11_Cell Cycle I Flashcards
cell cycle specific agents/ “anti-metabolites”:
advantages/ and disadvantages
- 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
why is it helpful to have a cell cycle?
so there are many different places/stopping points for drugs to act on;
cell cycle specific and nonspecific
list the antimetabolites used (cancer chemotherapy cell cycle-specific agents)
- 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
what do we need to know to understand antimetabolite cancer chemo?
- understand nucleic acid biochemistry
- recognize that small change in structure can result in large change in activity/function
antimetabolites:
various mechanisms of action
- 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
what are the 2 key mechanisms of action for ANTI-MITOTICS?
- DISRUPTION of microtubule structure
- SPINDLE POISONS
ANTI-MITOTICS:
drugs examples
- vincristine
- vinblastine
- paclitaxel
- docetaxel
Overview of Biosynthetic pathways
which enzymes are involved in the nucleotide synthesis pathways?
- 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
mechanisms of enzyme action
- COVALENT binding to enzyme –> INHIBITION OF CATALYSIS
- High affinity of non-covalent interactions –> DECREASING ENZYME ACTIVITY
- Substrate utilization –> PRODUCES ALTERED/DEFECTIVE PRODUCT
what’s the difference between URACIL and 5-Fluorouracil?
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
how is 5-Fluorouracil metabolized?
metabolized by the various SALVAGE PATHWAYS
5-Fluorouracil:
- major site of action,*
- mechanism of action as cancer chemo drug,*
- metabolism*
- 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
how are the mechanisms of 5-Fluorouracil and 5-Fluoro-2’-deoxyuridine 5’-monophosphate SIMILAR?
Both bind COVALENTLY in a ternary complex with thymidylate synthase and its cofactor, N5,10- methyltetrafolate
if 5-FU acts on thymidylate synthetase, what effect does this have on the cell?
- inhibits thymidylate synthease enzyme
- blocks synthesis of the pyrimidine thymidine, (which is a nucleoside required for DNA replication)
- blocking DNA replication
- killing the cell
where in the pathway was 5-FU act?
acts as THYMIDYLATE SYNTHASE inhibitor
preventing conversion of dUMP to dTMP
(deoxyuridine monophosphate –> thymidine monophosphate)
5-FU:
indications for therapy
- 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)
what are the 2 key types of adjuvant combination chemo for breast CA?
- CAF: cyclophosphamide, doxorubicin and 5-fluorouracil
- CMF: cyclophosphamide, methotrexate and 5-fluorouracil
BOTH use cyclophosphamide, and 5-FU
5-FU:
admin, and adverse effects
- 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
levamisole:
use, mechanism
- 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
levamisole:
toxicity
- possible flu like sxs and neutropenia (abnormally low number of neutrophils) in the blood)
- but generally safe
capecitabine:
use, bioavail, metabolism
- 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
capecitabine:
indications
- 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)
capecitabine:
toxicity
- 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
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
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
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?)
methotrexate:
use, mechanism
- use: folic acid ANTAGONIST –> inhibiting 1 carbon transfer rxns
- mech:
- binds to active site of dihydrofolate reductase enzyme
- (non-covalent) affinity constant is high enough to maintain binding
- inhibiting 1 carbon transfer rxns
- inhibits DNA synthesis, purine synthesis, synthesis of serine and methionine
how do agents act on thymidylate synthase?
we can find agents that block use of thymidylate synthase by:
- (indirectly) depriving cell of tetrahydrofolate using methotrexate
- directly inhibiting thymidylate synthase (5-FU)
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
methotrexate:
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)
leucovorin:
purpose
leucovorin rescue: chemoprotectant; rescue cells from delayed toxicity of methotrexate
leucovorin rescue:
use, description, process
- used in some cases
- des: pulse-chase protocol
- process:
- administer methotrexate
- give for defined period
- discontinue treatment
- admin leucovorin
cytarabine:
difference between cytosine deoxyriboside and cytosine arabinoside
- cytosine deoxyriboside: has methyl group
- cytarabine: (cytosine arabinoside) has hydroxy group
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;
cytarabine (cytosine arabinoside, araC):
mechanism of action
- **S phase specific
- **A nucleoside is metabolized to the corresponding dNTP
- acts as competitive inhibitor of dCTP
- incorporated into DNA during replication
- inhibits chain elongation; induces defective ligation –> apoptosis
cytarabine (cytosine arabinoside, araC):
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
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
