Immunomodulators and Anti-Neoplastics Flashcards Preview

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

Flashcards in Immunomodulators and Anti-Neoplastics Deck (58):
1

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

F

1 Cardiac
2 Vascular diseases
3 Cancer

2

pRB (retinoblastoma protein) blocks ___

p53 detects ___

pRB blocks E2F

p53 detects DNA damage

3

pRB control occurs at which phase? How?

S (DNA synthesis) phase

(pRB binds and inhibits transcription factors of the E2F family)

4

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

P53 - detects DNA damage

50%

5

P53 - 2 possible responses to DNA damage

1. Acts as a transcription factor (p21 expression activated -> CDK/G1 cyclin inhibited -> DNA repair)

2. Triggers Apoptosis (if damage is irreparable)

6

"Executioner" proteins that break down the cell

Caspases

7

Receptor tyrosine kinases can activate ___

ras ("molecular switch") - for cell proliferation

8

CCSA vs CCNSA - effectiveness

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

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

9

Classifications of classical cancer chemotherapeutic agents (3)

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

10

2 kinds of CCNS

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

Antibiotics

11

Main lethal effect of alkylating agents

What else can it target?

Alkylation of DNA at N7 position of guanine

N1, N3 adenine
N3 cytosine

12

Alkylating agents undergoes intramolecular cyclization, forming what?

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

Ethyleneimonium ions

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

13

Most important consequence of intra- or inter-strand linking

S phase replication block -> G2 block -> apoptosis

14

Most widely-used alkylating agent

Cyclophosphamide

15

Nitrogen mustards (5)

Mechlorethamine
Chlorambucil
Cyclophosphamide
Ifosfamide
Malphalan

16

Nitrosoureas (3)

Streptozocin, carmustine (BCNU), lomustine

17

Alkyl sulfonate

*specificity for?
*may cause what?

Busulfan (oral)

Granulocyte series (for chronic myelogenous leukemia)
Pulmonary fibrosis

18

Less likely than other alkylating agents to cause leukemia later

Which of these is acutely toxic

Platinum analogs - cisplatin, carboplatin, oxaliplatin

Oxaliplatin

19

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

Mesna - detoxifies acrolein

20

Activation of nitrosoureas produces (2)

a DNA-alkylating grp and a protein-alkylating grp

*alkylated proteins produce toxicity

21

Cisplatin MOA:

Cl- dissociates, reacts with H2O, causing what?

Carboplatin has fewer side effects but

Intrastrand cross-linking, eventual DNA denaturation

More myelotoxic

22

CCSA: Anti-metabolites kill cells in what phase?

S phase

23

Folic acid is essential for the synthesis of (2)

Purines and thymidylates

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

24

MTX inhibits

Dihydrofolate reductase (DHFR) (higher affinity than FH2)

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

25

Depletion of FH4 causes?

Depletion of dTMP -> "thymineless death"; inhibition of DNA synthesis

26

Effects of MTX can be reversed by

Leucovorin

27

5-Fluorouracil:

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

"Fraudulent" nucleotide (FdUMP)

28

A prodrug converted to 5-FU in the liver

Capecitabine

29

araC (cytosine arabinoside) analog with fewer side effects

Gemcitabine

30

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

6-MP

31

6-MP, 6-TG are metabolized by?

HGPRT

32

What purine analog has a MOA similar to araC?

Fludarabine

(-> triphophate, inhibits DNA polymerase)

33

Purine analog that inhibits adenosine deaminase, catalyzes adenosine to inosine

Pentostatin

34

Most cytotoxic antibiotics are CCNS, except

Bleomycin (G2-specific)

35

4 major mechanisms of cytotoxic action

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

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

Anthracycline main MOA (2)

Structurally related molecules?

Intercalation, topo II inhibition

Mitozantrone (doxorubicin, daunorubicin, epirubicin, idarubicin)

37

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

Dactinomycin

38

Chelates Fe; generation of superoxide and/or hydroxyl radicals

Side effect?

Bleomycin (glycopeptide antibiotic)

Little myelosuppression BUT causes pulmonary fibrosis

39

Examples of mitotic inhibitors (4)

These induce effect on what?

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

Tubulins

40

(Delayed toxicity)

Vincristine vs vinblastin

Vincristine
Mild myelosuppression
Paresthesia, muscle weakness

Vinblastin
More potent myelosup
Less neurotoxic
Leucopenia

41

Topoismoerase inhibitors arrest cell cycle at what phase?

Examples?

G2

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

42

Glucocorticoids used against?

Leukemias, lymphomas

43

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

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

44

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

Endometrial, renal tumors

45

How do GnRH analogs (goserelin) work?

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

46

Flutamide, cyproterone for

Prostate tumors (androgen antagonists)

47

Trilostane, aminoglutethimide inhibit?

Formestane inhibits?

Sex hormone synthesis

Aromatase

(Adrenal gland)

48

Protein Kinase inhibitors (imatinib mesylate) for?

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

(inhibit transduction signals transmission)

49

Monoclonal Ab against EGFR

Used for?

Cetuximab

Metastatic colorectal, head and neck CA

50

Monoclonal Ab for lymphoma therapy

Rituximab

51

Monoclonal Ab indicated in HER2 Neu positive breast CA therapy

Trastuzumab

*HER2 structurally similar to EGFR)

52

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

Imatinib (Gleevec, Glivec)

Unique to CML

53

Similar to imatinib

Gefitinib

54

Adverse effects of prototype antineoplastic agents:

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

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

Counteracts MTX toxicity

THF

56

Solution for relapse and met

Combination therapy

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

57

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

Brain - drug can't cross BBB

Liver - difficulty going to actual tumor

CNS - intrathecal, need very high doses

58

Most common dose limiting toxicity?

What is not considered?

Myelosuppression

Cyclophosphamide - hair loss