11_Cell Cycle I Flashcards
1
Q
cell cycle specific agents/ “anti-metabolites”:
advantages/ and disadvantages
A
- advantages: more specific, and these are “picking the lock”
- most of them work really well!
- disadvantage:
- we don’t have a lot of them
- there is a preference for cancer cells, but may also target dividing cells
2
Q
why is it helpful to have a cell cycle?
A
so there are many different places/stopping points for drugs to act on;
cell cycle specific and nonspecific
3
Q
list the antimetabolites used (cancer chemotherapy cell cycle-specific agents)
A
- 5-Fluorouracil
- Methotrexate
- Cytarabine (Cytosine Arabinoside, araC) – these are 3 names for the same drug
- Purine antagonists (6-thioguanine, 6-mercaptopurine) – shows that a small change in structure –> large change in activity
4
Q
what do we need to know to understand antimetabolite cancer chemo?
A
- understand nucleic acid biochemistry
- recognize that small change in structure can result in large change in activity/function
5
Q
antimetabolites:
various mechanisms of action
A
- INHIBITION of deoxynucleoside triphosphate (dNTP) formation –> inhibits DNA replication
- 5-Fluorouracil and methotrexate
- SUBSTITUTION of dNTP during DNA polymerization –> inhibits DNA replication
- cytarabine
- INHIBITION of purine synthesis
- 6-thioguanine, 6-mercaptopurine, methotrexate
- Effect on RNA processing and function
- methotrexate, 5-Fluorouracil, cytarabine
6
Q
what are the 2 key mechanisms of action for ANTI-MITOTICS?
A
- DISRUPTION of microtubule structure
- SPINDLE POISONS
7
Q
ANTI-MITOTICS:
drugs examples
A
- vincristine
- vinblastine
- paclitaxel
- docetaxel
8
Q
Overview of Biosynthetic pathways
A
9
Q
which enzymes are involved in the nucleotide synthesis pathways?
A
- Nucleotide pyrophosphorylase –> convert base to ribonucleotide
- Nucleoside phosphorylase –> bases <–> nucleosides (interconversion)
- Nucleoside kinase –> convert nucleoSIDE to nucleoTIDE
- Nucleoside transglycosylases –> base exchanges into deoxynucleoSIDES
- Deminases –> inverconversions by base alterations
- Nucleoside monophosphate kinase –> reutilization of nucleotides
- Nucleoside diaphosphate kinase –> reutilization of nucleotides
10
Q
mechanisms of enzyme action
A
- COVALENT binding to enzyme –> INHIBITION OF CATALYSIS
- High affinity of non-covalent interactions –> DECREASING ENZYME ACTIVITY
- Substrate utilization –> PRODUCES ALTERED/DEFECTIVE PRODUCT
11
Q
what’s the difference between URACIL and 5-Fluorouracil?
A
5-FU has a Fluorine at C5 which makes it more electronegative (group is same size as methyl group), whereas uracil has an H group
12
Q
how is 5-Fluorouracil metabolized?
A
metabolized by the various SALVAGE PATHWAYS
13
Q
5-Fluorouracil:
- major site of action,*
- mechanism of action as cancer chemo drug,*
- metabolism*
A
- Major site: inhibition of thymidylate synthetase (synthase)
- mech:
- Binds COVALENTLY in a ternary complex w/ thymidylate synthase as its cofactor (N5, 10-methyltetrafolate)
- COVALENT interaction is potentiated by LEUCOVORIN
- metabol:
- 5-FluoroUracil is metabolized to RIBONUCLEOTIDES; –> inhibits RNA synthesis
14
Q
how are the mechanisms of 5-Fluorouracil and 5-Fluoro-2’-deoxyuridine 5’-monophosphate SIMILAR?
A
Both bind COVALENTLY in a ternary complex with thymidylate synthase and its cofactor, N5,10- methyltetrafolate
15
Q
if 5-FU acts on thymidylate synthetase, what effect does this have on the cell?
A
- inhibits thymidylate synthease enzyme
- blocks synthesis of the pyrimidine thymidine, (which is a nucleoside required for DNA replication)
- blocking DNA replication
- killing the cell
16
Q
where in the pathway was 5-FU act?
A
acts as THYMIDYLATE SYNTHASE inhibitor
preventing conversion of dUMP to dTMP
(deoxyuridine monophosphate –> thymidine monophosphate)
17
Q
5-FU:
indications for therapy
A
- primary chemotherapeutic agent: for colon cancer
- adjuvant combination chemo for breast cancer (CAF or CMF)
- solid tumors
- pancreatic CA
- esophageal CA
- liver CA
- head and neck CA
- *new use: to shrink GI stromal tumors –> so surgery may be indicated
- (used in preparative tx prior to surgery)
18
Q
what are the 2 key types of adjuvant combination chemo for breast CA?
A
- CAF: cyclophosphamide, doxorubicin and 5-fluorouracil
- CMF: cyclophosphamide, methotrexate and 5-fluorouracil
BOTH use cyclophosphamide, and 5-FU
19
Q
5-FU:
admin, and adverse effects
A
- admin:
- *intravenous (or injection);
- oral admin possible (but variable/not great bioavailability)
- adverse effects:
- NO ACUTE TOXICITY
- delayed toxicity:
- nausea
- oral and GI ulceration
- bone marrow depression
20
Q
levamisole:
use, mechanism
A
- use: supportive therapy ofr 5-fluorouracil –> to counter effects of bone marrow suppression
- mech:
- restores normal major immunostimulatory responses
- affects neutrophils, T cells, phagocytes
- NO EFFECT ON B CELLS
21
Q
levamisole:
toxicity
A
- possible flu like sxs and neutropenia (abnormally low number of neutrophils) in the blood)
- but generally safe
22
Q
capecitabine:
use, bioavail, metabolism
A
- use: a fluoropyrimidine carbamate prodrug
- bioavail:
- oral bioavail 70-80%
- metabolism:
- metabolized by liver –> into intermediates
- metabolized by tumor cells into 5-Fluorouracil (but didn’t work well)
- THEN metabolized by salvage pathways into active drug
23
Q
capecitabine:
indications
A
- single agent or combo w/ docetaxel for metastatic breast cancer
- adjuvant therapy for stage III colon cancer
- metastatic colon cancer as single agent
(Cells respond differently to 5-FLU than to Capecitabine)
24
Q
capecitabine:
toxicity
A
- diarrhea
- **hand-foot syndrome: numbness, tingling, pain, redness, or blistering of the palms of the hands and soles of the feet
- to a lesser degree:
- myelosuppression
- nausea
- vomiting
25
which anti-cancer drug is associated w/ hand-foot syndrome?
CAPECITABINE;
\***\*hand-foot syndrome:** numbness, tingling, pain, redness, or blistering of the palms of the hands and soles of the feet
26
**methotrexate:**
compared to which biological structure?
similarities and differences?
* similar in structure to Folic Acid --\>
* differences:
* size: methotrexate is a **larger** molecule
* electronegative charge: methotrexate is more **basic** whereas Folic Acid is an acid
27
where does **methotrexate** act in the cell cycle?
* **inhibits formation of tetrahydrofolate --\> can't methylate dUMP**
* Prevents de novo synthesis of purines
* prevents DNA replication
* cell dies
* (so toxicity is lower?)
28
**methotrexate:**
*use, mechanism*
* use: **folic acid ANTAGONIST --\> inhibiting 1 carbon transfer rxns**
* mech:
1. binds to active site of **dihydrofolate reductase** enzyme
2. (non-covalent) affinity constant is high enough to maintain binding
3. inhibiting 1 carbon transfer rxns
4. inhibit**s DNA synthesis, purine synthesis, synthesis of serine and methionine**
29
how do agents act on **thymidylate synthase?**
we can find agents that block use of thymidylate synthase by:
1. (indirectly) depriving cell of tetrahydrofolate using methotrexate
2. directly inhibiting thymidylate synthase (5-FU)
30
**methotrexate:**
*administration, and indications*
* admin:
* **IV or oral**
* *NOT metabolized to an active form*
* *serum levels proportional to dose*
* indications:
* breast CA
* head and neck CA
* choriocarcinoma (occurs in woman's uterus (womb))
* lung CA
31
**methotrexate**:
## Footnote
*adverse effects*
* acute:
* NO ACUTE TOXICITY (for anti-metabolites)
* delayed:
* oral and GI ulceration
* bone marrow depression
* leukopenia *(decrease in the number of leukocytes)*
* thrombocytopenia *(low blood platelet count)*
32
**leucovorin:**
purpose
**leucovorin rescue:** chemoprotectant; rescue cells from delayed toxicity of methotrexate
33
**leucovorin rescue:**
*use, description, process*
* used in some cases
* des: **pulse-chase protocol**
* process:
1. administer methotrexate
2. give for defined period
3. discontinue treatment
4. admin leucovorin
34
**cytarabine:**
difference between cytosine deoxyriboside and cytosine arabinoside
* **cytosine deoxyriboside**: has methyl group
* **cytarabine**: (cytosine arabinoside) has hydroxy group
35
where does the **cytarabine** act in the salvage pathway metabolism?
* **prevents formation of nucleotide** (from nucleoside);
* PREVENTS REPLICATION by blocking conversion of CMP to dCMP
* *acts in conversion between ATP and ADP;*
36
**cytarabine (**cytosine arabinoside, araC):
mechanism of action
* \*\***S phase specific**
* **\*\*A nucleoside** is metabolized to the corresponding dNTP
1. acts as **competitive inhibitor of dCTP**
2. **incorporated into DNA during replication**
3. **inhibits chain elongation; induces defective ligation --\> apoptosis**
37
**cytarabine** (cytosine arabinoside, araC):
## Footnote
*admin and indications*
* admin:
* highly scheduled --\> given by continuous infusion (*must be continuously present during replication to ensure competitive inhibitor is present during S phase)*
* can be admin. every 8-12 hrs for 5-7 days
* indications: \*\***only for combination chemo**
* comb. chemo of acute **myelocytic** leukemia
* comb chemo of acute **myelomonocytic** leukemia
38
**cytarabine** (cytosine arabinoside, araC):
adverse effects
* no acute toxicity (as it's an anti-metabolite)
* delayed toxicity:
* nausea
* severe **myelosuppression**
* varying degrees of stomatitis and allopecia
