Anthracyclines play an important role in the treatment of cancer, and doxorubicin was one of the first
anthraycyclines isolated from Streptomyces peucetius. Doxorubicin is an essential part of treatment for
breast cancer, childhood solid tumors, soft tissue sarcomas and aggressive lymphomas. However, tumor cells
quickly develop resistance to these drugs and healthy cells become toxic, the main toxic effect is cardiac
failure. Doxorubicin is a cell cycle-specific drug that slows or stops the growth of cancer cells by inhibiting
DNA synthesis in S phase. Its exact mechanism of antineoplastic activity is still unknown but may involve
binding to DNA by intercalation between base pairs and inhibition of DNA and RNA synthesis.
ATP binding cassette transporters play an important role in the efflux of doxorubicin and are important in
cell-resistance to treatment. These genes, ABCC1, ABCB1, ABCG2, and ABCC2, are being studied for their
integration into future gene-therapy vectors.
TOP2A is involved in DNA mismatch repair during DNA synthesis. In the proposed mechanism of action for
doxorubicin, doxorubicin inhibits TOP2A, which causes the cells to become mismatch repair-deficient and
to eventually die. Loss of mismatch repair, including that caused by loss of MLH1 and MSH2, has been
reported to result in resistance to doxorubicin.
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| Tina Hernandez-Boussard, Sharon Marsh, Howard McLeod, Xing Jian Lou
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| December, 19 2007 |
| April, 30 2007 | |
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