Download Cancer II

CLASS: 11:00 – 12:00
DATE: December 9, 2010
PROFESSOR: Martin Johnson
I.
II.
III.
Cancer
Scribe: Ross Isbell
Proof: Bo Bradford
Page 1 of 5
CATEGORIES OF CHEMOTHERAPY DRUGS [S27]
a. Alkylating agents
i. Nitrogen mustard, modify DNA
ii. Nitrosoureas are actually part of the alkylating agent group.
iii. Unique because they are used to treat brain tumor
1. Can cross the blood brain barrier
iv. Latest introduction into nitrosoureas consolimide for brain tumor treatment
b. Anti-metabolites are the next oldest after alkylating agents.
i. Purine or pyrimidine derivatives.
ii. When cancer cells were first cultured, they noticed that they used a lot of purines and
pyrimidines and would suck them out of the medium
iii. Obviously, cancer cells have a high rate of division and they replicate their genome a lot and
they need these for building blocks for DNA.
c. Approach to develop most of the current anti-metabolites was to make every synthetic
derivative of purine and pyrimidine possible, put them in the petri dish, and see which one
kills cancer cells.
i. Oral cancer treatment drug found was 5-fluorauracil
1. Still the 3rd most widely used anticancer drug in the world
2. Introduced in the mid-50s and was synthesized by this bulldozer in a china shop
method
d. Antitumor antibiotics prevent replication.
i. Steroid hormones, in terms of breast cancer.
e. Vinca alkaloids
i. Used by Egyptians
ii. plant derived, from periwinkle or bark of the Ute tree.
iii. Some structures to show how complicated they are.
iv. Mechanism of action varies some
1. Interferes with the development of mitotic spindles in cell division.
2. Results in a mitotic freeze.
3. If you look at a spread of cell affected by this agent, you will see the cells are locked in
mitosis
CURRENT (2010) NCCN GUIDELINES [S28]
a. For treatment for different types of cancer between the eyes and the shoulder blades.
b. Cisplatin, 5-fluorauracil, paclitaxel.
i. These 3 listed are by far most commonly used
ii. Different drugs for treating lip and salivary cancer.
c. Guidelines mostly have to do with staging.
i. Treatment, first choice is surgery.
1. For when you are diagnosed in stage 1 or 2.
ii. Treatment, second choice is chemotherapy
1. Stage 3 or 4 and have evidence of nodal or metastatic involvement
2. If you have recurrent or advanced type cancer
ALKYLATING DRUGS [S29]
a. Alkylating agents.
i. Wide variety of malignancies.
ii. Solid tumors and hematological tumors.
iii. The dose limiting toxicity is neutropenia
CLASS: 11:00 – 12:00
DATE: December 9, 2010
PROFESSOR: Martin Johnson
IV.
V.
VI.
VII.
Cancer
Scribe: Ross Isbell
Proof: Bo Bradford
Page 2 of 5
1. Causes bone marrow suppression - white count drops dramatically.
2. Modify DNA.
iv. Mechanisms of Action
1. Alkylation and nucleophilic attack, guanine residues cause cross-linking.
a. You can reverse the effects of these by DNA repair enzymes.
v. Mechanism of Resistance
1. Channels that cause uptake into the cells
a. Both passive and ATP driven – uptake can be modulated
b. Pharmacokinetics can be modulated like we saw with DBP deficiency
c. Clearance of drug was affected because catabolic pathway was knocked out.
2. Modulate cytochrome P450 levels,
3. Upregulation of DNA repair enzymes is the primary mechanism of resistance for
alkylating agents
ALKYLATING DRUGS 2 [S30]
a. An example of some but not all alkylating agents.
b. Nitrogen mustards are derived from WWI compounds.
c. Nitrosoureas were used to treat brain tumor – not effective at all
i. BiCNU was called BC.
ii. Median survival of brain tumor remains 9 months, even now.
d. Temozolamide was recently introduced as an alkylating agent.
e. Other alkylating agents are the platinums
PLATINUMS [S31]
a. Here are the platinums.
b. Cisplatin, Carboplatin, and oxaliplatin.
c. Cisplatin and Carboplatin
i. Used for types of cancers we care about (oral and optical?).
ii. Chemical structures shown
d. This could be bisphenols, cancer-causing agents.
ALKYLATING DRUGS – MECHANISM OF DNA CROSS-LINKINGS [S32]
a. This is basically how they work.
b. Neutrophilic attack on the guanine residue  the bridge  cross-linking  interferes with
DNA replication.
c. The damage can be repaired by, for example, methylguanine methyltransferase (MGMT)
i. A known mechanism of these agents is upregulation of the MGMT gene in cancer cells.
1. Regulated by promoter regulation
2. Test whether a tumor will respond to some particular alkylating agents by looking at
that one gene.
3. If the tumor level is high going in, there is no point in giving them alkylating agent, that
tumor won’t respond.
d. In the case of brain cancer, alkylating agents and MGMT is upregulated 80% of the time. 80%
of the people don’t respond.
i. If your levels are lower, like in oral cancer, people really respond well.
e. Alkylating agents are given in combination with chemotherapy. Very effective.
i. Hitting DNA 2 different ways.
ii. DNA double-stranded breaks and chemical modification
ANTI-METABOLITES [S33]
a. Anti-metabolites, the next group
b. Purines analogues
CLASS: 11:00 – 12:00
DATE: December 9, 2010
PROFESSOR: Martin Johnson
VIII.
IX.
Cancer
Scribe: Ross Isbell
Proof: Bo Bradford
Page 3 of 5
i. Mercaptopurine was most widely used, not used too much any more
1. Was used for leukemia in pediatric patients
2. There was a pharmacogenomic defect in an enzyme called TPMT that caused
unanticipated toxicity – similar to DPD story.
3. If you have a molecular defect in TPMT you can’t clear the drug.
4. The mutations in TMPT don’t increase enzyme activity. They increase ubiquitination,
which targets the enzyme for protein degradation  less circulating levels of TMPT 
buildup of the drug.
5. Folic acid antagonist, methotrexate.
a. Still widely used.
6. Pyrimidine analogues
a. Fluorauracil, capsidobene, gemcitabine.
b. Gemcitabine is still the only one used in pancreatic cancer.
i. Probably one of the worst agents, if pancreatic cancer wasn’t so lethal it
wouldn’t have been approved, it only extends life by weeks.
ii. Side effects are horrible.
ANTI-METABOLITES 2 [S34]
a. 5-fluorauracil is still one of the most effective drugs at treating oral cancers
i. It is a derivative of uracil – cancer cells use more uracil.
ii. They put a fluorine moiety on every position and it turns out that the fluorine on the 5th
member of the pyrimidine ring is the most cytotoxic.
iii. Mechanisms of action
1. Inhibition of thymidylate synthetase (TS)
2. This compound is incorporated into DNA
a. Single and double stranded breaks and you can have it incorporated into RNA
and cause problems with translation.
iv. Mechanism of resistance
1. Upregulate the target, if the cell starts making more TS, the same thing that happens
when you can’t inhibit it all, it bleeds through.
2. Upregulate cell’s DPD. If you are deficient, you can’t clear the drug, but if you
upregulate it, you can clear the drug more rapidly
(FLUORO)PYRIMIDINE METABOLIC PATHWAY [S35]
a. Here is your parent compound phosphoric uracil
b. Goes through this metabolic pathway and makes fluoradeoxyuridine monophosphate,
i. The body doesn’t know it has a fluoride on it, normally the substrate is deoxyuridine
monophosphate
ii. When it binds to thymidylate synthase, a normal substrate, you get a methyl group from the
folate, convert uridine to thymine, and get deoxythymine monophosphate
iii. In the presence of fluoride, the enzyme can’t let go of substrate and it is a suicide inhibitor.
iv. Knock out TS levels, then you can’t convert it and you can’t make deoxythymidine
monophosphate (DTMP)
1. DTMP pools dry up and you can’t replicate the genome.
v. Also generates these two derivatives (FdUTP and FUTP) in some significant quantity
1. Cause some cytotoxicity.
2. Can actually get incorporation of the compound into DNA and RNA and prevent
replication, transcription, or translation.
vi. Mechanism of action
1. Upregulate the target and you don’t make enough of this(?) to inhibit all of that(?)
CLASS: 11:00 – 12:00
DATE: December 9, 2010
PROFESSOR: Martin Johnson
X.
XI.
XII.
XIII.
Cancer
Scribe: Ross Isbell
Proof: Bo Bradford
Page 4 of 5
2. Upregulate DPD and clear the drug more rapidly.
VINCA ALKALOIDS [S36]
a. Ever see the movie “Medicine Man” with Sean Connery?
i. Connery plays a doctor looks for magic drug that cures cancer.
ii. Johnson proceeds with long plot summary.
1. Sounds like an awesome flick for a rainy depressing Monday.
iii. The point is, you can’t synthesize some of drugs or the synthesis route is really tortuous.
b. What you see in vinca alkaloids is that most of them are plant derived.
i. Broad range of use.
1. Hematological cancer, leukemias, lymphoid, breast, pediatric type patients, bone
marrow suppression
2. Also have GI toxicity.
ii. Because of bone marrow suppression, you don’t normally combine vinca alkaloids with
cisplatinum for example, which also has bone marrow suppression.
c. Watch what you are combining to make sure they don’t have the same toxicity.
d. Mechanism of action
i. Inhibit microtubule polymerization and disrupt the mitotic spindle
1. Get M phase cell cycle arrest.
ii. Upregulation of P glycoprotein gene.
1. Causes this drug being pumped out of the cancer cell.
PLANT (VINCA) ALKALOIDS [S37]
a. Here are some common examples of vinca alkaloids.
b. Campotothecins are a little unusual.
i. Cause inhibition of Topoisomerase 1 or 2.
1. Topo 1 cuts 1 strand
2. Topo 2 cuts both strands
3. These are the mechanism for unwrapping DNA for transcription.
4. If you hit topo’s you can’t unwrap it.
ii. Nice target, effectively used.
iii. Taxans, paclitaxel , docetacel are the ones really used in oral cancer
TAXANES [S38]
a. Nice little picture of some taxans, pacliotaxel actually.
b. Primarily used in breast cancer, still widely used.
c. Work slightly different by stabilizing GDP bound tubulin and freezing microtubule synthesis.
d. Also, block mitosis.
e. Mechanism of resistance
i. Found some mutations in alpha tubulin that caused resistance to this.
ii. Important to demonstrate the versatility of cells to be able to mutate something to get
around a toxic agent like this.
iii. If you incubate a population of cells long enough with any toxic agent, you will get a resistant
population. That’s what occurs in the clinic.
WHY DOES CHEMO FAIL? [S39]
a. That kind of goes into why chemotherapy fails.
b. We talked about intrinsic and acquired resistance.
i. Intrinsic is because of Goldie-Coldman Principle.
ii. Acquired resistance – mass population, not clonal.
1. When you are actually treating cells, sensitive cells die off, resistant cells are the ones
that recur.
CLASS: 11:00 – 12:00
DATE: December 9, 2010
PROFESSOR: Martin Johnson
iii.
iv.
v.
vi.
vii.
viii.
XIV.
Cancer
Scribe: Ross Isbell
Proof: Bo Bradford
Page 5 of 5
Decrease of intracellular drug levels because they are pumped out by MDR.
Increased drug inactivation or decreased conversion,
5-fluourouracil increased drug inactivation would be upregulation of DPD  clears the drug
Increased synthesis of target like TS.
For alkylating agents especially, enhanced translation of repair drug enzymes.
Other factors associated are large tumor size of burden and localization of the tumor such as
in brain tumor, where you have issues like blood brain barrier.
[End 20:08 mins]