Reversal of multidrug resistance in human colon carcinoma cells
View Patent ↗The present invention describes the use of fumitremorgin A, B and C and a series of diketopiperazines of Formula (I) to resensitize multidrug resistant (MDR) cancer cells to the cytotoxic effects of chemotherapeutic drugs.
1. A method for resensitizing S1-M1-3.2 multiple drug resistant cancer cells to treatment with a chemotherapeutic agent to which said cancer cells have developed resistance comprising administration of an effective amount of a chemosensitizing reversal agent selected from compounds of Formula (I)
wherein:
n is an integer of 0, 1, or 2;
R 1 is hydrogen or alkoxy of 1 to 10 carbon atoms;
R 2 is hydrogen or alkenyl of 2 to 10 carbon atoms;
R 3 is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms,
R 7 NH(CH2)v- or
m is an integer of 1 to 6;
v is an integer of 1 to 4;
R 4 , R 5 and R 6 are hydrogen;
R 7 is H or
R 8 is selected from alkyl of 1 to 10 carbon atoms, —(CH 2 ) m CO 2 H,
or a pharmaceutically acceptable salt thereof, Fumitremorgin A, Fumitremorgin B and Fumitremorgin C and a chemotherapeutic agent resistant to said cancer cells.
2. The method according to claim 1 wherein the chemotherapeutic agent is selected from the group consisting of mitoxantrone, doxorubicin and topotecan.
3. The method of claim 1 wherein the chemosensitizing reversal agent is administered prior to, concurrently with, or after administration of the chemotherapeutic agent.
4. A method for resensitizing BCRP-mediated multiple drug resistant cancer cells S1-M1-3.2 to treatment with a chemotherapeutic agent to which said cancer cells have developed resistance comprising administration of an effective amount of a chemosensitizing reversal agent selected from compounds of Formula (I)
wherein:
n is an integer of 0, 1, or 2;
R 1 is hydrogen or alkoxy of 1 to 10 carbon atoms;
R 2 is hydrogen or alkenyl of 2 to 10 carbon atoms;
R 3 is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms,
R 7 NH(CH2)v- or
m is an integer of 1 to 6;
v is an integer of 1 to 4;
R 4 , R 5 and R 6 are hydrogen;
R 7 is H or
R 8 is selected from alkyl of 1 to 10 carbon atoms, —(CH 2 ) m CO 2 H,
or a pharmaceutically acceptable salt thereof, Fumitremorgin A, Fumitremorgin B and Fumitremorgin C and a chemotherapeutic agent resistant to said cancer cells.
5. The method according to claim 4 wherein the chemotherapeutic agent is selected from the group consisting of mitoxantrone, doxorubicin, and topotecan.
6. The method according to claim 4 wherein the chemosensitizing reversal agent is administered prior to, concurrently with, or after administration of the chemotherapeutic agent.
7. A method of reversing BCRP or other non P-gp/non MRP mediated resistance of cancer cells to chemotherapeutic agents in a mammal which comprises administration of an effective amount of a chemosensitizing reversal agent selected from compounds of Formula (I)
wherein:
n is an integer of 0, 1, or 2;
R 1 is hydrogen or alkoxy of 1 to 10 carbon atoms;
R 2 is hydrogen or alkenyl of 2 to 10 carbon atoms;
R 3 is hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms,
R 7 NH(CH2)v- or
m is an integer of 1 to 6;
v is an integer of 1 to 4
R 4 , R 5 and R 6 are hydrogen;
R 7 is H or
R 8 is selected from alkyl of 1 to 10 carbon atoms, —(CH 2 ) m CO 2 H,
or a pharmaceutically acceptable salt thereof, Fumitremorgin A, Fumitremorgin B and Fumitremorgin C to said mammal in need thereof having a BCRP or other non-P-gp/non MRP mediated resistant cancer and a chemotherapeutic agent to which said cancer cells are resistant.
8. The method according to claim 7 wherein the chemotherapeutic agent is selected from the group consisting of mitoxantrone, doxorubicin, and topotecan.
9. The method according to claim 7 wherein the chemosensitizing reversal agent is administered prior to, concurrently with, or after administration of the chemotherapeutic agent.