Inhibitors of ABC drug transporters in multidrug resistant cancer cells
OwnerGrant L. Schoenhardinventor
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Abstract
The present invention relates to multidrug resistance in cancer and, in particular, to compounds that modulate drug transporters of the ABC protein superfamily. The invention also relates to methods for selecting or designing compounds for the ability to inhibit drug transporter proteins and to methods of inhibiting drug transporter proteins. The invention concerns the new use of opioid receptor antagonists in the treatment of a cancer patient who has developed a resistance to a therapeutically active substance.
Claims59
A method of increasing efficacy of an anti-tumor agent comprising co-administering to a patient suffering from a multidrug resistant cancer:
- (a) a dose of the anti-tumor agent, wherein the anti-tumor agent is a substrate of an ABC drug transporter, and
- (b) a dose of an opioid inhibitor of the ABC drug transporter,
- wherein the dose of the opioid inhibitor of the ABC drug transporter is sufficient to reduce efflux of the anti-tumor agent from a cancer cell and wherein the co-administration of the anti-tumor agent and the inhibitor is sufficient to inhibit growth of the cancer.
A method of increasing efficacy of an anti-tumor agent comprising co-administering to a patient having a cancer:
- (a) a dose of the anti-tumor agent, wherein the anti-tumor agent is a substrate of an ABC drug transporter, and
- (b) a dose of an opioid inhibitor of the ABC drug transporter, wherein the dose of the opioid inhibitor of the ABC drug transporter is sufficient to increase the intracellular concentration of the anti-tumor agent in a cancer cell and wherein the co-administration of the anti-tumor agent and the opioid inhibitor of the ABC drug transporter is sufficient to inhibit growth of the cancer.
A method of decreasing toxicity associated with treating a cancer patient with an anti-tumor agent comprising co-administering to a patient having a cancer:
- (a) a sub-therapeutic dose of the anti-tumor agent, wherein the anti-tumor agent is a substrate of an ABC drug transporter, and
- (b) a dose of an opioid inhibitor of the ABC drug transporter,
- wherein the dose of the opioid inhibitor of the ABC drug transporter is sufficient to reduce efflux of the anti-tumor agent from a cancer cell and wherein the co-administration of the anti-tumor agent and the inhibitor is sufficient to inhibit growth of the cancer.
A method of decreasing toxicity associated with treating a cancer patient with an anti-tumor agent comprising co-administering to a patient having a cancer:
- (a) a sub-therapeutic dose of the anti-tumor agent, wherein the anti-tumor agent is a substrate of an ABC drug transporter, and
- (b) a dose of an opioid inhibitor of the ABC drug transporter, wherein the dose of the opioid inhibitor of the ABC drug transporter is sufficient to increase the intracellular concentration of the anti-tumor agent in a cancer cell and wherein the co-administration of the anti-tumor agent and the opioid inhibitor of the ABC drug transporter is sufficient to inhibit growth of the cancer.
A composition for treating multidrug resistant cancer cells comprising:
- (a) an anti-tumor agent, wherein the anti-tumor agent is a substrate of an ABC drug transporter protein;
- and
- (b) an opioid inhibitor of the ABC transporter protein.
A method of enhancing the anti-tumor activity of an anti-tumor agent against a multidrug resistant cancer cell comprising:
- contacting the cancer cell with the anti-tumor agent and an opioid inhibitor of an ABC drug transporter in an amount effective to inhibit a drug transporter in the cancer cell.
A method of suppressing growth of a multidrug resistant cancer cell comprising:
- contacting the cancer cell with a sub-therapeutic amount of an anti-tumor agent in the presence of an opioid inhibitor of an ABC drug transporter.
A method of inhibiting a P-glycoprotein in a patient suffering from cancer comprising administering to the patient a P-glycoprotein inhibiting amount of an inhibitor of an ABC drug transporter, wherein the inhibitor is selected from the group consisting of naltrexone, naloxone and nalmefene,
- wherein the inhibitor is administered before, with, or after the administration to the patient of a therapeutic or sub-therapeutic amount of an anti-tumor agent.
A method of inhibiting a P-glycoprotein in a patient suffering from cancer comprising administering to the patient a P-glycoprotein inhibiting amount of an inhibitor of an ABC drug transporter, wherein the inhibitor of the ABC drug transporter is a compound of the formula:
- 25
- wherein R1 is CH2 or O;
- wherein R2 is a cycloalkyl, unsubstituted aromatic, alkyl or alkenyl;
- and
- wherein R3 is O, CH2 or NH,
- wherein the inhibitor is administered before, with, or after the administration to the patient of a therapeutic or sub-therapeutic amount of an anti-tumor agent.
A method of identifying a compound for improved treatment of multidrug resistant cancers comprising:
- (a) identifying an anti-tumor agent;
- (b) assaying the ability of the anti-tumor agent to be transported across a membrane by an ABC protein;
- and
- (c) repeating the transport assay to determine whether addition of an opioid receptor antagonist inhibits transport of the anti-tumor agent across the membrane, whereby the compound which is active in the brain, is transported by an ABC protein and whose ABC protein-mediated transport is inhibited by the opioid receptor antagonist is identified.
A method for screening for an opioid inhibitor of an ABC drug transporter, comprising determining whether a potential opioid inhibitor inhibits growth of a cancer cell in the presence of sub-therapeutic amount of anti-tumor agent,
- wherein the cancer cell expresses an ABC drug transporter, and
- wherein said determining comprises comparing the growth of the cancer cell which expresses the ABC drug transporter, with growth of a second cancer cell which does not produce the ABC drug transporter, wherein the first and second cancer cells are grown in the presence of the sub-therapeutic amount of the anti-tumor agent.
A method for screening for an opioid inhibitor of an ABC drug transporter, comprising:
- contacting a potential opioid inhibitor of an ABC drug transporter protein with the ABC drug transporter protein in the presence of a compound selected from the group consisting of naltrexone, naloxone and nalmefene, wherein the compound is detectably labeled;
- measuring the amount of detectably labeled compound bound to the ABC drug transporter;
- and
- comparing the measured amount to the amount of detectably labeled compound bound by the ABC drug transporter when the drug transporter is contacted with the compound alone,
- whereby a measured amount lower than the amount of compound bound to the ABC drug transporter when contacted alone identifies an opioid inhibitor of the ABC drug transporter.
A method of treating a cancer in an animal, comprising administering to the animal suffering from the cancer an anti-tumor agent and an ABC drug transporter inhibitor in an amount sufficient to increase the intracellular concentration of the anti-tumor agent in a cancer cell,
- wherein the ABC drug transporter inhibitor increases the susceptibility of the cancer to the anti-tumor agent, and
- wherein the ABC drug transporter inhibitor is selected from the group consisting of naltrexone, naloxone and nalmefene.
A method of treating a cancer in an animal, comprising administering to the animal suffering from the cancer an anti-tumor agent and an ABC drug transporter inhibitor in an amount sufficient to increase the intracellular concentration of the anti-tumor agent in a cancer cell,
- wherein the ABC drug transporter inhibitor increases the susceptibility of the cancer cell to the anti-tumor agent, and
- wherein the ABC drug transporter inhibitor is a compound of the formula:
- 26
- wherein R1 is CH2 or O;
- wherein R2 is a cycloalkyl, unsubstituted aromatic, alkyl or alkenyl;
- and
- wherein R3 is O, CH2 or NH.
Dependencies are inferred from the claim text.