Cancer Chemotherapy Lecture3

Cancer Chemotherapy Lecture Notes

Learning Outcomes

By the end of these sessions, you will be able to:

  • Demonstrate an understanding of cancer and how it occurs in the body.

  • Explain the role of carcinogens and the associated risk factors for developing cancer.

  • Explain preventative strategies and UK screening schedules for various cancers.

  • Describe the role of the pharmacist in cancer care within the UK.

  • Explain the mechanism of action for the main classes of traditional cancer chemotherapy agents, including their side effects.

  • Describe the limitations of traditional chemotherapy agents.

  • Understand the principles behind the drug design of non-traditional agents.

Session Plan

  • Recap on previous material.

  • Discussion on the role of tumor markers.

  • Overview of newer chemotherapy agents and their mechanisms of action.

  • Examples of specific drug classes:

    • Monoclonal antibodies.

    • Genetic damage examples.

    • Tyrosine kinase inhibitors.

Chemotherapeutic Agents: Mechanism of Action Summary

  • Purines and Pyrimidines:

    • Essential for nucleic acid biosynthesis.

  • Ribonucleotides and Deoxyribonucleotides:

    • Building blocks of DNA and RNA.

  • Proteins:

    • Targeted by certain chemotherapeutic agents.

  • Microtubules:

    • Target for some drugs that inhibit mitotic spindle formation.

Main Drug Classes:

  • Antimetabolites:

    • Disrupts nucleic acid biosynthesis.

    • Examples:

    • Folic acid analogues: Methotrexate.

    • Purine analogues: Fludarabine; may be incorporated into DNA.

    • Pyrimidines: Cytarabine, dNTP e.g. 5-FU.

  • Platinum Compounds:

    • Covalently binds to DNA; e.g., Cisplatin.

  • Alkylating Agents:

    • Covalently interacts with DNA base residues; e.g., Cyclophosphamide.

  • Plant-derived Agents:

    • Inhibit spindle formation; e.g., Vincristine.

  • Intercalating Agents:

    • Intercalates DNA; e.g., Doxorubicin.

Revision Points

  • Alkylating Agents: How they work.

  • Platinum Agent: Give an example.

Cytotoxic Antibiotics

  • Identify which of the following is a cytotoxic antibiotic:

    • Cyclophosphamide

    • Methotrexate

    • Cisplatin

    • Vincristine

    • Doxorubicin

Doxorubicin: Mode of Action

  • Doxorubicin works by inhibiting the enzyme topoisomerase II.

  • This is crucial for facilitating the cutting of DNA strands during replication.

  • Doxorubicin also interacts with DNA by intercalating with the base pairs.

Vinca Alkaloids: Vincristine

  • Vincristine must be given by the intravenous route.

  • Administration via alternate routes can be fatal.

Newer Chemotherapy Agents

  • Characterized by being more targeted.

  • Designed for specific cancers.

  • Often orally administered.

  • Side effect profiles differ significantly from traditional chemotherapy agents.

Drug Design Considerations

  • When designing a new anti-cancer drug consider:

    • Current agents and their mechanisms.

    • Common side effects and limitations.

    • Target alterations or proteins that are central to cancer pathology.

Ideas for New Targets

  • Preventing cancer initiation.

  • Targeting angiogenesis.

  • Focusing on cancer-specific antigens.

  • Inhibiting protease production by cancer cells.

  • Hormone-dependent cancers may be treated by blocking hormone action.

Monoclonal Antibodies

  • Increasingly common in cancer treatment.

  • Target very specific receptors.

    • Example: Trastuzumab (Herceptin).

    • Targets the HER2 gene, which is often over-expressed in breast cancer.

  • The EGF receptors promote normal cell division; overexpression leads to overstimulation and excess division.

Trastuzumab - Place in Therapy

  • Can be used alone or in combination with other chemotherapies for breast cancer.

  • Licensed for metastatic gastric cancer as well, in combination with other drugs.

  • Possible side effects include:

    • Cardiac dysfunction.

    • Anemia.

    • Neutropenia.

The Philadelphia Chromosome

  • An abnormality identified in chromosome 22:

    • Genetic information is exchanged between chromosome 22 and chromosome 9.

    • The fusion of BCR and Abl genes leads to the formation of the BCR-Abl gene, resulting in the production of a continuously active tyrosine kinase.

  • This causes uncontrolled cell proliferation.

  • Commonly associated with chronic myeloid leukemia (CML). Patients are classified as ‘Philadelphia positive.’

Tyrosine Kinase Inhibitor: Imatinib (Glivec)

  • A potent inhibitor of the BCR-Abl tyrosine kinase.

  • Mechanism: Prevents phosphorylation by binding to the ATP binding site.

  • Results in slowed growth of cancer cells and promotes apoptosis.

  • Administered orally, but it does have side effects:

    • Common: Headaches, loss of appetite.

    • Gastrointestinal disturbances (diarrhea, constipation).

    • Joint pain and skin reactions.

Diagnosing Cancer

  • Cancer diagnosis is dependent on the type of cancer.

  • Involves a combination of techniques:

    • Signs and Symptoms.

    • Imaging techniques.

    • Usage of tumor markers.

Tumor Markers

  • Some tumors secrete substances into the bloodstream or surrounding areas, which can assist in:

    • Diagnosis.

    • Monitoring and detection of recurrence.

  • However, they can be crude and non-specific for a single type of cancer.

Examples of Tumor Markers

  • PSA: Prostate cancer.

  • CEA: Colon cancer.

  • CA 125: Ovarian cancer.

  • Human chorionic gonadotropin (hCG): Germ cell tumors.

CEA (Carcinoembryonic Antigen)

  • Elevated in several conditions, not solely cancer:

    • Example: Smokers, patients with Crohn's disease.

  • Normal levels are usually less than 2.5 ng/ml.

Revision Overview

  • Key topics covered:

    • Definition of cancer.

    • Prevention strategies.

    • Range of cancer treatments, their mechanisms, and side effects.

    • Production and administration of traditional chemotherapy agents.

    • Role of tumor markers and methods of cancer screening.

Example Questions

  1. Which statement regarding tumor markers is MOST accurate?

    • A. Tumor markers are diagnostic when used alone.

    • B. Elevated tumor markers always indicate cancer.

    • C. Tumor markers are useful for screening the general population.

    • D. Tumor markers are mainly used to monitor disease progression and response to therapy.

    • E. Tumor markers are specific to only one type of cancer.

  2. Regarding the mechanisms of action discussing vinca alkaloids, which statement is correct?

    • A. Inhibition of DNA topoisomerase II.

    • B. Prevention of microtubule polymerization.

    • C. Stabilization of microtubules and prevention of depolymerization.

    • D. Alkylation of DNA bases.

    • E. Inhibition of thymidylate synthase.

Summary of Learning Outcomes

By the end of this session, you will have:

  • An understanding of cancer pathophysiology.

  • Insight into risk factors and preventive measures.

  • Knowledge of treatment methodologies and implications.

  • Familiarity with tumor markers and screening processes for cancer detection.

  • Awareness of the pharmacist's role in cancer care in the UK.