Mechanisms of Carcinogenesis and Overview of Anticancer Drugs

What is neoplasia?

New growth or autonomous growth of tissue.

What is a neoplasm?

The lesion resulting from neoplasia.

What is metastasis?

Secondary growths formed when cancer cells migrate from the primary tumor and establish in new locations.

What is cancer?

A malignant neoplasm.

What is a carcinogen?

A physical or chemical agent that causes or induces neoplasia.

What is a genotoxic carcinogen?

A carcinogen that interacts with DNA, resulting in mutation.

What is a nongenotoxic carcinogen?

A carcinogen that modifies gene expression without damaging DNA.

What does an antineoplastic agent refer to?

A drug that acts against cancer.

What characterizes malignant tumors?

Invasiveness and ability to metastasize.

How does DNA mutation contribute to cancer?

Altered DNA expression (genotoxic) can initiate tumor development.

Are all carcinogens genotoxic?

No, some alter gene expression without damaging DNA.

What happens during Initiation in carcinogenesis?

DNA mutation occurs; it's nonreversible and needs only one cell division to lock in.

What happens during Promotion in carcinogenesis?

Nongenotoxic stage with no direct DNA modification; it's reversible and involves clonal expansion.

What happens during Progression in carcinogenesis?

Irreversible changes, including DNA modification and neoplasia.

What is the role of oncogenes in cancer?

Mutated genes that promote uncontrolled cell growth and division.

What is angiogenesis in cancer?

Formation of new blood vessels to supply the tumor.

Why do cancer cells induce angiogenesis?

To support rapid growth by ensuring oxygen and nutrient supply.

What is the significance of P53 in cancer?

It's a tumor suppressor protein crucial for DNA repair and apoptosis.

What is the result of P53 malfunction?

Failure to regulate cell cycle and induce apoptosis, contributing to cancer.

What does chemical carcinogenesis involve?

DNA damage by chemicals (e.g. smoking), leading to cancer after repair failure.

What happens when a cell cannot repair damage?

It may undergo apoptosis or become cancerous.

Can all DNA damage lead to cancer?

No, the body has mechanisms to repair damage, and not all mutations are harmful.

What role do promoter agents play in carcinogenesis?

Promote proliferation of mutated cells without causing further DNA damage.

What defines a reversible stage in carcinogenesis?

Promotion stage, where cell changes can still be reversed.

What defines an irreversible stage in carcinogenesis?

Progression stage, involving stable genetic changes.

What is the link between HPV and cancer?

HPV is a carcinogenic agent that can lead to cancer.

What is sustained proliferative signaling?

Continuous stimulation of cell division and growth in cancer.

What are examples of DNA damage?

Single and double strand breaks, abasic sites (apurinic/apyrimidinic), DNA adduct formation, and crosslinking.

What can cause DNA damage?

UV rays, x-rays, gamma rays, chemicals (e.g. ROS, RNS), and antineoplastic drugs.

What does depurination mean?

Loss of a purine or pyrimidine base from DNA.

Why are double strand breaks more severe?

They are harder to repair and can lead to chromosomal abnormalities.

What is DNA crosslinking?

Chemical bonding between both strands of DNA, preventing strand separation.

What is a DNA adduct?

A piece of DNA covalently bonded to a cancer-causing chemical.

What happens during chromosomal translocation?

Two chromosomes break and fuse incorrectly, creating a new chromosome.

What happens during chromosomal duplication?

A gene segment is copied more than once.

What is chromosomal inversion?

A segment of a chromosome is reversed end to end.

What is the effect of chromosomal rearrangements?

Can lead to gain/loss of function mutations, fusion proteins, and cancer development.

How can gene duplication contribute to cancer?

It can cause overexpression of oncogenes.

What is HER2 and its role in cancer?

An oncogene involved in breast cancer, encoding a growth factor receptor.

What is P53's function?

It induces apoptosis and acts as a tumor suppressor.

What are examples of oncogenes?

EGFR, HER2, KRAS, BCR-ABL.

What are examples of tumor suppressor genes?

TP53, BRCA1/2, PTEN, Rb, APC.

What happens when the balance between oncogenes and tumor suppressors is disrupted?

Increased cell proliferation and reduced growth regulation, promoting cancer.

What does PTEN do?

Inhibits cell proliferation.

How do growth factor ligands affect cell signaling?

More ligands activate more signaling, promoting cell division.

What happens if growth factor receptors are activated without a ligand?

It can cause unregulated cell growth (often due to mutations).

How do stimulatory signals affect cell cycle entry?

They promote activation of transcription and replication proteins.

What controls the phases of the cell cycle?

Cyclins and cyclin-dependent kinases (CDKs).

What are CDKs?

Enzymes that phosphorylate substrates to regulate the cell cycle.

What is the role of Cyclin D and CDK4/CDK6?

Control the G1 phase and entry into S phase.

What is the role of Cyclin E and CDK2?

Facilitates G1 to S phase transition.

What is the role of Cyclin A and CDK2?

Promotes DNA replication in S phase.

What is the role of Cyclin A and CDK1?

Helps the cell transition from G2 to M phase.

What is the role of Cyclin B and CDK1?

Regulates entry into mitosis.

How are different cyclins expressed during the cell cycle?

They peak at different phases: D (G1), E (G1/S), A (S/G2), B (M).

Why is CDK1 unique?

It pairs with both Cyclin A and B to regulate late cell cycle stages.

What happens if CDKs are not regulated?

Cells may enter division at inappropriate times, leading to cancer.

What is the mechanism of action of Palbociclib, Ribociclib, and Abemaciclib?

They are CDK4 inhibitors that prevent phosphorylation of Rb, halting the cell cycle in G1 phase.

What is the role of CDK4-cyclin D1 in the cell cycle?

Phosphorylates Rb to release E2F, allowing transition from G1 to S phase.

What happens when Rb is not phosphorylated?

E2F is not released, and the cell cycle is halted in G1 phase.

What is E2F?

A transcription factor that promotes progression from G1 to S phase.

What do CDK4 inhibitors like Palbociclib prevent?

They block Rb phosphorylation, thereby preventing G1 to S phase progression.

What are conventional antineoplastic agents?

Drugs like alkylating agents, antimetabolites, and antimicrotubule agents that kill both cancerous and normal cells.

What are hormonal antineoplastic agents?

Drugs like SERMs, aromatase inhibitors, and anti-androgens targeting hormone-sensitive cancers.

What are targeted antineoplastic treatments?

Agents like tyrosine kinase inhibitors and signal pathway inhibitors that target specific molecular pathways in cancer.

What is immunotherapy in cancer treatment?

Therapies like monoclonal antibodies, immune checkpoint inhibitors, and therapeutic vaccines.

Why do conventional antineoplastics lack selectivity?

They cannot differentiate between normal and cancerous cells.

What is the role of SERMs in cancer therapy?

Selective Estrogen Receptor Modulators block estrogen signaling in hormone-dependent cancers.

How do tyrosine kinase inhibitors work?

They block signaling pathways essential for cancer cell growth and survival.

What are some classes of antineoplastic agents that directly damage DNA?

Alkylating agents and topoisomerase inhibitors.

How do topoisomerase inhibitors work?

They induce DNA strand breaks by interfering with DNA unwinding enzymes.

How do efflux pumps contribute to resistance?

They remove drugs from cells, reducing their effectiveness.

What is decreased cellular uptake in cancer resistance?

Drugs are less absorbed into cancer cells due to downregulation of transporters.

What happens with increased expression of efflux pumps?

The drug fails to accumulate in the cell to a therapeutic level.

What role does DNA repair play in drug resistance?

Cancer cells may enhance DNA repair mechanisms, avoiding apoptosis.

What is glutathione's role in drug resistance?

It detoxifies reactive drug species, reducing their effectiveness.

How do mutations in drug targets lead to resistance?

They change the structure of the target, reducing drug binding and efficacy.

What is the EPR effect?

Enhanced Penetration and Retention—drug particles like liposomes accumulate in tumors more than in normal tissues.

Why do liposomes help in cancer therapy?

They encapsulate drugs, allowing them to concentrate in tumor cells due to the EPR effect.

What are hypoxic tumor regions?

Areas with low oxygen that show slow proliferation and resistance to anticancer drugs.

Why do cancer cells in hypoxic regions resist treatment?

They grow slowly and are less responsive to cytotoxic agents targeting dividing cells.

What are some examples of DNA synthesis inhibitors in conventional drugs?

Methotrexate, 5-fluorouracil.

What are some protein synthesis inhibitors used as antineoplastics?

Antibiotics like actinomycin D that inhibit RNA synthesis.

How does resistance develop in cancer similar to bacteria?

Sensitive cells die, leaving resistant cells to survive and proliferate.

Why might lipid-soluble drugs be less affected by transporter resistance?

They can diffuse into cells without relying on uptake transporters.