Cancer Drug Therapy

Question 1

How can cancer cells be selectively targeted using the differences between normal and cancerous cells

Answer 1

cancer cells have a higher demand for energy and anabolic substrates
cancer cells have a less well-regulated cell cycle and need to replicate DNA more frequently

Question 2

What are the 10 hall marks of cancer

Answer 2

1. resisting cell death
2. inducing angiogenesis
3. Enabling replicative immortality
4. Sustaining proliferative signalling
5. Evading growth suppressors
6. Activating invasion and metastasis
7. Deregulating cellular energetics
8. Avoiding immune destruction
9. Genome instability and mutation
10. Tumour-promoting inflammation

Question 3

What is cancer chemotherapy

Answer 3

kill cancerous cells then administration of agents that are cytotoxic may affect normal cells and lead to unwanted side effects

Question 4

Describe the cell cycle

Answer 4

G1 – metabolic changes to prepare cell for division. The restriction point of G1 is
where the cell is committed to division and moves into the S phase.
• S – DNA synthesis wherein each chromosome consists of 2 sister chromatids
• G2 – metabolic changes and assembly of cytoplasmic materials required for mitosis
and cytokinesis
• M – nuclear division (mitosis) followed by cell division (cytokinesis)

Question 5

what is growth faction

Answer 5

percentage of cells engaged in proliferative versus resting phases
if low - fraction of cell killed by chemotherapy will be small
if high- cells will be more responsive to chemotherapy as there are more proliferative cells

Question 6

What are the five main types of anti-cancer drugs

Answer 6

alkylating and intercalating drugs
antibiotics 
antimetabolites 
microtubule inhibitors 
hormones

Question 7

Action of Alkylating agents

Answer 7

• To detects damage and initiates programmed cell death after incurred damage in DNA and chemical modification that prevents cell division
  
  • Alkylating agents covalently bind to DNA in order to alkylate it

Question 8

Example of alkylating agents

Answer 8

cyclophosphamide,

B) mechlorethamine,
C) methchlorethamine derivative estramustine phosphate,
D) malphalan.

Question 9

what are special about the structure of the alkylating agents

Answer 9

there is one teritary agents that Participate in nucleophilic substitution reactions with DNA alkylating agents
there are two chloroethane groups that allow compounds to react at two separate sites in order to alkylate and crosslink nucleotides

Question 10

What side effects do alkylating agents have

Answer 10

• Alopecia
  
  • Nausea
  • Diarrhoea
  • Body Pain
  • Immunosuppression
  • Bone marrow depression

Question 11

What are anti-tumour antibiotics and give two examples

Answer 11

they cause cytotoxicty by disrupting DNA function

1Dactinomycin and doxorubicin

Question 12

Action of Dactinomycin

Answer 12

• Intercalates into the minor groove between G-C base pairs
  § Forming stable dactinomycin-DNA complex

This complex interferes with RNa polymerase and hinders DNA synthesis and cause single strand breaks due to free-radical generation or topoisomerase II activity

Question 13

Action of Doxorubicin in three ways

Answer 13

1. Intercalation of DNA
   § Drug inserts non-specifically between adjacent base pairs and bind to sugar-phosphate backbone of DNA
   § Causing local uncoiling and thus block DNA and RNA synthesis
   2. Altering the function of cellular transport processes by binding to cell membranes.
   3. Generation of oxygen radicals when doxorubicin is reduced to semiquinone free radicals by Cytochrome P450 reductase
   • which reduce O2 into superoxide ions and H202 which mediate single strand scission of DNA

Question 14

What are antimetabolites

Answer 14

• Drugs which are structurally related to normal cellular components and interfere with normal metabolic processes
  
  • Inhibit synthesis of normal purine or pyrimidine nucleotide precursors
  • More specifically affect proliferating cells

examples are methotrexate, 5- fluorouracil and mercaptopurine

Question 15

What is methotrexate and its mode of action

Answer 15

it is structurally related to folic acid and inhibits dihydrofolate reductase enzyme which results in a
deficiency of the folate coenzymes, decreasing DNA, RNA and protein
biosynthesis to induce apoptosis.

Question 16

What is 5-fluorouracil and its mode of action

Answer 16

• Drug enters the cell through carrier-mediated transport system and converted into 5-flurodoxyuridine monophosphate (5-FdUMP)
  - Competes with deoxyuridine monophosphate for thymidylate synthase
  - by acting as a pseudosubstrate and forms a ternary complex with it and its coenzyme N5, N10-methylene tetrahydrofolic acid that cannot proceed to release products
  - DNA synthesis decreases due to lack of thymidine
  • Imbalanced cell growth and cell death

Question 17

What is mercaptopurine and its mode of action

Answer 17

• Converted into nucleotide 6-mercaptopurine ribose phosphate
  • 6-thioinosinic acid (thio-IMP) it is dehydrogenated into thio-GMP and tri-phosphorylated which can be incorporated into RNA and DNA to trigger cell death

Question 18

Name a microtubule inhibitor and its action

Answer 18

Vinca
alkaloids (Vincristine and Vinblastine) bind to tubulin in order to prevent polymerisation to
microtubules and arrest cells in metaphase. Vinca alkaloid binding forms paracrystalline
aggregates consisting of tubulin dimers and alkaloid drug leading to dysfunctional spindle
apparatus.

Question 19

What can be the tumours be to hormones

Answer 19

• Hormones sensitive in which tumour regresses following treatment
  
  • Hormone dependent in which removal of hormonal stimulus causes tumour regression
  • Treatment is palliative (relieve pain without treatment the disease)
    
    • except in the case of glucocorticoids which have cytotoxic effects on lymphomas at high enough doses
    • Removal of hormonal stimuli from hormone -dependent tumours can be accomplished by surgery or by drugs

Question 20

Action of prednisone

Answer 20

• Its ia prodrug reduced by 1-b-hydroxysterioid dehydrogenase to its active form, prednisolone

    - Bind to intracellular receptor that then dimerise
    - Migrate to the nucleus and interact with DNA to modify gene transcription 
        § By Inducing synthesis of some proteins and inhibiting synthesis of others

Question 21

Action of estrogen

Answer 21

• Inhibit the growth of prostatic tissue by blocking the production of luteinizing hormone
  Decreasing the synthesis of androgens in the testis

Question 22

Action of Tamoxifen

Answer 22

Tamoxifen binds to the oestrogen receptor and is not transcriptionally productive which
means oestrogen-responsive genes are not induced and RNA synthesis does not occur.
Oestrogen receptors and their growth-promoting effects are therefore downregulated

Question 23

What affects bioavailability of anticancer drugs

Answer 23

• Pharmaceutical limitations – disintegration, dissolution, physicochemical factors
• Physiological limitations – absorption, transporter proteins and metabolism
Patient specific factors – malabsorption, liver impairment, elderly patients and genetic polymorphism

Question 24

What mechanisms can cancer cells develop resistance

Answer 24

1. Decrease accumulation of cytotoxic drugs in cells due
   - to increase expression of cell surface, energy-dependent drug transport proteins (e.g. doxorubicin, vinblastine and dactinomycin).
   - Increase efflux through pumps such as p-glycoprotein
   
   2. A decrease in the amount of drug taken up by the cell (e.g. methotrexate).
   3. Insufficient activation of the drug (e.g. mercaptopurine and 5-fluorouracil).
      
      • Some drugs require metabolic activation to produce antitumour activity.
      • If not, they may be unable to block the metabolic pathways required to exert their effects.
   4. Increased concentration of target enzyme (methotrexate).
   5. Increased utilisation of alternative metabolic pathways (antimetabolites)
   6. Rapid repair of drug-induced lesions (alkylating agents).
   7. Altered activity of target, for example modified topoisomerase II (doxorubicin).
   8. Mutations in various genes, giving rise to resistant target molecules.
      
      • For example, the p53 gene and overexpression of the Bcl-2 gene family (several cytotoxic drugs).
   9. Gene amplification causing overproduction of a protein that can render the anti-cancer drug ineffective
   10. Cancer cells may pump the drug out of the cell as fast as it is going in using a drug efflux pumps such as p-glycoprotein.