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PARP Inhibitors And Breast Cancer Treatment

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Updated April 03, 2009

Poly (ADP-Ribose) Polymerase-1 (PARP)

Solution structure of the first zf-PARP domain of human Poly(ADP-ribose)polymerase-1

Image © Nagashima, T., Hayashi, F., Yokoyama, S., RCSB Protein Data Bank

About PARP and DNA Repair:

PARP is an acronym for poly (ADP-ribose) polymerase. PARP is a protein that has several roles in cellular processes, most notably in DNA repair and programmed cell death. Healthy cells can use PARP to repair themselves and live out their normal life cycle. But cancer cells may also use PARP to repair DNA damage, thus extending their uncontrolled growth. Such cancers can become resistant to treatment. There are several different PARP proteins, and they each have their own role in functions within cells.

PARP Inhibitors And Breast Cancer Treatment:

A PARP inhibitor is a drug that blocks PARP proteins from performing their roles in repairing damaged cancer cells. Chemotherapy and radiation work by breaking the DNA of cells so that they may not reproduce. Some types of cancer cells use PARP enzymes to repair their DNA damage and recover from the assault of cancer treatments. Clinical trials are being done to see if PARP inhibitors, in combination with other cancer treatments, can block PARP protein from damaged cancer cells.

Effects On Breast Cancer Treatment:

If a PARP inhibitor is added to chemotherapy treatments for breast cancer, researchers hope cancer cells that have resisted anticancer drugs will be become vulnerable to fatal DNA damage. In some cases, a PARP inhibitor may be used alone, rather than in conjunction with chemo and radiation. Even better news is that PARP inhibitors do not appear to affect normal, non-cancerous cells. That means fewer side effects for patients and faster recovery from treatments.

Hope for Hereditary Breast Cancers:

PARP inhibitors may be especially helpful for patients with hereditary breast cancer. People who have BRCA1 and BRCA2 genetic mutations are at very high risk for developing breast cancer. Healthy BRCA genes can suppress tumor formation, but mutated BRCA genes are powerless against cancer cells. PARP inhibitors may exploit the weakness inherent in cancer cells with mutated BRCA. One possible use for PARP inhibitors may be prevention of hereditary breast cancer. Perhaps PARP inhibitors will become a preventative treatment for high-risk women and would make prophylactic mastectomies obsolete.

Encouraging News for Triple-Negative Breast Cancers:

A phase 2 clinical trial of a PARP inhibitor, BSI-201, was done with patients who were diagnosed with metastatic triple negative breast cancer. The 89 patients enrolled in this trial had already been treated with no more than two chemotherapy regimens. Half of the patients were treated with Gemcitabine and Carboplatin, the other half had the same chemotherapy with the addition of BSI-201. Side effects for both groups were about the same, suggesting that the PARP inhibitor was well tolerated. Preliminary data suggests clinical benefits may include slower tumor growth or tumor regression.

Other Uses For PARP Inhibitors:

Drugs developed with PARP inhibitors are being tested on several kinds of cancer: breast and ovarian, uterine, brain, and pancreatic.

Potential Importance of PARP Inhibitors:

The addition of PARP inhibitors to the current arsenal of weapons against breast cancer looks very promising. PARP inhibitors increase the effectiveness of chemotherapy against aggressive hereditary and triple-negative breast cancers, potentially without adding many serious side effects. These drugs appear to improve quality of life as well as extend survival for patients. Fighting breast cancer at the level of its DNA looks like the wave of the future.

Sources:
National Cancer Institute. Dictionary of Cancer Terms. PARP-1 inhibitor AG014699.

Triple Negative Metastatic Breast Cancer: A Phase 2, Multi-Center, Open-Label, Randomized Trial of Gemcitabine/Carboplatin (G/C) With or Without BSI-201, a PARP Inhibitor. J. O’Shaughnessy, C. Osborne, J. Blum, J. Pippen, M. Yoffe, D. Patt, G. Monaghan, C. Rocha, V. Ossovskaya, B. Sherman, and C. Bradley. SABCS Poster, December 2008.

Recombination repair and a treatment for BRCA2 tumours. Helleday, Thomas, Arnaudeau, C., Lundin, C. Nature 434, 913-7. (2005).

Image from:
Nagashima, T., Hayashi, F., Yokoyama, S. Solution structure of the first zf-PARP domain of human Poly(ADP-ribose)polymerase-1. To be Published. RCSB Protein Data Bank.
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