Compositions and methods for cancer treatment
The invention described herein pertains to the use of oxazolidinone antibiotics, alone or in combination, in the treatment of cancer. In particular, the invention pertains to the treatment of malignant gliomas, thyroid cancer or melanoma, or borderline forms of malignant glioma, thyroid cancer or melanoma.
1. A method for treating a patient with malignant glioma or thyroid cancer, the method comprising the step of administering to the patient a therapeutically effective amount of an oxazolidinone antibiotic, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein the oxazolidinone antibiotic is a compound of formula (I)
wherein Ar is an optionally substituted aryl or heteroaryl group and R 1 is an N-substituted amino(1-3C)alkyl group, a hydroxy(1-3C)alkyl group or a (5-membered-heteroaryl)oxy(1-3C)alkyl group.
3. The method of claim 2 wherein Ar is a group
wherein X is O, S, SO, SO 2 , SNR 4 , S(O)NR 4 , NR 4 or NC(O)CH 2 OR 4 , wherein R 4 is selected from hydrogen, R 5 and C(O)R 5 groups wherein R 5 is (C 1 -C 8 ) hydrocarbyl optionally substituted with one or more hydroxy, fluorine or chlorine groups; R 6 and R 7 are independently selected from hydrogen, methyl and cyano groups; and R 8 and R 9 are independently selected from hydrogen, fluorine and chlorine atoms.
4. The method of claim 2 wherein R 1 is a group (CH 2 ) n N(R 2 )COR 3 , a group (CH 2 ) n OH or a group (CH 2 ) n OR 10 wherein n is 1, 2 or 3, and R 2 and R 3 are independently selected from hydrogen and (C 1 -C 8 ) hydrocarbyl optionally substituted with one or more hydroxy, fluorine or chlorine groups and R 10 is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (C 1 -C 4 ) alkyl, amino, (C 1 -C 4 ) alkylamino, (C 1 -C 4 ) alkoxy and halo, and/or on an available nitrogen atom, provided the ring is not thereby quaternized, by (C 1 -C 4 ) alkyl.
5. The method of claim 1 wherein the oxazolidinone antibiotic is (S)—N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, N-[(5 S)-[3-[[3-fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]phenyl]-2-oxooxazolidin-5-yl]methyl]acetamide, N-[[(5 S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, (S)—N-[[3-[5-(4-pyridyl)pyrid-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide, or (S)—N-[[3-[5-(3-pyridyl)thiophen-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide, or a pharmaceutically acceptable salt of the foregoing.
6. The method of claim 1 wherein the oxazolidinone antibiotic is a compound of the formula
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 wherein the oxazolidinone antibiotic is a compound of the formula
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 wherein the oxazolidinone antibiotic is a compound of the formula
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 wherein the oxazolidinone antibiotic is a compound of the formula
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 wherein the oxazolidinone antibiotic is administered in combination with an anti-cancer agent.
11. The method of claim 10 wherein the anti-cancer agent is selected from the group consisting of agomelatine, temozolomide, a corticosteroid, dacarbazine, carmustine, lomustine, vinblastine, vincristine, procarbazine, etoposide, irinotecan, bevacizumab, cetuximab, imatinib, gefitinib, erlotinib, tamoxifen, isotretinoin, thalidomide, vorinostat, bortezomib, interferon alpha-2b, and a platinum-containing drug, where the platinum-containing drug is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin.
12. The method of claim 1 wherein the glioma is an astrocytoma, an oligodendroglioma, an oligoastrocytoma, or an ependymoma, or borderline form thereof.
13. The method of claim 1 wherein the oxazolidinone antibiotic is administered in combination with a therapeutically effective amount of an anti-cancer agent or in combination with a therapeutically effective amount of radiotherapy.
14. The method of claim 13 wherein the anti-cancer agent is agomelatine.
15. The method of claim 13 wherein the anti-cancer agent is temozolomide.
16. The method of claim 1 wherein the thyroid cancer is papillary, follicular, hurthle cell, medullary or anaplastic.
17. The method of claim 13 wherein the oxazolidinone antibiotic is administered in combination with a therapeutically effective amount of radiotherapy, delivered through external beam radiation, radioactive iodine, or a combination thereof.