Chemotherapy and Toxicity Case Study Quiz

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

What is the role of dihydropyrimidine dehydrogenase (DPD) in the context of 5-fluorouracil therapy?

DPD enhances the drug's efficacy by increasing its concentration

DPD facilitates the absorption of 5-fluorouracil in the gastrointestinal tract

DPD is essential for the biotransformation of fluoropyrimidines (correct)

DPD inactivates fluoropyrimidines to reduce side effects

Which of the following adverse effects was NOT mentioned in relation to the chemotherapy regimen used in the case study?

Diarrhea

Myelosuppression

Nausea (correct)

Altered mental state

What was the primary cause of cancer identified by Percival Pott in chimney sweepers?

Exposure to coal tar soot (correct)

Inadequate nutrition

Poor hygiene practices

Genetic predisposition

In the case study, what potential genetic factor could explain the severe toxicity experienced by the patient?

Genetic polymorphisms in dihydropyrimidine dehydrogenase Signup and view all the answers

What condition is specifically associated with 'Pott’s Fracture' as described by Percival Pott?

A fracture of the lower end of the fibula Signup and view all the answers

What is the role of anticancer drugs in terms of cell population reduction?

They kill a constant proportion of cells regardless of population size. Signup and view all the answers

Which chemotherapy approach is primarily used for localized cancers?

Neoadjuvant Chemotherapy Signup and view all the answers

What is an effect of drug combinations in cancer chemotherapy?

They can reduce the likelihood of drug resistance. Signup and view all the answers

Which of the following is NOT a mechanism of resistance to anticancer drugs?

Decreased production of metabolic enzymes Signup and view all the answers

Which phase of the cell cycle is primarily affected by antimetabolites?

S phase Signup and view all the answers

Which of the following therapeutic approaches is most common in cancer treatment?

Adjuvant Chemotherapy Signup and view all the answers

What is the approximate cure rate of chemotherapy alone for most cancers?

10-15% Signup and view all the answers

Which type of cancer is chemotherapy most effectively combined with as a primary induction?

Hodgkins lymphoma Signup and view all the answers

What is one mechanism of drug resistance relating to altered target enzymes?

Enzyme target becomes less sensitive to drug’s inhibition Signup and view all the answers

Which of the following describes a common property of alkylating agents?

Alkylate DNA bases causing cross-links Signup and view all the answers

What is a fundamental characteristic of Cyclophosphamide as an anticancer drug?

It is classified as a prodrug. Signup and view all the answers

What happens during the formation of trapping agents in relation to anticancer drugs?

They bind to and neutralize the drug. Signup and view all the answers

Which of the following factors contributes to decreased drug accumulation in resistant cancer cells?

Increased expression of multi-drug transporters Signup and view all the answers

Which modification might protect cells from the effects of purine antimetabolites?

Decreased activation of prodrugs due to enzyme activity changes Signup and view all the answers

Cyclophosphamide was discovered primarily for its application during which historical context?

World War II Signup and view all the answers

What is the primary mechanism of action of procarbazine in cancer treatment?

It generates hydrogen peroxide leading to DNA strand scission. Signup and view all the answers

Which of the following drugs is considered a direct-acting alkylating agent?

Cisplatin Signup and view all the answers

What is one of the major adverse drug reactions (ADRs) associated with cisplatin?

Nephrotoxicity Signup and view all the answers

Which of these antimetabolite drugs specifically antagonizes folic acid?

Methotrexate Signup and view all the answers

During cancer chemotherapy, which mechanism is not attributed to traditional alkylating agents?

Inhibition of RNA transcription Signup and view all the answers

In the ABVD-MOPP regimen, which drug is NOT included?

Methotrexate Signup and view all the answers

What is a common side effect of procarbazine when used in chemotherapy?

Peripheral neuritis Signup and view all the answers

Which of the following cancer types is NOT typically treated with alkylating agents?

Prostate cancer Signup and view all the answers

What term describes the uncontrolled growth of cells that often invades healthy tissue?

Neoplasia Signup and view all the answers

What significant change was made in British law regarding chimney sweeps in 1840?

Hiring age raised to 16 years old Signup and view all the answers

Which of the following statements about Percival Pott is true?

He first described a carcinogen linked to chimney sweeping. Signup and view all the answers

What does the prefix 'onco-' refer to?

Swelling or mass Signup and view all the answers

In the context of workplace safety, what significance does Pott's work have?

It proved that jobs could lead to the onset of cancer. Signup and view all the answers

What common name is given to a condition related to chimney sweeps caused by soot exposure?

Soot wart Signup and view all the answers

Which occupation is NOT mentioned as having associated health disorders in the provided content?

Carpenters Signup and view all the answers

Which term is used to describe a gene that can induce a cell to become malignant?

Oncogene Signup and view all the answers

What is one of the major functions of laboratory testing for tumor markers?

Classification (staging) Signup and view all the answers

Which type of tumor marker is Prostate Specific Antigen (PSA)?

Enzyme Signup and view all the answers

When are elevated levels of Human Chorionic Gonadotropin (hCG) typically found?

In pregnancy and germ cell tumors Signup and view all the answers

Which of the following is an application of tumor markers in clinical practice?

Estimation of tumor volume Signup and view all the answers

What is the molecular weight of the beta subunit of hCG?

45,000 Signup and view all the answers

Alpha-fetoprotein (AFP) serves as a marker for which type of cancers?

Liver and germ cell carcinoma Signup and view all the answers

What does an increase in CEA levels indicate?

Possible recurrence of colorectal and other associated cancers Signup and view all the answers

What characterizes the genes related to the return of high levels of oncofetal proteins later in life?

They are suspected to be reactivated as a potential initial step in cancer formation Signup and view all the answers

Study Notes

Cancer Chemotherapy

Case Study: A 55-year-old man with colorectal cancer (CRC) and 5 positive lymph nodes had surgery. Treatment with 5-fluorouracil, leucovorin, and oxaliplatin resulted in severe toxicity including myelosuppression, diarrhea, and altered mental state.
Fluoropyrimidines: Require dihydropyrimidine dehydrogenase (DPD) for biotransformation. Genetic polymorphisms in DPD can alter biotransformation, possibly explaining the toxicity.
Percival Pott (1714-1788): A London physician who described and treated compound fractures of the lower fibula and medial malleolus of the tibia with foot dislocation (Pott's Fracture).
Chimney Sweepers: In 1700, coal was the primary heating source. Narrow chimney flues needed annual cleaning. Young boys were hired to clean the flues.
Pott (1775): Found cancer of the scrotum in boys (aged 10-14) who worked as chimney sweeps, but not in age-matched controls who lived outside of London. He established a link between the workplace and cancer (tar soot, benzo pyrene).
Terms:
- Cancer: Uncontrolled growth of cells, often with invasion into healthy tissues.
- Malignant: Disease tending towards death.
- Neoplasia: Formation of tissue.
- Neoplasm: New or abnormal formation of tissue.
- Tumor: Swelling.
- Onco-: Gr. Onkos, bulk or mass.
- Oncogene: A gene that can induce a cell to become malignant.

Theories of Cancer Causes

Environmental Exposure: Ionizing radiation.
Chemical Carcinogen: Azo dyes, aflatoxins, asbestos, tobacco.
Viruses: Human papillomavirus.

Treatment Modalities

Chemotherapy Alone: Cures only about 10–15% of cancers.
Increased Cure Rates Require: Surgery, radiation, and chemotherapy.

Treatment Modalities (Further details)

1. Primary Induction Chemotherapy: For widespread systemic diseases like Hodgkin's lymphoma.
2. Neoadjuvant Chemotherapy: For localized cancers such as breast, bladder cancer, etc.
3. Adjuvant Chemotherapy: Used along with surgery and radiation. This is a common treatment.

Anticancer Drugs

Action: Can act on cells during cell cycling or in the resting phase.
Kinetics: Follow first-order kinetics (kill a constant proportion of cells, instead of a constant number).
Dosing: Based on log kill function. A 3-log dose decreases cell population from 10¹² to 10⁹ cells.
Examples: cyclophosphamide, cisplatin, methotrexate, leucovorin, mercaptopurine, vinblastine, paclitaxel, bleomycin, imatinib, cetuximab, tamoxifen, fluorouracil, procarbazine.

Cell Cycles

G₀: Resting phase (many anticancer drugs).
G₁: Synthesis phase, components for DNA synthesis.
S: DNA synthesis.
G₂: Synthesis of components for mitosis.
M: Mitosis.

Cell Cycle Specific Drugs

Examples:
- Antimetabolites
- Podophyllotoxins
- Bleomycin
- Vinca alkaloids.

Non-Cell Cycle Specific Drugs:

Act in resting (G₀) and all other phases.

Drug Combinations

(a) Maximize cell kill.
(b) Increase coverage for heterogeneous tumor types.
(c) Slow or prevent drug resistance (same as antibiotic chemotherapy).

Mechanisms of Resistance

1. Increased DNA Repair: (cisplatin and most alkylating agents).
2. Formation of Trapping Agents: Increased glutathione synthesis (binds to anticancer drugs).
3. Change in Target Enzymes: Enzyme target becomes less sensitive to drug inhibition.
4. Decreased Activation of Prodrugs: Decreased activity of enzymes to convert prodrugs to active drugs.
5. Inactivation of Drugs: Increased activity of drug inactivating enzymes.
6. Decreased Drug Accumulation: Increased expression of multi-drug transporter (MDR).

Alkylating Agents

Target: DNA, intercalate with DNA and lead to cell death.
Examples: cyclophosphamide, nitrogen mustards (chlorambucil, mechlorethamine), nitrosoureas (carmustine, lomustine), alkyl sulfonates (busulfan), cisplatin, procarbazine.
- Resistance: Increased expression of DNA repair enzymes. Reduced drug transport into the cell. Increase glutathione levels.
Mechanism of Action: Direct-acting on DNA; Phase I CYP450 required for activation of some to a metabolite (e.g. cyclophosphamide).
Wide range of Clinical uses: breast, ovarian, neuroblastomas, bladder etc.

Cisplatin

Inorganic platinum analog.
Binding to DNA blocks replication.
Adverse drug reactions (ADRs): nausea, vomiting, peripheral neuropathy, nephrotoxicity, ototoxicity, etc.
Free radical generation: Procarbazine forms hydrogen peroxide which causes free radicals, resulting in DNA strand scission.

Procarbazine

Orally active with wide tissue distribution.
Alkylating agent with a different MOA.
Used primarily for Hodgkin's Disease
Major ADRs: Myelosuppressant, GI irritant, CNS dysfunction, peripheral neuropathy, skin reactions.

Antimetabolites

Drugs are cell cycle-specific inhibitors.
Resemble endogenous compounds, acting as antagonists to systems that use those compounds.
All are antagonists of either folic acid (methotrexate), purines (mercaptopurines, thioguanine), or pyrimidines (fluorouracil, cytarabine).

Methotrexate

Inhibits dihydrofolate reductase (an enzyme that activates folate).
Antimetabolite acting as a sulfa drug.
Blocks folate synthesis in cancer cells (and other cells).
Resistance: Reduced drug transport into the cell. Decreasing cytotoxic drug metabolites. Increasing expression of reductase enzyme. Decreasing enzyme affinity.

Leucovorin

Rescue drug given with high dose methotrexate to reduce toxicity (myelosuppression).

Mercaptopurine (6-MP)

Purine antimetabolite activated by hypoxanthine-guanine phosphoribosyltransferase (to toxic nucleotide).
Inhibits enzymes involved in purine metabolism.
A thiopurine analog that needs activation to a monophosphate form.

Fluorouracil (5-FU)

Converted into a metabolite that inhibits thymidylate synthase, causing cell death.

Plant Alkaloids

Cell-cycle selective drugs.
Vinca alkaloids (vinblastine) block mitotic spindle formation by preventing tubulin dimers in microtubules.
Taxanes (paclitaxel) block mitotic spindle through inhibition of microtubule disassembly into tubulin monomers.

Bleomycin

Cell cycle-selective (G₂ phase) drug.
Generates free radicals and causes DNA strand breaks.

Hormonal Agents

Certain cancers require steroid hormones for continued growth. Tumors produce receptors for steroids. Measuring estrogen and progesterone receptors is standard practice. Hormone therapy is not effective on ER/PR receptor-negative cancers.

Tamoxifen

Drug is an antagonist at estrogen receptors on tumors.

Enzyme Inhibitors and Antibodies

A wide range of drugs, targeting enzymes and metabolic pathways to shut down cancer cell growth.

Imatinib

Inhibitor of tyrosine kinase.
Prevents phosphorylation and activation of the Bcr-Abl oncogene.
Used in the treatment of chronic myelogenous leukemia.

Growth Factor Receptor Inhibitors

Many solid tumors overexpress epidermal growth factor receptors (EGFR).
Blocking these receptors prevents angiogenesis.
Examples include Cetuximab (a monoclonal antibody).

Cancer Chemotherapy: Drug Selection

Only active against cancer cells.
Different mechanisms of action for combined drugs.
Minimal cross-resistance.
Different toxic effects to avoid cumulative effects.

Cancer Chemotherapy: Drug Usage

Pulse therapy: High doses for short periods (to allow the body to recover).
Recruitment: Cell cycle-selective drugs cause increased levels of cell death and recruit resting cells into cell division (to target actively dividing cells).
Synchrony: Use drugs to stop cells in M or S phase.
Rescue Therapy: Reverse side effects of anticancer drugs using drugs like leucovorin (rescuing cells by providing target of the toxic agent given earlier).

The First Tumor Marker (1846)

Bence Jones proteins in urine precipitate (in acidic solutions).
Now recognized as light chains from immunoglobulins overproduction by plasma cells (multiple myeloma).

Tumor Markers

Substances present in or produced by tumors or the host in response to tumors.
Used to determine tumor presence in blood or secretions.
Tumors resemble fetal tissues morphologically.

Tumors

Graded based on differentiation: Well-, poorly differentiated, and anaplastic.
Tumor markers are re-expressions of substances produced by embryogenically related tissues.

Tumor Markers Classification

Enzymes: Catalytic activity vs. mass.
Hormones: Immunoassay.
Oncofetal Antigens: AFP, CEA, PSA.
Tumor Antigen Cell Surface Markers: CA 125, CA 15-3, CA 19-9.

Applications of Tumor Markers

Screening general population.
Differential diagnosis in symptomatic patients.
Clinical staging in cancer.
Estimating tumor volume.
Evaluating treatment outcomes.
Detecting recurrence.
Monitoring therapy response.
Guiding immunotherapy.

Prostate-Specific Antigen (PSA)

Protease enzyme found in prostate tissue.
Discovered in 1971.
MW 28,430 single chain glycoprotein.
Bound and free forms in serum.

Human Chorionic Gonadotropin (hCG)

Glycoprotein produced by the placenta.
Used for pregnancy detection.
Alpha and beta subunits.
Elevated levels can indicate germ cell tumors.

Oncofetal Proteins

Proteins produced in normal fetal tissues, elevated levels in later life suggest reactivated genes.
Alpha feto protein (AFP), carcinoembryonic antigen (CEA)
Levels are high at birth and decline. Elevated levels later in life can indicate cancer development.

Alpha-fetoprotein (AFP)

Liver and germ cell carcinoma marker.
Glycoprotein, single polypeptide chain.
High levels at birth, lower in adults.
Elevated levels can indicate incomplete tumor removal after surgery (liver tumor).

Carcinoembryonic Antigen (CEA)

Marker for colorectal, GI, lung and breast cancers.
Single glycoprotein polypeptide chain.
Elevated levels in many non-cancer conditions.
Primarily used to monitor therapy and recurrence.

Carbohydrate Markers

Either antigens on tumor cell surfaces or secreted by the tumor cell.
Tend to be more specific than hormones or enzymes.
Examples include CA 15-3, CA 549, CA 19-9, CA 19-5, CA 72-4, and CA 50.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

This quiz explores the roles of dihydropyrimidine dehydrogenase and the adverse effects related to 5-fluorouracil therapy. Additionally, it examines historical cancer causes identified by Percival Pott and the genetic factors that may influence chemotherapy toxicity. Test your knowledge on these critical oncology concepts!