Science of PARP
What is PARP?
PARP, or poly (ADP-ribose) polymerase, is a ubiquitous nuclear enzyme whose function in the human body includes repairing damage to our DNA. PARP regulates the nuclear machinery used for repairing damaged DNA. If left unrepaired, DNA damage can stall the cell cycle and lead to cell death.
In normal, noncancerous cells, DNA repair is beneficial, promoting healthy cell growth and proliferation. However, studies have suggested that cancer cells may use the PARP-dependent DNA repair pathway to their advantage. For example, PARP1 expression and activity are significantly upregulated in many cancers, implying an important role for this enzyme in survival and proliferation of cancer cells.1,2
What makes PARP a promising target?
While inhibition of PARP has demonstrated significant anti-tumor effects in several cancers, its activity does not appear to be critical for normal, non-cancerous cells.3 Thus, PARP inhibition has the potential to impair a fundamental mechanism of tumor growth without rendering damage to normal cells, implying a lower risk for side effects in patients who receive PARP-inhibitor-based therapies.
PARP inhibition and chemotherapy - disrupting mechanisms of chemotherapy-resistance in cancer cells
Chemotherapy regimens used in the treatment of cancer, including alkylating agents, topoisomerase inhibitors, and platinum drugs, are designed to damage DNA in order to prevent cancer cells from reproducing. DNA repair enzymes such as PARP, whose activity and expression are upregulated in tumor cells, are believed to dampen the intended effect of chemotherapy and generate resistance. PARP inhibitors, such as BSI-201, prevent cancer cells from repairing their own DNA, thus enhancing the potential of chemotherapy and radiation therapy to induce cell death.3
PARP inhibition and BRCA - Exploiting Cancer's Inherent Defects
PARP inhibitors represent a new, targeted approach to treating certaintypes of cancers. PARP inhibition has the potential to overwhelm cancer cellswith lethal DNA damage by exploiting impaired DNA repair function inherent in somecancers, including those with defects in BRCA1/2 and other DNA repair molecules.Inhibition of PARP leads to failure to repair single strand DNA breaks, which,in turn, causes double strand DNA breaks via collapse of the replication fork.These effects are particularly detrimental to cancer cells that are deficientin repairing double strand DNA breaks and ultimately lead to cancer cell death.
PARP, or poly (ADP-ribose) polymerase, is a ubiquitous nuclear enzyme whose function in the human body includes repairing damage to our DNA. PARP regulates the nuclear machinery used for repairing damaged DNA. If left unrepaired, DNA damage can stall the cell cycle and lead to cell death.
In normal, noncancerous cells, DNA repair is beneficial, promoting healthy cell growth and proliferation. However, studies have suggested that cancer cells may use the PARP-dependent DNA repair pathway to their advantage. For example, PARP1 expression and activity are significantly upregulated in many cancers, implying an important role for this enzyme in survival and proliferation of cancer cells.1,2
What makes PARP a promising target?
While inhibition of PARP has demonstrated significant anti-tumor effects in several cancers, its activity does not appear to be critical for normal, non-cancerous cells.3 Thus, PARP inhibition has the potential to impair a fundamental mechanism of tumor growth without rendering damage to normal cells, implying a lower risk for side effects in patients who receive PARP-inhibitor-based therapies.
PARP inhibition and chemotherapy - disrupting mechanisms of chemotherapy-resistance in cancer cells
Chemotherapy regimens used in the treatment of cancer, including alkylating agents, topoisomerase inhibitors, and platinum drugs, are designed to damage DNA in order to prevent cancer cells from reproducing. DNA repair enzymes such as PARP, whose activity and expression are upregulated in tumor cells, are believed to dampen the intended effect of chemotherapy and generate resistance. PARP inhibitors, such as BSI-201, prevent cancer cells from repairing their own DNA, thus enhancing the potential of chemotherapy and radiation therapy to induce cell death.3
PARP inhibition and BRCA - Exploiting Cancer's Inherent Defects
PARP inhibitors represent a new, targeted approach to treating certaintypes of cancers. PARP inhibition has the potential to overwhelm cancer cellswith lethal DNA damage by exploiting impaired DNA repair function inherent in somecancers, including those with defects in BRCA1/2 and other DNA repair molecules.Inhibition of PARP leads to failure to repair single strand DNA breaks, which,in turn, causes double strand DNA breaks via collapse of the replication fork.These effects are particularly detrimental to cancer cells that are deficientin repairing double strand DNA breaks and ultimately lead to cancer cell death.
References
1Virag L and Szabo C. The therapeutic potential of Poly(ADP-Ribose)Polymerase Inhibitors. Pharm Rev. 2002; 54:375-429.
2Ossovskaya V et al. PARP1 gene over-expression in primary human cancers: a potential marker for PARP inhibition. 2007.
AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapy.
3BiPar Sciences, data on file.
1Virag L and Szabo C. The therapeutic potential of Poly(ADP-Ribose)Polymerase Inhibitors. Pharm Rev. 2002; 54:375-429.
2Ossovskaya V et al. PARP1 gene over-expression in primary human cancers: a potential marker for PARP inhibition. 2007.
AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapy.
3BiPar Sciences, data on file.