Platinum-Based Chemotherapy (PBC)
Platinum-based Chemotherapy (PBC): Overview and Mechanism of Action
Platinum-based chemotherapy (PBC) drugs, such as cisplatin, carboplatin, and oxaliplatin, are widely used in cancer treatment due to their ability to form DNA crosslinks that inhibit DNA replication and transcription, leading to cancer cell death. They are effective against various cancers including lung, ovarian, colorectal, and breast cancers.
Mechanism of Action
- DNA Binding and Crosslinking:
These drugs enter tumor cells mainly via active transporters like copper transporter 1 (CTR1). Once inside, they undergo activation through aquation, replacing chloride ligands with water molecules, which makes them reactive. They then bind covalently to DNA, primarily at the N7 position of guanine bases, forming intra- and inter-strand crosslinks. These crosslinks distort DNA structure, inhibit DNA repair, and block DNA synthesis, ultimately triggering cell cycle arrest and apoptosis. - Induction of Cell Death:
The extensive DNA damage caused by platinum drugs activates cellular pathways involving proteins like p53, leading to apoptosis. The damage is often too severe for repair, resulting in programmed cell death. - Additional Effects:
Platinum drugs can also stimulate other forms of cell death, including necroptosis and ferroptosis, especially when apoptosis pathways are blocked or resistant. These processes involve complex signaling pathways and can help overcome tumor resistance.
Clinical Uses
- Treatment of cancers such as lung, ovarian, testicular, bladder, and head and neck cancers.
- Often combined with other chemotherapeutic agents to enhance efficacy.
Side Effects
- Nephrotoxicity (kidney damage)
- Neurotoxicity (peripheral neuropathy)
- Ototoxicity (hearing loss)
- Nausea and vomiting
- Myelosuppression (bone marrow suppression)
- Electrolyte disturbances
Summary
Platinum-based chemotherapy agents exert their anti-cancer effects primarily through covalent DNA binding, leading to crosslink formation that halts DNA replication and induces cell death. Their ability to trigger multiple cell death pathways, including apoptosis, necroptosis, and ferroptosis, underpins their effectiveness but also contributes to their toxicity profile.
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References
- PMC: Mechanisms of Action of Cisplatin
- DrugBank: Cisplatin – Uses, Interactions, Mechanism
- ScienceDirect: Advancements in Platinum-based Anticancer Drugs
