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Bloc F - Defense > Mar23 M3-Principles of Management of Cancer of Blood > Flashcards

Mar23 M3-Principles of Management of Cancer of Blood Flashcards

1
Q

goal of cancer therapy + one example of targetted process

A
  • take advantage of what’s different in cancer cells

- cells proliferating is one thing different

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2
Q

solid tumor vs blood (liquid) tumors preferred modalities of treatment

A 
solid = surgery and radiation
liquid = chemotherapy and host immunodefense (stimulate the immune system)
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3
Q

4 chemotherapeutic drug types

A
  • DNA alkylating
  • anti-metabolites
  • anti-microtubules (natural products)
  • topoisomerase inhibitors (natural products)
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4
Q

examples of specific targets of chemotherapy

A
  • steroid hormone Rs (with prednisone, a glucocorticoid)
  • enzymes involved in signaling (tyrosine kinase inhibitors (imatinib))
  • cell surface molecules (target with Abs like rituximab (anti-CD20), brentuximab (anti-CD30), pembrolizumab (anti-PD1)
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5
Q

4 phases of the cell cycle in order + main checkpoints

A

G1, (checkpoint), S, G2, (checkpoint), M, (checkpoint), G0 or G1 again

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6
Q

S-phase specific chemotherapy drugs and some examples

A
  • anti-metabolites*
    1. S phase specific and SELF LIMITING
  • methotrexate
  • 5-fluorouracil
    2. S phase specific
  • cytosine arabinoside, also called cytarabine, (a nucleotide analog. blocking transformation of oxynts to deoxynts
  • hydroxyurea
  • topoisomerase inhibitors* (block S-G2 phase)
  • daunorubicin
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7
Q

M-phase specific chemotherapy drugs and some examples

A

microtubules blocking

  • vincristine
  • vinblastine
  • taxols
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8
Q

non cell cycle specific chemo drugs and some examples

A

DNA alkylating and damaging drugs

  • cyclophosphamide
  • dicarbazine
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9
Q

cyclophosphamide active portion

A
  • looks like adenine, can bind guanine on position N7
  • active part is N with 2 CH2CH2Cl branches
  • 1 molecule of the drug binds with other molecule that is next to it on other DNA strand (cross
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10
Q

cyclophosphamide mechanism of action

A
  • 1 molecule of the drug binds with other molecule that is next to it on other DNA strand (cross-linking)
  • cross-linking is hard to repair. get mispairing mutations that have to be repaired.
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11
Q

dacarbazine mechanism of action (other alkylating agent)

A
  • methylates guanine at O-6 and N-7 positions
  • causes mispairing because it modifies guanine
  • DNA damage kills the cell
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12
Q

problem of alkylating agents as chemo drugs

A
  • toxicity to rapidly proliferating cells (BM, GIT, gonads)
  • resistance to them (increased inactivation by nucleophilic trapping agents, increased DNA repair, decreased activation)
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13
Q

normal thymidine (TMP) formation cycle in the cell

A
  1. dihydrofolate is made into tetrahydrofolate by dihydrofolate reductase
  2. methylation reaction by thymidylate synthase to synthesize TMP
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14
Q

methotrexate (anti-metabolite, acts on S phase) mechanism of action

A
  • inhibits dihydrofolate reductase (acts on normal folic acid biochem)
  • methotrexate polyglutamates inhibit thymidylate synthase
  • *no TMP made, building block of DNA, can’t make DNA**
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15
Q

ways cancer cells develop resistance to methotrexate

A
  • inhibit active transport
  • inhibit polyglutamate
  • change dihydrofolate reductase
  • amplify dihydrofolate reductase (more genes for it)
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16
Q

5-fluorouracil (anti-metabolite, S phase specific) mechanism of action

A
  • transfers fluorine on thymine to replace its methyl group*
  • inhibition of RNA processing
  • incorporation into DNA
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17
Q

cytarabine (also called cytosine arabinoside) (anti-metabolite, S phase specific) mechanism of action

A
  • modifies sugar (deoxyribose) on nts.

- competes with dCTP (cytosineTP) and induces strand breaks and triggers apoptosis

18
Q

vincristine and vinblastine (vinca alkaloids) mechanism of action

A
  • bind mtb monomers (tubulin)
  • terminate assembly of mtbs causing depolymerization and mitotic arrest
  • bad chromosome segregation: cell dies
19
Q

taxols mechanism of action

A

promote microtubule assembly and inhibit their disassembly (necessary for chromosome segregation)

20
Q

daunorubicin (doxorubicin) (topoisomerase inhibitor) mechanism of action

A
  • intercalates in DNA

- inhibits topoisomerase II causing DNA strand breaks (this enzyme normally repairs DNA)

21
Q

topoisomerase inhibitors (block cell cycle at S-G2) structure of the molecule + used in what conditions

A
  • tetracycline, flat ring structure

- in some leukemias (AML, ALL, CML)

22
Q

bleomycin what kind of drug + mechanism of action

A
  • DNA damaging drug*
  • binds DNA, Fe and forms radicals
  • consequence = single and double strand breaks + chromosomal aberrations
23
Q

prednisone mechanism of action (in the more specific drugs) + used more in what cancers

A
  • glucocorticoid receptor agonist
  • in response to this TF, many genes are expressed, and are involved in immune response
  • blood cancers, breast cancers (act on estrogen R activation), prostate cancer (act on androgen R activation)
24
Q

most discussed example of translocation in leukemia

A

chronic myelocytic leukemia. translocation of Abl on chrom 9 and Bcr on chrom 22. forming philadelphia chrom with both on it

25
Q

behavior of the bcr-abl fused protein

A
  • tyrosine kinase that is always active (bc abl had a kinase domain that can phosphorylate stuff)
  • constantly activating GRB-2, SHC, etc. and promoting proliferation
26
Q

drug used in CML (M for myelocytic or myelogenous or myeloid) and also in ALL (acute lymphoblastic leukemia)

A

imatinib (Ab to the kinase domain of the bcr-abl fusion protein). bcr-abl stops phosph. everything all the time
*cells don’t die but stop proliferating

27
Q

rituximab mechanism of action and used in what cancers

A
  • destroys both normal and malignant B cells (bc binds CD20)
    1. complement mediator cytotoxicity 2. engulfing by macrophages bc of Ab recognition 3. direct lysis by NK cells
  • used in CD20+ NHLs (non Hodgkin lymphomas)
28
Q

brentuximab vedotin mechanism of action

A
  • drug delivery Ab (NOT for targeting by macrophages)
  • a CD30 Ab conjugated to a potent anti-mtb agent by a linker that can be cleaved by proteases
    1. Ab binds CD30, complex engulfed by the cell, proteases cleave the complex, mtb drug cleaves mtbs
29
Q

brentuximab used in what conditions

A

Hodgkin lymphomas with CD30+ cells

30
Q

normal T cell-tumour cell interaction and how this leads to the tumor cell not being killed

A
  • receptor on T cell recognizes a surface molecule on tumor cell
  • PD-1 R on T cell interacts with PD-1 ligand (PD-L1) on tumor cells, which tells the T cell not to kill the tumor cell
31
Q

pembrolizumab mechanism of action

A
  • Ab that binds PD-1 on T cells
  • PD-1 and PD-L1 (on tumor cells) interaction can’t occur
  • tumor cell will get killed
32
Q

3 principles of classical cancer chemo

A
  1. cure means death of every malignant cell
  2. you can’t rely on host mechanisms to eliminate a moderate nbr of cancer cells
  3. cell-kill follows first order kinetics (a constant % of cells are killed)
33
Q

principles of chemo drugs administration (what kind of strategy is usually used)

A
  • high dose
  • intermittent (give drug, wait, give drug, wait)
  • drug combinations
34
Q

special strategy of chemotherapy used in some cancers like prostate cancer

A

take out patient cells, do chemo, put cells back (idea to help immune system recognize that cancer cells are foreign)

35
Q

consequence each time you give a chemo treatment

A

patient gets weaker and sicker (each treatment has its adverse effects)

36
Q

how chemo drugs are selected (5)

A
  • efficacy
  • toxicity
  • optimum scheduling
  • mechanism of interaction
  • avoidance of arbitrary dose changes
  • synergistic toxicity has to be only to tumor cells, not normal cells
37
Q

why combination chemotherapy is what is done usually

A
  • max cell killing with tolerable toxicity
  • broader range of drug-tumor interactions
  • prevents slow development of resistance
38
Q

chemo combination usually used in ALL

A
  • vincristine (blocks mtb assembly)
  • prednisone (glucocort R agonist)
  • doxorubicin or daunorubicin (also called adriamycin) (intercalating agent + topoisomerase II inhibitor)
39
Q

chemo in CML

A

imatinib (tyrosine kinase bcr-abl inhibitor)

40
Q

chemo combination in Hogkin lymphoma

A

ABVD

  • adriamycin (doxorubicin) (intercalating agent + topoisomerase II inhibitor)
  • bleomycin (DNA damaging)
  • vinblastine (blocks mtb assembly)
  • dacarbazine (alkylating agent, modifies guanine, causing mispairing and cell death)
41
Q

chemo used in non Hodgkin lymphoma

A

CHOP

  • cyclophosphamide (alkylating agent, 2 CH2CH2Cl cross-linking. cytotoxic)
  • doxorubicin (H)
  • vincristine (O)
  • prednisone (P)

Bloc F - Defense (57 decks)

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