MEDI 344 |
| Drug resistance is a major cause of cancer treatment failure. Doxorubicin induces the production of damaging reactive oxygen species as part of its mechanism of action, and resistance to doxorubicin can develop through increased levels of the intracellular antioxidant glutathione. Mechanisms of increasing the state of oxidative stress could enhance the sensitivity of cancer cells toward doxorubicin. Modulation of intracellular glutathione via a combination of glutathione reductase inhibition and glutathione synthesis inhibition is a novel approach to increasing oxidative stress and improving the activity of cancer chemotherapy. A novel irreversible glutathione reductase inhibitor, 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid (2-AAPA), and a glutathione synthesis inhibitor, buthionine sulfoximine (BSO) were used to increase the oxidative state in OVCAR-3 cells followed by treatment with doxorubicin. The combination exhibited a higher synergistic effect with doxorubicin than either compound alone. The methods and results will be presented. |
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Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |