Day 16, Lecture 2: Cancer III: Chemotherapy

Question 1

Incidence of Cancer

Answer 1

• 1.66 million new cases annually in the U.S.
  
  • 0.59 million deaths annually in the U.S. each year
  • 2nd leading cause of death

Question 2

Rank the what are the three highest types of cancers diagnosed each year (highest incidence)?

What are the 3 highest cancers that causes mortality each year?

Answer 2

• Incidence:
  
  1. Prostate/Breast
  2. Lung/Bronchus
  3. Colon and Rectum
• Mortality:
  
  1. Lung and Bronchus
  2. Prostate/Breast
  3. Colon and Rectum

Question 3

Why did the male incidence rate of cancer greatly increase in 1992

Answer 3

• Invention of PSA lead to greater number of diagnosis

Question 4

Question 5

Why might obesity lead to increase risk of cancer

Answer 5

Question 6

Etiology of Cancer

Answer 6

Question 7

What is Cancer?

Answer 7

Question 8

Question 9

Is cancer a genetic and epigenetic disease?

Answer 9

Yes

Question 10

Cancer Treatment

Answer 10

• Surgery
• Radiotherapy
• Chemotherapy
  
  • often an adjuvant therapy (with/after primary therapy)
  • Can be first line therapy
    
    • if surgery/radiotherapy not safe or effective
  • can be neoadjuvant therapy
    
    • before surgery/radiotherapy to reduce tumor burden
  • Can be mono or combination therapy
• Immunotherapy
• Gene therapy
• Virotherapy

Question 11

Question 12

Question 13

Log-Kill Hypothesis

Answer 13

• Drug kills a constant fraction of cells
• Multiple rounds of administration are required to eradicate all tumor cells
• Problem arises from dormant tumor cells and cancer stem cells
  
  • these cells are insensitive to therapy
• It is easier to kill dividing cells, which is why there are many cell cycle-specific drugs

Question 14

Chemotherapy Resistance

Answer 14

• Contributes to >50% of failure of chemotherapy
• Types of resistance:
  
  • Single agent
  • Multidrug resistance (MDR)
    
    • resistance often builds up to many drugs after treatment with only one drug
• Potential Mechanisms:
  
  • Increased influx of drug out of cell
  • decreased influx of drug into cell or nucleus
  • increased detoxification mechanisms
  • decreased activation of drug
  • amplified or altered drug target
  • increased ability to tolerate damage

Question 15

Combination Chemotherapy

Answer 15

• Multiple agents in specific sequence (or together) to overcome resistance and enhance antitumor effects
• Sometimes cycled ever 2-4 weeks
  
  • due to side-effects of drugs
  • the worst side-effects are gone by week 4
• Criteria for combination therapy
  
  • should act by different mechanisms of action
  • should have different mechanisms of resistance

Question 16

Systemic Toxicity of Chemotherapy

Answer 16

• Direct Toxicities
  
  • ​Bone Marrow
    
    • Myelosuppression
    • Neutropenia
    • thrombocytopenia
    • anemia
  • GI mucosa
    
    • mucositis
    • nausea
    • vomiting
    • diarrhea
  • Oral mucosa
  • Skin, including light sensitivity
  • Hair follicles
    
    • Alopecia
  • Gonads
• Other Toxicities
  
  • ​Heart
  • Liver
  • Lung
  • CNS
  • Kidney
  • Bladder
• Secondary Malignancies

Question 17

What are the types of responses to chemotherapy

Answer 17

• Complete response
• Partial response
• 5-year or 10-year disease-free is often regarded as curative
• Quality of life
  
  • pain versus small gain of lifetime

Question 18

Question 19

Most cancer drugs treat what stage of the cell cycle?

Answer 19

• G₁

Question 20

Antimetabolites

Answer 20

• Cancer drug
• Agents that block the biosynthesis of metabolites required for cell growth
• inhibits S-phase
• Examples:
  
  • Methotrexate
    
    • folic acid analog
    • inhibits dihydrofolate reductase
      
      • thus retards DNA/RNA and protein synthesis
  • Thiopurines
    
    • e.g.
      
      • Mercaptopurine or 6-Thioguanine
    • prodrugs requiring activation through purine salvage pathway
    • act by inducing mutations (pair with C and T) and inhibiting de novo purine synthesis
    • also effective as anti-inflammatory and immunosuppressive drugs
  • Flurouraci (5-FU)
    
    • blocks thymidylate synthase
      
      • ​thus inhibiting thymidine synthesis

Question 21

Methotrexate

Answer 21

• type of Antimetabolite
• inhibits S-phase
• folic acid analog
• mechanism:
  
  • inhibits dihydrofolate reductase
    
    • ​thus retards DNA/RNA and protein synthesis

Question 22

Thiopurines

Answer 22

• Type of Antimetabolite
  
  • ​Blocks S-phase
• e.g.
  
  • Mercaptopurine
    
    • used to treat:
      
      • acute leukemia
      • CML
  • 6-Thioguanine
• Mechanism:
  
  • Prodrugs requiring activation through purine salvage pathway
    
    • act by ​inducing mutations (pair with C and T) and inhibiting de novo purine synthesis
  • also effective as anti-inflammatory and immunosuppressive drugs

Question 23

Fluorouracil (5-FU)

Answer 23

• Type of Antimetabolites
  
  • ​Inhibit S-phase
• Mechanism:
  
  • Blocks Thymidylate Synthase
    
    • ​inhibits Thymidine synthesis

Question 24

Microtubule targeting (M-phase) drugs

Answer 24

• Vinca alkaloids
  
  • ​e.g. Vinblastine
    
    • These agents bind to tubulin and prevent mitotic spindle formation
• Taxoids
  
  • ​e.g. Paclitaxel/Taxol
  • These agents induce the polymerization/stabilization of microtubules

Question 25

Question 26

Vinca alkaloids

Answer 26

Question 27

Taxoids

Answer 27

Question 28

Epipodophyllotoxins

Answer 28

* **Topoisomerase II inhibitors (G₁/S-phase)** * E.g. * Etoposide * These agents lead to DNA double-strand breaks and cause errors in DNA replication (and eventually apoptosis)

Question 29

Cell cycle nonspecific drugs

Answer 29

* **Alkylating agents** * **​**cause irreversible changes in DNA * oftne leadin to cross-linking * Unwanted effects * mutagenic * teratogenic * carcinogenic * Example * Cyclophosphamide * **​****Antitumor antibiotics** * **​**intercalate into DNA and inhibit gene transcription * many isolated from Streptomyces * example * Doxorubicin (Adriamycin) * **Topoisomerase I inhibitors** * **​**Camptothecins * bind to DNA topoisomerase I * leads to single-strand breaks in the DNA and inhibits replication as well as transcription * examples: * Irinotecan * Topotecan * **Platinum compounds** * Induce crosslinks in DNA * thereby blocking DNA replication and transcription * Examples: * Cisplatin * Carboplatin

Question 30

Alkylating Agents

Answer 30

* **cell cylce-nonspecific drugs** * mechanism: * irreversible changes especially in DNA * often leading to cross-linking * Also changes in RNA and protein * unwanted effects: * mutagenic * teratogenic carcinogenic * Example: * Cyclophosphamide * Treats: * Lymphoma * leukemia * prostate * lung * breast * ovarian cancer

Question 31

Antitumor antibiotics

Answer 31

Question 32

Camptothecins

Answer 32

* **Cell cycle non-specific drugs** * **Topoismerase I inhibitors** * leads to single strand breaks in the DNA and inhibits replication as well as transcription * Examples: * Topotecan * Metastatic carcinoma of ovary * Irotecan * metastatic cancer of colon and rectum

Question 33

Platinum compounds

Answer 33

* **nonspecific cell-cylce drugs**

Question 34

Question 35

Tamoxifen

Answer 35

* Estrogen receptor antagonist * treats: * Postmenopausal breast cancer

Question 36

Enzalutamide

Answer 36

* Androgen receptor antagonist * Treats * Prostate Carcinoma

Question 37

Letrozole

Answer 37

* Aromatase inhibitor * Inhibit the conversion of testoterone to estrogen

Question 38

Fulvestrant

Answer 38

* Selective estrogen receptor downregulator * lead to the degradation and destruction of estrogen receptors * given to Tamoxifen (estrogen receptor antagonist) resistant patients

Question 39

Abiraterone

Answer 39

* inhibits CYP17A1, an enzyme involved in androgen sysnthesis * **blocks androgen synthesis** * used to treat castration-resistant prostate cancer patients

Question 40

Answer 40

Question 41

Tretinoin

Answer 41

* All-trans retinoic acid/ATRA * acid form of Vitamin A * Treatment for acute Promyelocytic Leukemia (APL), which harbors PML-RARalpha gene fusion t(15;17) * **induces differentiation of undifferentiated cancer cells**