Poly Adp Ribose Polymerase Inhibitor

• Poly ADP Ribose Polymerase (PARP) inhibitors are a class of drugs used in cancer treatment.
• They primarily function by blocking PARP enzymes, which are crucial for repairing single-strand DNA breaks in cells.
• PARP inhibitors are particularly effective in cancers with existing DNA repair deficiencies, such as those with BRCA mutations.
• Their clinical uses include treating ovarian, breast, prostate, and pancreatic cancers.
• Common PARP inhibitors side effects include fatigue, nausea, anemia, and myelosuppression.

What is Poly ADP Ribose Polymerase (PARP) Inhibitor?

A Poly ADP Ribose Polymerase (PARP) inhibitor is a type of targeted therapy used in cancer treatment. It works by blocking the activity of PARP enzymes, which are proteins involved in DNA repair within cells. By inhibiting these enzymes, PARP inhibitors prevent cancer cells from repairing damaged DNA, leading to their death. This therapeutic approach is particularly effective in cancer cells that already have compromised DNA repair mechanisms, such as those with mutations in the BRCA1 or BRCA2 genes, creating a synthetic lethality.

The concept behind PARP inhibition leverages the fact that cancer cells often rely heavily on alternative DNA repair pathways when primary ones are defective. By blocking PARP, these cells are left without a viable means to fix DNA damage, making them highly susceptible to the drug’s effects while sparing healthy cells that have intact DNA repair systems.

How PARP Inhibitors Work: Mechanism of Action

How do PARP inhibitors work involves a sophisticated mechanism centered on DNA repair. PARP enzymes are crucial for detecting and initiating the repair of single-strand DNA breaks (SSBs). When PARP is inhibited, these SSBs accumulate and can progress into more severe double-strand DNA breaks (DSBs) during DNA replication. Cancer cells with existing deficiencies in homologous recombination repair (HRR), a major pathway for repairing DSBs (often due to mutations in genes like BRCA1/2), cannot effectively fix these new DSBs.

This inability to repair DSBs leads to genomic instability, cell cycle arrest, and ultimately, programmed cell death (apoptosis) in cancer cells. Healthy cells, which typically have functional HRR pathways, can still repair DSBs even when PARP is inhibited, thus minimizing harm to non-cancerous tissues. This selective toxicity is a hallmark of PARP inhibitors, making them valuable agents in precision oncology.

Types, Clinical Uses, and Side Effects of PARP Inhibitors

There are several types of PARP inhibitors currently approved for clinical use, each with specific indications and profiles. These include olaparib, rucaparib, niraparib, and talazoparib. While they all target PARP enzymes, their pharmacokinetic properties and specific approved uses can vary. The development of these inhibitors has expanded treatment options for patients with certain genetic profiles.

The PARP inhibitors uses have primarily focused on cancers with homologous recombination deficiency (HRD), particularly those with BRCA1/2 mutations. They are approved for the treatment of various advanced cancers, including:

• Ovarian cancer (maintenance therapy and treatment for recurrent disease)
• Breast cancer (HER2-negative, BRCA-mutated metastatic disease)
• Prostate cancer (metastatic castration-resistant, BRCA-mutated)
• Pancreatic cancer (germline BRCA-mutated, maintenance therapy)

Despite their efficacy, PARP inhibitors side effects can occur, ranging from mild to severe. Common side effects include fatigue, nausea, vomiting, diarrhea, constipation, and abdominal pain. Hematologic toxicities such as anemia, neutropenia, and thrombocytopenia are also frequently observed and may require dose adjustments or treatment interruptions. Less common but serious side effects can include myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), though these are rare. Patients receiving PARP inhibitors are closely monitored for these adverse events to ensure optimal management and safety.