PARP Inhibitors Overview PDF

PARP Inhibitors Overview: Key Learnings 1. Function and Target: PARP inhibitors (Poly ADP-Ribose Polymerase inhibitors) target the PARP enzyme family, which helps repair single-strand DNA breaks. When PARP is inhibited, cancer cells with defective DNA repair mechanisms, like th...

PARP Inhibitors Overview: Key Learnings 1. Function and Target: PARP inhibitors (Poly ADP-Ribose Polymerase inhibitors) target the PARP enzyme family, which helps repair single-strand DNA breaks. When PARP is inhibited, cancer cells with defective DNA repair mechanisms, like those with BRCA mutations, cannot repair damaged DNA effectively, leading to cell death. This is especially useful in cancers that already have DNA repair pathway deficiencies, such as certain breast, ovarian, and prostate cancers. 2. Mechanism of Synthetic Lethality: In cancer cells with BRCA1 or BRCA2 mutations, a concept called "synthetic lethality" comes into play. These cells rely heavily on PARP for DNA repair because of pre-existing repair deficits. Inhibiting PARP selectively targets these cells, causing accumulation of DNA damage and resulting in cell death, while sparing normal cells that still have other functional repair pathways. 3. Clinical Applications: Approved PARP inhibitors like olaparib, rucaparib, and niraparib are primarily used for BRCA-mutated ovarian and breast cancers, with expanding applications to prostate and pancreatic cancers. They are often used as monotherapy or in combination with chemotherapy or immunotherapy. 4. Advantages: PARP inhibitors offer targeted treatment with generally fewer side effects compared to conventional chemotherapy. They have shown significant efficacy in improving progression-free survival in patients with specific genetic mutations (e.g., BRCA1/2). 5. Limitations and Resistance: Some cancers develop resistance to PARP inhibitors over time, potentially due to genetic reversion (restoration of BRCA function) or alternative DNA repair pathways. Ongoing research explores combination strategies to address these resistance mechanisms and extend efficacy. In summary, PARP inhibitors provide a targeted approach for patients with BRCA mutations or homologous recombination deficiencies, leveraging their DNA repair weaknesses to combat cancer cells effectively. Cisplatin Overview Mechanism of Action: Cisplatin is a platinum-based chemotherapy drug. It works by binding to DNA in cancer cells, forming cross-links that prevent DNA replication and transcription, ultimately leading to cell death. This mechanism is particularly effective because it targets cells that divide rapidly, a hallmark of cancer cells. 1. Uses: Cisplatin is widely used in the treatment of various cancers, including testicular, ovarian, bladder, lung, and head and neck cancers. It’s often a first-line treatment for these cancers and is commonly used alone or in combination with other chemotherapies for increased efficacy. 2. Side Effects: Cisplatin is known for its severe side effects, including nephrotoxicity (kidney damage), ototoxicity (hearing loss), neurotoxicity (nerve damage), and  nausea. To manage toxicity, careful dosing, hydration protocols, and monitoring of kidney function are essential in patients undergoing treatment. 3. Resistance: Cisplatin resistance is a significant clinical challenge. Cancer cells can develop mechanisms to repair DNA damage caused by cisplatin or enhance drug efflux, leading to reduced effectiveness. Researchers are studying combination therapies and other agents to help overcome this resistance and extend cisplatin's efficacy. 4. Role in Cancer Treatment: Despite its toxicity, cisplatin remains a cornerstone in cancer treatment due to its effectiveness, especially for testicular and ovarian cancers. Advances in supportive care and dosing strategies help mitigate some side effects, allowing it to remain a widely-used option. In essence, cisplatin's effectiveness in targeting cancer through DNA damage makes it indispensable, although its side effects and resistance challenges highlight areas for ongoing research. 4o