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Y1 - Pharm > 11_Cell Cycle I > Flashcards

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
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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

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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
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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
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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
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6
Q

what are the 2 key mechanisms of action for ANTI-MITOTICS?

A
  • DISRUPTION of microtubule structure
  • SPINDLE POISONS
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7
Q

ANTI-MITOTICS:

drugs examples

A
  • vincristine
  • vinblastine
  • paclitaxel
  • docetaxel
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8
Q

Overview of Biosynthetic pathways

A
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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
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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
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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

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12
Q

how is 5-Fluorouracil metabolized?

A

metabolized by the various SALVAGE PATHWAYS

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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:
    1. Binds COVALENTLY in a ternary complex w/ thymidylate synthase as its cofactor (N5, 10-methyltetrafolate)
    2. COVALENT interaction is potentiated by LEUCOVORIN
  • metabol:
    • 5-FluoroUracil is metabolized to RIBONUCLEOTIDES; –> inhibits RNA synthesis
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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

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15
Q

if 5-FU acts on thymidylate synthetase, what effect does this have on the cell?

A
  1. inhibits thymidylate synthease enzyme
  2. blocks synthesis of the pyrimidine thymidine, (which is a nucleoside required for DNA replication)
  3. blocking DNA replication
  4. killing the cell
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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
Q

which anti-cancer drug is associated w/ hand-foot syndrome?

A

CAPECITABINE;

**hand-foot syndrome: numbness, tingling, pain, redness, or blistering of the palms of the hands and soles of the feet

26
Q

methotrexate:

compared to which biological structure?

similarities and differences?

A
  • 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
Q

where does methotrexate act in the cell cycle?

A
  • inhibits formation of tetrahydrofolate –> can’t methylate dUMP
    • Prevents de novo synthesis of purines
    • prevents DNA replication
    • cell dies
  • (so toxicity is lower?)
28
Q

methotrexate:

use, mechanism

A
  • 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. inhibits DNA synthesis, purine synthesis, synthesis of serine and methionine
29
Q

how do agents act on thymidylate synthase?

A

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
Q

methotrexate:

administration, and indications

A
  • 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
Q

methotrexate:

adverse effects

A
  • 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
Q

leucovorin:

purpose

A

leucovorin rescue: chemoprotectant; rescue cells from delayed toxicity of methotrexate

33
Q

leucovorin rescue:

use, description, process

A
  • used in some cases
  • des: pulse-chase protocol
  • process:
    1. administer methotrexate
    2. give for defined period
    3. discontinue treatment
    4. admin leucovorin
34
Q

cytarabine:

difference between cytosine deoxyriboside and cytosine arabinoside

A
  • cytosine deoxyriboside: has methyl group
  • cytarabine: (cytosine arabinoside) has hydroxy group
35
Q

where does the cytarabine act in the salvage pathway metabolism?

A
  • prevents formation of nucleotide (from nucleoside);
  • PREVENTS REPLICATION by blocking conversion of CMP to dCMP
  • acts in conversion between ATP and ADP;
36
Q

cytarabine (cytosine arabinoside, araC):

mechanism of action

A
  • **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
Q

cytarabine (cytosine arabinoside, araC):

admin and indications

A
  • 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
Q

cytarabine (cytosine arabinoside, araC):

adverse effects

A
  • no acute toxicity (as it’s an anti-metabolite)
  • delayed toxicity:
    • nausea
    • severe myelosuppression
    • varying degrees of stomatitis and allopecia

Y1 - Pharm (12 decks)

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