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Ther 201 LE 3 > Immunomodulators and Anti-Neoplastics > Flashcards

Immunomodulators and Anti-Neoplastics Flashcards

1
Q

T/F Cancer is the second leading cause of mortality in the Philippines.

A

F

1 Cardiac
2 Vascular diseases
3 Cancer

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2
Q

pRB (retinoblastoma protein) blocks ___

p53 detects ___

A

pRB blocks E2F

p53 detects DNA damage

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3
Q

pRB control occurs at which phase? How?

A

S (DNA synthesis) phase

pRB binds and inhibits transcription factors of the E2F family

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4
Q

What is “The Last Gatekeeper?” Function? It is involved in what percent of cancers?

A

P53 - detects DNA damage

50%

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5
Q

P53 - 2 possible responses to DNA damage

A
  1. Acts as a transcription factor (p21 expression activated -> CDK/G1 cyclin inhibited -> DNA repair)
  2. Triggers Apoptosis (if damage is irreparable)
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6
Q

“Executioner” proteins that break down the cell

A

Caspases

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7
Q

Receptor tyrosine kinases can activate ___

A

ras (“molecular switch”) - for cell proliferation

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8
Q

CCSA vs CCNSA - effectiveness

A

CCSA - for high growth fraction malignancies (e.g. hematologic cancers)

CCNSA - for both high and low growth fractions (e.g. solid tumors)

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9
Q

Classifications of classical cancer chemotherapeutic agents (3)

A
  1. Chemical structure and resource
  2. Cycle or phase specificity
  3. Biochem mechanisms
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10
Q

2 kinds of CCNS

A

Alkylating agents (nitrogen mustards, alkyl sulfonates, ethylenimines, nitrosoureas, platinum analogs)

Antibiotics

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11
Q

Main lethal effect of alkylating agents

What else can it target?

A

Alkylation of DNA at N7 position of guanine

N1, N3 adenine
N3 cytosine

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12
Q

Alkylating agents undergoes intramolecular cyclization, forming what?

Then targets a nucleophilic cell component directly or through formation of carbonium ions, which targets what?

A

Ethyleneimonium ions

Nucleophilic grps such as -NH2, -OH, and -SH

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13
Q

Most important consequence of intra- or inter-strand linking

A

S phase replication block -> G2 block -> apoptosis

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14
Q

Most widely-used alkylating agent

A

Cyclophosphamide

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15
Q

Nitrogen mustards (5)

A 
Mechlorethamine
Chlorambucil
Cyclophosphamide
Ifosfamide
Malphalan
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16
Q

Nitrosoureas (3)

A

Streptozocin, carmustine (BCNU), lomustine

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17
Q

Alkyl sulfonate

  • specificity for?
  • may cause what?
A

Busulfan (oral)

Granulocyte series (for chronic myelogenous leukemia)
Pulmonary fibrosis
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18
Q

Less likely than other alkylating agents to cause leukemia later

Which of these is acutely toxic

A

Platinum analogs - cisplatin, carboplatin, oxaliplatin

Oxaliplatin

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19
Q

One of the side effects of cyclophosphamide is hemorrhagic cystitis, due to acrolein toxicity. This can be ameliorated by the use of what adjuvant?

A

Mesna - detoxifies acrolein

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20
Q

Activation of nitrosoureas produces (2)

A

a DNA-alkylating grp and a protein-alkylating grp

*alkylated proteins produce toxicity

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21
Q

Cisplatin MOA:

Cl- dissociates, reacts with H2O, causing what?

Carboplatin has fewer side effects but

A

Intrastrand cross-linking, eventual DNA denaturation

More myelotoxic

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22
Q

CCSA: Anti-metabolites kill cells in what phase?

A

S phase

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23
Q

Folic acid is essential for the synthesis of (2)

A

Purines and thymidylates

  • folate -> (F(glu)n) -> FH2 -> FH4
  • FH4 - methyl grp donor to deoxyuridine (dUMP -> dTMP), also regenerating FH2
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24
Q

MTX inhibits

A

Dihydrofolate reductase (DHFR) (higher affinity than FH2)

*interrupts synthesis of thymidylate, purine nucleotides, serine, methionine

25
Q

Depletion of FH4 causes?

A

Depletion of dTMP -> “thymineless death”; inhibition of DNA synthesis

26
Q

Effects of MTX can be reversed by

A

Leucovorin

27
Q

5-Fluorouracil:

Converted to?
*Competitive inhibitor or covalently binds to thymidylate synthetase

A

“Fraudulent” nucleotide (FdUMP)

28
Q

A prodrug converted to 5-FU in the liver

A

Capecitabine

29
Q

araC (cytosine arabinoside) analog with fewer side effects

A

Gemcitabine

30
Q

First of the thiopurine analogs found to be effective in cancer therapy

A

6-MP

31
Q

6-MP, 6-TG are metabolized by?

A

HGPRT

32
Q

What purine analog has a MOA similar to araC?

A

Fludarabine

-> triphophate, inhibits DNA polymerase

33
Q

Purine analog that inhibits adenosine deaminase, catalyzes adenosine to inosine

A

Pentostatin

34
Q

Most cytotoxic antibiotics are CCNS, except

A

Bleomycin (G2-specific)

35
Q

4 major mechanisms of cytotoxic action

Which of these is the established cause of cardiotoxicity and associated side effects?

A
  1. Inhibition of topoisomerase II
  2. High-aff binding to DNA through intercalation (-> block DNA, RNA synth; DNA strand scission)
  3. Binding to cellular membranes (alter fluidity, ion transport)
  4. Generation of semiquinone free radicals & oxygen free radicals – cause of side effects
36
Q

Anthracycline main MOA (2)

Structurally related molecules?

A

Intercalation, topo II inhibition

Mitozantrone (doxorubicin, daunorubicin, epirubicin, idarubicin)

37
Q

Intercalates in DNA minor groove between adjacent GC’s; interfere w RNA pol

A

Dactinomycin

38
Q

Chelates Fe; generation of superoxide and/or hydroxyl radicals

Side effect?

A

Bleomycin (glycopeptide antibiotic)

Little myelosuppression BUT causes pulmonary fibrosis

39
Q

Examples of mitotic inhibitors (4)

These induce effect on what?

A

Taxanes
Epothilones
Vinca alkaloids (vincristine - childhood acute leukemia)
Estramustine

Tubulins

40
Q

(Delayed toxicity)

Vincristine vs vinblastin

A

Vincristine
Mild myelosuppression
Paresthesia, muscle weakness

Vinblastin
More potent myelosup
Less neurotoxic
Leucopenia

41
Q

Topoismoerase inhibitors arrest cell cycle at what phase?

Examples?

A

G2

Topo I - camptothecins
Topo II - podophyllotoxin derivatives (can inc risk of 2nd cancer, AML)

42
Q

Glucocorticoids used against?

A

Leukemias, lymphomas

43
Q

Estrogen (e.g. fosfestrol) recruit cells in…

A

G0 -> G1; better targets for cytotoxic drugs (haha di ko ‘to gets??)

44
Q

Progestogens (e.g. megestrol, medroxyprogesterone) used for?

A

Endometrial, renal tumors

45
Q

How do GnRH analogs (goserelin) work?

A

Inhibit gonadotropin release (duh huhu) -> dec circulating estrogens

46
Q

Flutamide, cyproterone for

A

Prostate tumors (androgen antagonists)

47
Q

Trilostane, aminoglutethimide inhibit?

Formestane inhibits?

A

Sex hormone synthesis

Aromatase

(Adrenal gland)

48
Q

Protein Kinase inhibitors (imatinib mesylate) for?

A

CML (chronic myeloid leukemia), GIST (gastrointestinal stromal tumors)

(inhibit transduction signals transmission)

49
Q

Monoclonal Ab against EGFR

Used for?

A

Cetuximab

Metastatic colorectal, head and neck CA

50
Q

Monoclonal Ab for lymphoma therapy

A

Rituximab

51
Q

Monoclonal Ab indicated in HER2 Neu positive breast CA therapy

A

Trastuzumab

*HER2 structurally similar to EGFR)

52
Q

Small inhibitor of kinase; inhibits PDGF activity and Bcr/Abl kinase (which is unique to?); also used against NSCLC

A

Imatinib (Gleevec, Glivec)

Unique to CML

53
Q

Similar to imatinib

A

Gefitinib

54
Q

Adverse effects of prototype antineoplastic agents:

Vincristine
Cisplatin
Bleomycin, busulfan
Doxorubucin (Adriamycin)
6-thioguanine, 6-mercaptopurine
Cyclophosphamide
A

Vincristine - cranial nerve palsies

Cisplatin - ototoxicity/tinnitus (C = ears)

Bleomycin, busulfan - pulmonary fibrosis (2B’s = lungs)

Doxorubucin (Adriamycin) - heart (“A”)

6-thioguanine, 6-mercaptopurine - liver/GI (6-TG - hepatotox; 6-MP - hepatitis, biliary stasis)

Cyclophosphamide - hemorrhagic cystitis (bladder)

55
Q

Counteracts MTX toxicity

A

THF

56
Q

Solution for relapse and met

A

Combination therapy

Targeted therapy - kill most cancer cells
Systemic - wipe out other cells

57
Q

Effect of location of cancer (brain, liver, CNS)

A

Brain - drug can’t cross BBB

Liver - difficulty going to actual tumor

CNS - intrathecal, need very high doses

58
Q

Most common dose limiting toxicity?

What is not considered?

A

Myelosuppression

Cyclophosphamide - hair loss

Ther 201 LE 3 (9 decks)

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