claim 6 , wherein the chemical is mitomycin C, adozelesin, cis-platinum, nitrogen mustard, adriamycin, etoposide, verapamil, podophyllotoxin, or 5-fluorouracil.
9. The method of claim 1 , wherein the DNA damaging agent is radiation.
10. The method of claim 6 , wherein the radiation is ionizing radiation such as x-rays, uv-light, γ-rays or microwaves.
11. The method of claim 1 , wherein said undesirable cell is hyperplastic cell.
12. The method of claim 11 , wherein the hyperplastic cell is a cancer cell.
13. The method of claim 12 , wherein said cancer cell is colon cancer, stomach cancer, pancreatic cancer, cancer of the oral cavity, breast cancer, or cancer of the head & neck.
14. The method of claim 1 , wherein said undesirable cell is a benign cell.
15. The method of claim 1 , wherein said undesirable cell is a B-cell.
16. The method of claim 1 , wherein inhibiting comprises inhibiting growth of, inducing apoptosis in or killing of said cell.
17. The method claim 1 , wherein said cell is contacted with said DNA damaging agent before said tyrosine kinase inhibitor.
18. The method claim 1 , wherein said cell is contacted with said DNA damaging agent after said tyrosine kinase inhibitor.
19. The method of claim 1 , wherein said cell is contacted with said DNA damaging agent and said tyrosine kinase inhibitor within about 12 hours of each other.
20. The method of claim 1 , wherein said cell is contacted with said DNA damaging agent and said tyrosine kinase inhibitor within about 6 hours of each other.
21. The method of claim 1 , wherein said cell is contacted with said DNA damaging agent and said tyrosine kinase inhibitor within about 4 hours of each other.
22. The method of claim 1 , wherein said DNA damaging agent and said tyrosine kinase inhibitor are contacted with the cell at the same time.
23. The method of claim 1 , wherein said cell is contacted in vivo.
24. The method of claim 1 , wherein said low molecular weight inhibitor is a synthetic inhibitor.
25. The method of claim 1 , wherein said low molecular weight inhibitor is a natural inhibitor.