Method of inhibiting ABCG2 and related treatments
Inventors
Henrich, Curtis J. • Bokesch, Heidi R. • Bates, Susan E. • Robey, Robert W. • Shukla, Suneet • Ambudkar, Suresh V. • Dean, Michael C. • McMahon, James B.
Assignees
US Department of Health and Human Services
Publication Number
US-9937217-B2
Publication Date
2018-04-10
Expiration Date
2028-11-05
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Abstract
Disclosed are methods of enhancing the chemotherapeutic treatment of tumor cells, reducing resistance of a cancer cell to a chemotherapeutic agent, a method of inhibiting ABCG2 or MRP1 in a mammal afflicted with cancer, and a method of increasing the bioavailability of an ABCG2 substrate drug in a mammal. The methods comprise administering peliomycin and other compounds described herein.
Core Innovation
The invention provides methods to enhance the chemotherapeutic treatment of tumor cells by administering an effective amount of a chemotherapeutic agent in conjunction with a compound that inhibits the ABCG2 protein. This method serves to increase the efficacy of chemotherapy by targeting ABCG2-mediated multidrug resistance mechanisms in cancer cells.
The problem being addressed is the challenge of multidrug resistance in cancer chemotherapy, primarily caused by the multidrug resistance transporter ABCG2. ABCG2 is known to limit the effectiveness of various anticancer drugs and reduce oral absorption of some drugs due to its transporter function at physiological barriers such as the blood-brain barrier. Consequently, the lack of clinically useful inhibitors of ABCG2 activity has limited successful cancer treatment outcomes.
To overcome this, the invention also provides methods of reducing cancer cell resistance to chemotherapeutic agents by inhibiting ABCG2, methods of inhibiting ABCG2 and/or MRP1 in mammals afflicted with cancer, and methods of increasing the bioavailability of ABCG2 substrate drugs by coadministering an ABCG2 inhibitor. The compounds exemplified include peliomycin (NSC 76455) and related compounds that inhibit the activity of these transporters, thereby enhancing chemotherapy, reducing resistance, and improving drug bioavailability and CNS penetration.
Claims Coverage
The patent includes three independent claims focusing on methods for enhancing chemotherapy, reducing resistance, and inhibiting specific transporter proteins using designated inhibitory compounds.
Methods of enhancing chemotherapy and increasing bioavailability
A method comprising administering an effective amount of a chemotherapeutic agent in conjunction with an effective amount of a compound that inhibits the ABCG2 protein, selected from a specified group of compounds, to enhance chemotherapeutic treatment of tumor or cancer or increase the bioavailability of an ABCG2 substrate drug in a mammal.
Method of reducing resistance by inhibiting ABCG2
A method of reducing resistance of a tumor or cancer to a chemotherapeutic agent by inhibiting ABCG2 in a mammal through administering, alongside the chemotherapeutic agent, an effective amount of a compound from a specified group that inhibits ABCG2.
Method of reducing resistance by inhibiting MRP1
A method of reducing resistance of a tumor or cancer to a chemotherapeutic agent by inhibiting MRP1 in a mammal through administering, alongside the chemotherapeutic agent, an effective amount of a compound from a specified group that inhibits MRP1.
The independent claims cover methods involving administering compounds that inhibit ABCG2 or MRP1 in combination with chemotherapeutic agents to enhance treatment effectiveness, reduce drug resistance, and increase bioavailability of substrate drugs in mammals afflicted with various tumors or cancers.
Stated Advantages
Inhibitors of ABCG2 activity can overcome drug resistance and enhance the efficacy of adjuvant chemotherapy.
ABCG2 inhibitors can enhance oral bioavailability and brain penetration of substrate drugs, improving therapeutic outcomes in cancers involving the digestive tract or central nervous system.
The compounds provide a way to reduce multidrug resistance mediated by ABCG2 and MRP1, major contributors to resistance in cancer cells.
Documented Applications
Enhancement of chemotherapeutic treatment of tumors and cancers in mammals.
Reduction of cancer cell resistance to cytotoxic drugs through inhibition of ABCG2 or MRP1.
Increasing oral bioavailability and brain penetration of ABCG2 substrate drugs.
Treatment of cancers that overexpress ABCG2 and/or MRP1, including leukemias, solid tumors (lung, endometrium, digestive tract), melanomas, lymphomas, breast, ovarian, colon, prostate, brain, stomach tumors, and non-small cell lung cancer.
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