Anti Cancer

Question 1

3 types of anti cancer drugs

Answer 1

1. Vincristine
   - Childhood leukemia
   - Accidental discovery
2. Taxol
   - Ovarian cancer
   - Random Screening
3. Gleevec
   - Leukemia
   - Rational design

Question 2

Success for anticancer drugs

Answer 2

1. From plants

2. From microorganisms

Question 3

What type of drug intercalates DNA?

Answer 3

• Doxorubicin
• used in treatments of wide range cancers
• SERIOUS EFFECT; life threatening heart damage

Question 4

Natural Product chemists

Answer 4

• perform random screening of extracts (from plants and microorganisms)

Question 5

Vincristine and Vinblastine

Answer 5

• folk remedy
• lifespan of mice with leukemia were prolonged by use of vinca prep
• This along with periwinckle treated children with leukemia (increased the 5 year survival rates from less than 20 to more than 50%)

Question 6

Taxol

Answer 6

• Isolated from yew tree in pacific
• cyto - toxic
• big amount of bark gives only 10g of crude compound
• violates 2 lipinski’s rules (molecular mass and H-bond donors)
• However, it has good IN VITRO activity

Question 7

Things that were needed in order to use taxol efficiently

Answer 7

1. supply (Bristol took name of Taxol)

2. bioavalibility via formulation and route of admin

Question 8

How was supply problem solved?

Answer 8

• Found another natural (less destructive) source = needles of various yew trees or related species

Question 9

Taxus canadiensus

Answer 9

• contains small amts of taxol and much larger amts of beccetin III
• convert beccetin III into taxol (very hard to do in real life compared to paper)
• This is also an opportunity to create more effective analogs such as Taxotere

Question 10

How to do a semi synthesis of Taxol via

Answer 10

• need beta lactam to correct relative and absolute stereochemistry

Question 11

Taxol formulation

Answer 11

• highly effective but not drug like according to lipinski’s rules
• poor bioavilibility which is why it has to be administrated through IV

Question 12

Taxol analog

Answer 12

• Taxomere is much easier to formulate and has better results than taxol
• can be administrated orally
• Highly bioavailable through administration AND IV
• No such side effects as Taxol (still some - similar to most cancer drugs)

Question 13

Gleevec

Answer 13

• Orphan disease drug
• Instead of poisoning every cell in an attempt to kill the cancer cell, this stops the division of cancer cells
• ABL gene
• CML (chronic myelogenous leukemia)

Question 14

What is cancer similar to?

Answer 14

like HIV - not a fatal disease but a chronic condition that could be manageable

Question 15

What chromosomes are defective in patients with CML?

Answer 15

9 and #22

Question 16

Philadelphia translocation

Answer 16

• specific chromosomal abnormality between 9 and 22

Question 17

BRC - ABL gene

Answer 17

• ABL coded to carry out tyrosine kinase
• BRC-ABL acts continually and is no longer regulates
• RESULT - stimulates cell growth and turns normal cells into cancer cells

Question 18

Tyrosine kinase

Answer 18

• phosporylation of the amino acid tyrosine necessary for normal cell growth

Question 19

Turn off activity of BRC-ABL?

Answer 19

• This affects the cells that depend on the activity of the BRC/ABL gene for duplication
• when people use gleevec, there is an absense of BCR-ABL in their blood

Question 20

What happens when people stop taking Gleevec?

Answer 20

relapse but patients can take it for a long time because it doesn’t have the same side effects as normal anticancer drugs

Question 21

Resistance to Gleevec

Answer 21

• enzyme mutates when bound to the drug and stops responding to it
• carries phosphorylation as usual

Question 22

Orphan disease drug

Answer 22

rationally designed drug that is based on the study of genetic origins of the disease –> rather than poisoning all cells

Question 23

What are the drugs that are more potent than gleevec?

Answer 23

Sprycel and Tagisgna (do it differently)