Antineoplastic Therapies Comparison

Antineoplastic Therapy Comparison

• Traditional antineoplastic therapies are broad-spectrum, targeting both cancerous and healthy rapidly dividing cells, leading to significant side effects.

• Goal of traditional therapies is to halt rapid division of cancer cells, as tumors are most vulnerable during their growth phase.

• The "Mitotoxicity Hypothesis" suggests that metabolically active cells are prone to drugs that disrupt cell growth and division.

• Mechanism involves interfering with cell division (mitosis) or damaging DNA, inhibiting cancer cell proliferation.

• Examples include alkylating agents, antimetabolites, and microtubule inhibitors.

• Adverse effects stem from the high toxicity due to damage to healthy cells (e.g., bone marrow, hair follicles).

• Signal target antineoplastic therapies focus on specific cancer-related pathways, resulting in fewer side effects, although some may be unique to the targets.

• These therapies target molecular pathways critical for cancer cell growth, survival, or proliferation, often centering on proteins or specific mutations.

• Examples include tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), and immune checkpoint inhibitors.

• Higher selectivity allows these therapies to spare most normal cells, although some normal tissues may be affected due to shared molecular pathways.

EGF Receptor Antagonists

• Gefitinib: A reversible TKI that blocks EGFR kinase activity, preventing activation of growth signaling pathways, particularly effective in tumors with activating EGFR mutations.
• Erlotinib: TKI that inhibits the tyrosine kinase domain of EGFR, stopping cell proliferation signals and providing significant survival benefits.
• Cetuximab: A mAb that targets the extracellular domain of EGFR, blocking ligand binding and activation, while engaging the immune system.
• Trastuzumab: A mAb targeting the extracellular domain of EGFR isoform ErbB2, blocking its signaling and reducing cancer recurrence by 50%.

BCR-ABL Inhibitors

• Imatinib: TKI that binds to the ATP-binding site of BCR-ABL, inhibiting its activity and preventing downstream signaling that promotes proliferation in CML and ALL.
• Dasatinib: A dual SRC-ABL inhibitor that manages resistance by inhibiting BCR-ABL in both active and inactive states.
• Nilotinib: Similar to imatinib but with a higher affinity for the ATP-binding site, offering improved inhibition in imatinib-resistant cases.

Ras, JAK2, mTOR, MAPK, and Proteasome Inhibitors

• Ras Inhibitors: Target Ras protein to block signaling pathways that promote growth; FTI’s inhibit Ras farnesylation, preventing membrane anchoring.

• Sorafenib: Multi-kinase inhibitor that disrupts MAPK/ERK signaling, reducing proliferation and inducing apoptosis.

• mTOR Inhibitors: Block the mTOR pathway crucial for cell growth, influencing apoptosis and proliferation.

  • Rapamycin: Inhibits mTORC1 to reduce cell proliferation.
  • Temsirolimus: A rapamycin derivative that also inhibits mTORC1.

• JAK2 Inhibitors: Block JAK2 activity in the JAK-STAT pathway, preventing STAT activation and downstream signaling, reducing proliferation in JAK2-related diseases.

• Proteasome Inhibitors (e.g., Bortezomib): Block proteasome activity, leading to accumulation of pro-apoptotic proteins, enhancing apoptosis and disrupting cell cycle regulation.

Microtubule Dynamics

• Microtubules rapidly assemble and disassemble essential for mitosis; disruption can occur via agents that prevent tubulin assembly or stabilize existing microtubules.

Classes of Chemotherapeutic Agents

• DNA Damaging Agents:

  • Alkylating Agents: Modify DNA structure directly (e.g., Cyclophosphamide, Mechlorethamine).
  • Antitumor Antibiotics: Damage DNA.
  • Platinum Complexes: (e.g., Cisplatin) act similarly to alkylating agents, causing DNA breaks.

• Inhibitors of DNA Synthesis: Include antimetabolites and topoisomerase inhibitors.

• Inhibitors of Microtubule Function:

  • Vinca Alkaloids: Prevent microtubule polymerization by binding to β-tubulin.
  • Taxanes: Promote microtubule polymerization while inhibiting depolymerization.

Mechanisms of Specific Chemotherapeutic Agents

• Alkylating Agents: Directly attach alkyl groups to DNA, causing damage.
• Platinum Compounds: Bind to DNA, leading to strand breaks, primarily used in treating testicular cancer.
• Microtubule Inhibitors: Disrupt microtubule dynamics leading to impaired mitosis.

Clinical Application

• Oncogenic mutation of Ras occurs in approximately 30% of cancers, making Ras a significant target for therapeutic intervention.

Explore the differences between signal target antineoplastic therapies and traditional antineoplastic therapies. This quiz will cover their mechanisms of action, adverse effects, and impacts on rapidly dividing cells. Test your knowledge on how these therapies aim to combat cancer effectively.