Compounds and methods for modulating cell-adhesion mediated drug resistance
Peptides and methods of their use for inhibiting drug and radiation-therapy resistance in cancerous cells in which efficacy of chemotherapy and/or radiotherapy of a patient is enhanced by administration of an effective amount of a peptide that inhibits cell adhesion mediated drug resistance (CAM-DR). Preferably, the peptide comprises D-amino acids having the sequence: kmviywkag (RZ-3) or is a variant or modified version thereof. The peptide is preferably administered to the patient prior to chemotherapy and/or radiation therapy. Inhibition of cell adhesion mediated drug resistance (CAM-DR) by RZ-3 in multiple myeloma cells is disclosed.
1. A method for inhibiting cell adhesion mediated drug resistance in a patient in need thereof, comprising:
administering to the patient an effective amount of a peptide that inhibits cell adhesion mediated drug resistance, wherein the peptide comprises the amino acid sequence Lys-Met-Val-Ile-Tyr-Trp-Lys-Ala-Gly (SEQ ID NO:5), or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the peptide comprises at least one D-amino acid.
3. The method of claim 1 , wherein the peptide comprises the amino acid sequence Lys-Met-Val-Ile-Tyr-Tru-Lys-Ala-Gly (SEQ ID NO:5).
4. A method for enhancing the efficacy of chemotherapy or radiation therapy in a patient in need thereof, comprising:
administering to the patient an effective amount of a peptide comprising the amino acid sequence Lys-Met-Val-Ile-Tyr-Trp-Lys-Ala-Gly (SEQ ID NO:5), or a pharmaceutically acceptable salt thereof, wherein the peptide inhibits cell adhesion mediated drug resistance in the patient; and
administering chemotherapy, radiation therapy, or both, to the patient;
whereby the efficacy of the chemotherapy, radiation therapy, or both, is enhanced.
5. The method of claim 4 , wherein the peptide comprises at least one D-amino acid.
6. The method of claim 5 , wherein the peptide comprises the amino acid sequence Lys-Met-Val-Ile-Tyr-Trp-Lys-Ala-Gly (SEQ ID NO:5).
7. A method for treating cancer in a patient in need thereof comprising:
administering to the patient an effective amount of a peptide comprising the amino acid sequence Lys-Met-Val-Ile-Tyr-Trp-Lys-Ala-Gly (SEQ ID NO:5), or a pharmaceutically acceptable salt, wherein the peptide inhibits cell adhesion mediated drug resistance in the patient; and
administering chemotherapy, radiation therapy, or both, to the patient.
8. The method of claim 7 , wherein the peptide comprises at least one D-amino acid.
9. The method of claim 7 , wherein the peptide comprises the amino acid sequence Lys-Met-Val-Ile-Tyr-Trp-Lys-Ala-Gly (SEQ ID NO:5).
10. The method of claim 7 , wherein the cancer is a myeloma.
11. The method of claim 7 , wherein the cancer is multiple myeloma.
12. A method for inhibiting cell adhesion mediated drug resistance in a patient in need thereof, comprising:
administering to the patient an effective amount of a peptide that inhibits cell adhesion mediated drug resistance, wherein the peptide comprises the amino acid sequence Lys-Met-Val-Ile-Tyr-Trp-Lys-Ala-Gly (SEQ ID NO:5), or a pharmaceutically acceptable salt or variant thereof, wherein the variant has at least one of the following modifications: the variant contains one or more hydroxyproline or hydroxylysine; the variant contains an organic acid or amide; the variant contains a C-terminal carboxylate; the variant is esterified; the variant is amidated; the variant has a modified N-terminal amino group; the variant has a side-chain modification or substitution selected from the group consisting of methylation, benzylation, t-butylation, tosylation, and alcoxycarbonylation; the variant has an N-acetyl group; the variant has a C-terminal amide group; or the variant has an amino acid selected from the group consisting of penicillamine, tetramethylene cysteine, pentamethylene cysteine, mercaptopropionic acid, pentamethylene-mercaptopropionic acid, 2-mercaptobenzene, 2-mercaptoaniline, 2-mercaptoproline, ornithine, diaminobutyric acid, aminoapidic acid, m-aminomethylbenzoic acid, and diaminopropionic acid.
13. A method for enhancing the efficacy of chemotherapy or radiation therapy in a patient in need thereof, comprising:
administering to the patient an effective amount of a peptide comprising the amino acid sequence Lys-Met-Val-Ile-Tyr-Trp-Lys-Ala-Gly (SEQ ID NO:5), or a pharmaceutically acceptable salt or variant thereof, wherein the peptide inhibits cell adhesion mediated drug resistance in the patient, and wherein the variant has at least one of the following modifications: the variant contains one or more hydroxyproline or hydroxylysine; the variant contains an organic acid or amide; the variant contains a C-terminal carboxylate; the variant is esterified; the variant is amidated; the variant has a modified N-terminal amino group; the variant has a side-chain modification or substitution selected from the group consisting of methylation, benzylation, t-butylation, tosylation, and alcoxycarbonylation; the variant has an N-acetyl group; the variant has a C-terminal amide group; or the variant has an amino acid selected from the group consisting of penicillamine, tetramethylene cysteine, pentamethylene cysteine, mercaptopropionic acid, pentamethylene-mercaptopropionic acid, 2-mercaptobenzene, 2-mercaptoaniline, 2-mercaptoproline, ornithine, diaminobutyric acid, aminoapidic acid, m-aminomethylbenzoic acid, and diaminopropionic acid; and
administering chemotherapy, radiation therapy, or both, to the patient, whereby the efficacy of the chemotherapy, radiation therapy, or both, is enhanced.
14. A method for treating cancer in a patient in need thereof comprising:
administering to the patient an effective amount of a peptide comprising the amino acid sequence Lys-Met-Val-Ile-Tyr-Trp-Lys-Ala-Gly (SEQ ID NO:5), or a pharmaceutically acceptable salt or variant thereof, wherein the peptide inhibits cell adhesion mediated drug resistance in the patient, and wherein the variant has at least one of the following modifications: the variant contains one or more hydroxyproline or hydroxylysine; the variant contains an organic acid or amide; the variant contains a C-terminal carboxylate; the variant is esterified; the variant is amidated; the variant has a modified N-terminal amino group; the variant has a side-chain modification or substitution selected from the group consisting of methylation, benzylation, t-butylation, tosylation, and alcoxycarbonylation; the variant has an N-acetyl group; the variant has a C-terminal amide group; or the variant has an amino acid selected from the group consisting of penicillamine, tetramethylene cysteine, pentamethylene cysteine, mercaptopropionic acid, pentamethylene-mercaptopropionic acid, 2-mercaptobenzene, 2-mercaptoaniline, 2-mercaptoproline, ornithine, diaminobutyric acid, aminoapidic acid, m-aminomethylbenzoic acid, and diaminopropionic acid; and
administering chemotherapy, radiation therapy, or both, to the patient.