7.7.5 Anticancer Drugs

Cisplatin

Cisplatin is a platinum(II) complex with the chemical structure [$PtCl₂(NH₃)₂$]. It has a square planar geometry, where two chloride ions ($Cl⁻$) and two ammonia molecules ($NH₃$) are arranged around a central platinum atom. Cisplatin has a cis configuration, meaning the two chloride ions are adjacent to each other. This is important as the cis configuration enables its therapeutic action, whereas its isomer transplatin does not have the same biological effectiveness.

Mechanism of Action: How Cisplatin Prevents DNA Replication

• Cisplatin prevents DNA replication in cancer cells by a ligand replacement reaction.
• This happens with DNA, a bond is formed between platinum and a nitrogen atom on guanine.
• A $N$ atom on a $G$ base in DNA forms a co-ordinate bond with cisplatin's platinum ion, replacing one of the chloride ion ligands. This is a ligand replacement reaction.

1. Entry into the Cell:

• Cisplatin passes through the cell membrane and enters the cell where it becomes active.
• Once inside, it undergoes a ligand exchange reaction where the chloride ions ($Cl⁻$) are replaced by water molecules ($H₂O$), a process called aquation. This substitution makes the platinum complex more reactive.

2. Binding to DNA:

• Cisplatin binds specifically to guanine bases in DNA through a ligand replacement reaction.
• In this reaction, the nitrogen atom on the guanine base replaces the water ligand on cisplatin, forming a dative covalent bond between the platinum atom and the nitrogen of guanine.
• Typically, cisplatin binds to two adjacent guanine bases, creating cross-links within the DNA strand. This binding distorts the DNA's shape and disrupts its double helical structure.

3. Inhibition of DNA Replication:

• By binding and cross-linking to DNA, cisplatin prevents the DNA strands from unwinding and separating, which are essential steps for replication.
• This disruption of the DNA structure blocks transcription (copying of DNA to RNA) and stops DNA replication. Without replication, the cancer cells cannot divide and proliferate, ultimately slowing down or stopping the growth of the tumor.

• A 2nd $N$ atom from a nearby $G$ molecule (either on the same strand of the DNA, or the opposite strand) can bond to the platinum, replacing the 2nd chloride ion as well.

Adverse Effects and Societal Considerations

1. Impact on Healthy Cells:

• Cisplatin does not exclusively target cancer cells; it can also bind to DNA in healthy cells.
• Since cisplatin primarily affects cells that are rapidly dividing, healthy cells with high replication rates, such as those in hair follicles, bone marrow, and the lining of the digestive tract, are also impacted.
• This non-specific action of cisplatin leads to side effects including hair loss, nausea, fatigue, and an increased susceptibility to infections due to bone marrow suppression.

2. Balancing Therapeutic Benefits and Adverse Effects:

• Despite its side effects, cisplatin is considered an effective anticancer drug, especially for certain cancers like testicular, ovarian, cervical, lung, and brain cancers.
• Society must weigh the benefits of cisplatin's therapeutic effects against its adverse effects on healthy cells. For many patients, the life-saving potential of cisplatin outweighs the side effects.
• Ongoing research seeks to improve anticancer drugs to specifically target cancer cells, potentially reducing harm to healthy cells and minimizing side effects.
• These side effected can be lessened by giving patients very low doses of cisplatin.
• They can also be reduced by targeting the tumours directly - i.e. using a method that deliver the drugs only to the cancer cells, so it doesn't get the chance to attack healthy cells.
• Despite the side effects of cisplatin, it is still used as a chemotherapy drug. - This is because the balance of the long-term positive effects (curing cancer) outweigh the short-term negative effects (Hair loss etc)