Anti Cancer Flashcards
3 types of anti cancer drugs
- Vincristine
- Childhood leukemia
- Accidental discovery - Taxol
- Ovarian cancer
- Random Screening - Gleevec
- Leukemia
- Rational design
Success for anticancer drugs
- From plants
2. From microorganisms
What type of drug intercalates DNA?
- Doxorubicin
- used in treatments of wide range cancers
- SERIOUS EFFECT; life threatening heart damage
Natural Product chemists
- perform random screening of extracts (from plants and microorganisms)
Vincristine and Vinblastine
- 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%)
Taxol
- 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
Things that were needed in order to use taxol efficiently
- supply (Bristol took name of Taxol)
2. bioavalibility via formulation and route of admin
How was supply problem solved?
- Found another natural (less destructive) source = needles of various yew trees or related species
Taxus canadiensus
- 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
How to do a semi synthesis of Taxol via
- need beta lactam to correct relative and absolute stereochemistry
Taxol formulation
- highly effective but not drug like according to lipinski’s rules
- poor bioavilibility which is why it has to be administrated through IV
Taxol analog
- 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)
Gleevec
- 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)
What is cancer similar to?
like HIV - not a fatal disease but a chronic condition that could be manageable
What chromosomes are defective in patients with CML?
9 and #22
Philadelphia translocation
- specific chromosomal abnormality between 9 and 22
BRC - ABL gene
- 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
Tyrosine kinase
- phosporylation of the amino acid tyrosine necessary for normal cell growth
Turn off activity of BRC-ABL?
- 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
What happens when people stop taking Gleevec?
relapse but patients can take it for a long time because it doesn’t have the same side effects as normal anticancer drugs
Resistance to Gleevec
- enzyme mutates when bound to the drug and stops responding to it
- carries phosphorylation as usual
Orphan disease drug
rationally designed drug that is based on the study of genetic origins of the disease –> rather than poisoning all cells
What are the drugs that are more potent than gleevec?
Sprycel and Tagisgna (do it differently)
