Methods for using macrocyclic lactone compounds as multidrug resistance reversing agents in tumor and other cells

• US 6,114,376 A
• Filed: 04/28/1998
• Issued: 09/05/2000
• Est. Priority Date: 04/30/1997
• Status: Expired due to Fees

• Current Assignee: International Business Machines Corporation, McGill University
• Original Assignee: McGill University
• Inventors: Georges, Elias, Pouliot, Jean-Fran.cedilla.ois, Prichard, Roger K.
• Primary Examiner(s): FONDA, KATHLEEN KAHLER
• Application Number:
  US09/067,677
• Time in Patent Office: 861 Days
• Field of Search: 514/450
• US Class Current: 514/450
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 493/22 in which the condensed system contains four or more hetero rings

Abstract

This invention describes methods for increasing the toxicity of a cytostatic hydrophobic chemotherapeutic agent against resistant tumor cells in mammals which comprise administering a multidrug resistant reversing agent to the mammal in connection with the administration of the cytostatic hydrophobic chemotherapeutic agent in an amount effective to increase the toxicity of the chemotherapeutic agent, wherein the multidrug resistant reversing agent is a macrocyclic lactone compound. Examples of the macrocyclic lactone compounds useful in the present invention include, but are not limited to, the LL-F28249α-λ series of compounds, the 23-oxo or 23-imino derivative thereof, the avermectins, the 22,23-dihydro derivatives thereof and the milbemycins. Compositions comprising the macrocyclic lactone compounds and the chemotherapeutic agents are also described herein.

Claims

1. A method for increasing the toxicity of a cytostatic hydrophobic chemotherapeutic agent against a resistant tumor cell in a mammal which comprises administering a multidrug resistant reversing agent to the mammal in connection with administering the cytostatic hydrophobic chemotherapeutic agent in an amount effective to increase the toxicity of the chemotherapeutic agent, wherein the multidrug resistant reversing agent is a macrocyclic lactone compound selected from the group consisting of LL-F28249α

-λ

, a 23-oxo derivative of LL-F28249α

-λ

, a 23-imino derivative of LL-F28249α

-λ

, an avermectin, a 22,23-dihydro derivative of avermectin and a milbemycin.

2. The method according to claim 1, wherein the macrocyclic lactone compound is administered orally, parenterally, topically or transdermally.

3. The method according to claim 1, wherein the macrocyclic lactone compound is LL-F28249α

, 23-(O-methyloxime)-LL-F28249α

, 23-(semicarbazone)-LL-F28249α

, 23-(thiosemicarbazone)-LL-F28249α

, an isomeric mixture of (E) and (Z)-26-formyl-(O-methyloxime)-LL-F28249α

, ivermectin, abamectin, doramectin, eprinomectin, milbemycin A or milbemycin D.

4. The method according to claim 1, wherein the chemotherapeutic agent is selected from the group consisting of vinblastine, vincristine, doxorubicin, paclitaxel, colchicine, actinomycin D and gramicidin D.

5. The method according to claim 1, wherein the mammal is selected from the group consisting of a human, a dog, a cat and a horse.

6. The method according to claim 1, wherein the resistant tumor cell is selected from the group consisting of a human lymphoma cell, a human breast cancer cell, a human ovarian cancer cell and a human lung cancer cell.

8. The method according to claim 2, wherein the macrocyclic lactone compound is administered before or concomitantly with the chemotherapeutic agent.

7. An improved method for treating a resistant tumor cell in a mammal which comprises administering to the mammal a tumor suppressing amount of a cytostatic hydrophobic chemotherapeutic agent and a multidrug resistant reversing agent, wherein the multidrug resistant reversing agent is a macrocyclic lactone compound selected from the group consisting of LL-F28249α

-λ

, a 23-oxo derivative of LL-F28249α

-λ

, a 23-imino derivative of LL-F28249α

-λ

, an avermectin, a 22,23-dihydro derivative of avermectin and a milbemycin.

9. The method according to claim 7, wherein the macrocyclic lactone compound is administered orally, parenterally, topically or transdermally.

10. The method according to claim 7, wherein the macrocyclic lactone compound is LL-F28249α

, 23-(O-methyloxime)-LL-F28249α

, 23-(semicarbazone)-LL-F28249α

, 23-(thiosemicarbazone)-LL-F28249α

, an isomeric mixture of (E) and (Z)-26-formyl-(O-methyloxime)-LL-F28249α

, ivermectin, abamectin, doramectin, eprinomectin, milbemycin A or milbemycin D.

11. The method according to claim 7, wherein the chemotherapeutic agent is selected from the group consisting of vinblastine, vincristine, doxorubicin, paclitaxel, colchicine, actinomycin D and gramicidin D.

12. The method according to claim 7, wherein the mammal is selected from the group consisting of a human, a dog, a cat and a horse.

13. The method according to claim 7, wherein the resistant tumor cell is selected from the group consisting of a human lymphoma cell, a human breast cancer cell, a human ovarian cancer cell and a human lung cancer cell.

14. An improved composition for treating a resistant tumor cell in a mammal which comprises a tumor suppressing amount of a cytostatic hydrophobic chemotherapeutic agent, a multidrug resistance reversing agent and a nontoxic pharmaceutically acceptable carrier, wherein the multidrug resistant reversing agent is a macrocyclic lactone compound selected from the group consisting of LL-F28249α

-λ

, a 23-oxo derivative of LL-F28249α

-λ

, a 23-imino derivative of LL-F28249α

-λ

, an avermectin, a 22,23-dihydro derivative of avermectin and a milbemycin.

15. The composition according to claim 14, wherein the chemotherapeutic agent is selected from the group consisting of vinblastine, vincristine, doxorubicin, paclitaxel, colchicine, actinomycin D and gramicidin D.