31. Cancer Chemotherapy

What is the primary role of p53 in the cell cycle?

• Tumor suppressor protein that regulates cell cycle in response to stress.

• Prevents proliferation of damaged cells by inducing cell cycle arrest, DNA repair, or apoptosis.

Why is p53 considered a critical tumor suppressor, and what is its clinical significance?

• Defective p53 → abnormal cells escape control and proliferate.

• ~50% of all human tumors contain p53 mutations, making it a key target in cancer biology.

What does the Log-Kill Hypothesis state about tumor cell growth and chemotherapy?

• Tumor cells grow exponentially.

• Chemotherapy kills a constant fraction of cells (not a fixed number) with each dose.

What is the relationship between tumor cell number and curability according to the Log-Kill Hypothesis?

• Inverse relationship: The fewer cells present, the higher the chance of cure.

• Early treatment improves survival because smaller tumors require fewer log-kills.

Why is treating cancer with chemotherapy challenging?

• Not all cancer cells divide rapidly, especially in later stages → replication inhibitors less effective.

• Incomplete kill: Drugs rarely eradicate all cancer cells.

• Drug resistance can develop.

• Drugs may not enter CNS

Which normal tissues are most affected by anticancer drugs and why?

• Rapidly dividing normal cells:

  • Bone marrow → myelosuppression

  • GI mucosa → nausea, vomiting, mucositis

  • Skin & hair follicles → alopecia

• Other toxicities: renal/bladder toxicity, neurocognitive effects (“chemo brain”).

What are the three generalized groups of cancer chemotherapeutic agents?

• Cytotoxic drugs

  • Examples: Alkylating agents, antibiotics, antimetabolites, miscellaneous.

  • Action: Kill cells, primarily those that are dividing.

• Hormonal drugs

  • Used for tumors of hormonally sensitive tissues (e.g., breast, prostate).

• Signal transduction inhibitors

  • Block chemical signaling between cells.

  • Typically kinase inhibitors.

How do Alkylating Agents work?

They transfer alkyl groups to DNA , causing cross-links and abnormal base pairing. This disrupts replication and transcription, leading to cell death. Alkylating agents are most effective in rapidly dividing cells as they effect cells in G1 and S phases.

What drug class is cyclophosphamide and its adverse effects?

It is an alkylating agent that crosslinks DNA. Adverse effects:

• Low WBC

• N/V

• Hairloss

• Many more…

What is the mechanism of action and key adverse effects of Cisplatin?

Cisplatin binds nuclear and cytoplasmic proteins, forming intra- and interstrand DNA cross-links → inhibits DNA synthesis and function. Adverse effects:

• Similar to cyclophosphamide

• Nephrotoxicity

• Ototoxicity

What drug class is Carmustine (Gliadel Wafer) and what is it used for?

Nitrosoureas, they are lipid soluble and cross into CNS. Good for treating brain tumors.

What are antimetabolites and their subgroups?

• Antimetabolites inhibit DNA synthesis and repair. Can compete for binding sites on enzymes or be incorporated into DNA or RNA

• Subgroups: Antifolates, pyrimadine analogues, purine analogues

What is Methotrexate (Trexall)?

A folic acid analog that binds to dihyrofolate reductase to inhibit tetrahydrofolate synthesis. This interefers with formation of DNA, RNA, and proteins.

What drug can reverse the effects of methotrexate?

Leucovorin (Folinic acid). It rescues normal cells in accidental overdose.

What is the mechanism of action of 5-Fluorouracil?

It is a fluoropyrimidine. Its metabolites bind thymidylate synthase, blocking dTMP synthesis causing “thymineless death” and inhibition of DNA synthesis. It is also incorporated into RNA, disrupting RNA processing and mRNA translation.

What is the mechanism of action of 6-Mercaptopurine?

It is a purine analogue that inhibits purine nucleotide synthesis and is incorporated into RNA and DNA, disrupting replication and transcription.

What is the mechanism of action of Vinblastine/ Vinca Alkaloids?

Derived from the periwinkle plant (Vinca rosea). They inhibit tubulin polymerization, preventing microtubule assembly in the cytoskeleton and mitotic spindle → mitotic arrest in metaphase, stopping cell division and causing cell death.

What is the mechanism of action of Paclitaxel (Taxol)/Taxanes?

Paclitaxel is a mitotic spindle poison derived from the yew tree (Taxus). They prevent microtubule disassembly, stabilizing microtubules and blocking mitotic spindle function → mitotic arrest and cell death.

What is the mechanism of action of Etoposide (an epipodophyllotoxin)?

Derived from the mayapple root. Etoposide inhibits topoisomerase II, preventing re-ligation of DNA strands during unwinding → causes double-strand DNA breaks, leading to apoptosis.

What is the mechanism of action of Irinotecan (a camptothecin)?

Camptothecins inhibit topoisomerase I, which normally cuts and re-ligates single DNA strands to allow unwinding. Inhibition causes DNA damage during replication and transcription, leading to cell death.

How do antitumor antibiotics work?

Antitumor antibiotics are a class of chemotherapy drugs that interfere with DNA function in cancer cells.

What is Doxorubicin and how does it work?

It is an antitumor antibiotic that crosslinks DNA and inhibits topoisomerase II.

What is Bleomycin and how does it work?

It is an antitumor antibiotic that causes breaks in DNA strands.

What is Mitomycin and how does it work?

It is an antitumor antibiotic and is a potent DNA crosslinker.

How are antibodies used to treat tumors?

Antibodies are developed to target proteins on tumor cells.

What is the target and clinical use of Alemtuzumab (Lemtrada)?

Alemtuzumab is a monoclonal antibody against CD52, a receptor on B cells. It is used to treat B-cell chronic lymphocytic leukemia (B-CLL), a slowly developing cancer characterized by B-cell accumulation.

How do immune checkpoint inhibitors work in cancer therapy?

Tumor cells exploit immune checkpoints (CTLA-4, PD-1) on T cells to evade immune attack. PD-L1 on tumor cells binds PD-1 on T cells → suppression (anergy, exhaustion, death). Checkpoint inhibitors block CTLA-4 or PD-1/PD-L1 interaction, restoring T-cell activation and anti-tumor immunity.

What are some examples of Anti-PD-L1 antibodies?

• Nivolumab

• Pembrolizumab

What is the mechanism of action of Imatinib and its main clinical use?

Imatinib (a tyrosine kinase inhibitor) blocks ATP binding to kinase, preventing phosphorylation of substrates. Used to treat chronic myelogenous leukemia (CML) caused by a constitutively active BCR-ABL tyrosine kinase that inhibits apoptosis.

How is Imatinib metabolized?

Metabolized by CYP3A4 in liver → avoid grapefruit juice and monitor for drug interactions.

How do Epidermal Growth Factor Receptor/EGFR inhibitors work, and what are key examples?

EGFR is often overexpressed in tumors, promoting cell growth, proliferation, invasion, metastasis, and angiogenesis. EGFR inhibitors block receptor signaling, enhancing chemotherapy response.
Examples:

• Cetuximab (Erbitux): Chimeric mAb against EGFR

• Erlotinib (Tarceva): Inhibits EGFR tyrosine kinase domain; 1st-line for non-small cell lung cancer (NSCLC).

How do VEGF-signaling inhibitors work, and what is a key example?

Tumors require VEGF for angiogenesis. VEGF inhibitors block this pathway via anti-VEGF antibodies, decoy receptors, or VEGF receptor tyrosine kinase inhibitors.
Example: Bevacizumab (Avastin): a monoclonal antibody that binds VEGF, preventing its interaction with VEGF receptors → inhibits tumor vascularization.

How are hormonal agents used to treat cancer?

They are used for hormonally sensitive tumors, like breast, prostate, & uterine cancers.

What is Tamoxifen?

A SERM used to treat in HR-positive breast cancer.

How do cancer cells develop resistance to anticancer drugs?

Cancer cells often harbor mutations enabling uncontrolled growth and can acquire additional mutations that confer drug resistance.

What are the major general adverse effects of anticancer chemotherapy?

• Bone marrow suppression → ↓ WBC, platelets → ↑ infection & bleeding risk

• GI toxicity → nausea/vomiting (CNS effect) + mucosal damage

• Alopecia → hair follicle damage

• Renal toxicity → Cisplatin, high-dose Methotrexate

• Hemorrhagic cystitis → Cyclophosphamide (prevent with Mesna)

• Cardiotoxicity → Doxorubicin (anthracyclines)

• Pulmonary fibrosis → Bleomycin

• Bone marrow toxicity → Vinblastine