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Mandie's Pharm test I > Antineoplastic Agents > Flashcards

Antineoplastic Agents Flashcards

1
Q

Conventional chemotherapeutic agents

A
  • inhibit metabolic processes necessary for cell replication (synth of RNA/DNA/PRO)
    *damage DNA in replicating cells
    *interfere with mitotic machinery
    Downside: difficult or impossible to destroy tumor cells without harming normal host cells; low TI
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2
Q

M Phase of Cell cycle

A

mitotic splindles pull DNA apart

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3
Q

G0 phase

A

resting

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4
Q

G1/G2 phase

A

restriction point (checkpoint)

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5
Q

S phase

A

macromolecules synth for cell division; DNA precursors

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6
Q

tumor cell growth fraction

A
  • fraction not in G0
  • dividing tumor cells are responsive to conventional chemo
  • differentiated tumor cells (g0) are not
  • tumor stem cells are often not responsive
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7
Q

micrometastases

A
  • presumably derived from tumor stem cells, generally the ultimate cause of lethality
  • may be present but undetectable at diagnosis
  • often susceptible to chemo
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8
Q

normal cells susceptible to toxic side effects

A
  • bone marrow precursors of blood cells
  • intestinal epithelial cells
  • oral mucosa
  • hair follicles
  • gonadal cells (spermatogonial stem cells and oocytes/follicular cells)
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9
Q

bischloroethyl amines

A

class of anti-tumor alkylating agents; chloroethyl groups are electrophilic and interact with nucleotides

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10
Q

mechlorethamine (nitrogen mustard)

A

*prototype of alkylating agents; bischloroethyl amine highly reactive DNA alkylating agent (IV-reacts with H20), can cause necrosis

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11
Q

cyclophosphamide

A

less reactive (po) bischloroethyl amine; DNA alkylating activity after activation in liver or tumor tissues (prodrug)

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12
Q

nitrosoureas

A

class of alkylating agents; little cross-resistance with other alkylating agents; cross BBB (useful for brain cancers)

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13
Q

procarbazine

A

metabolized to alkylating and free radical intermediates; effective against Hodgkin’s in MOPP regimen; little cross-resistance with antineoplastic agents; leukemogenic (5-10% risk with MOPP); mutagen

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14
Q

MOPP

A

chemo regimen for Hodgkin’s : mechlorethamine, vincristine (Oncovin), procarbazine, prednisone

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15
Q

methotrexate

A

folic acid analog
DHFR inhibitor: blocks synthesis of DNA/RNA/PRO precursors; stops dihydrofolate from becoming tetrahydrofolate–which inhibits thymiylate synthetase; accumulates in cells as a polyglutamate derivative; S phase specific

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16
Q

resistance to methotrexate

A

cells: -amplify DHFR gene
- mutate DHFR gene
- decreased uptake
- increased efflux (MRP 2/4)
- leucovorin “rescue:” source of tetrahydrofolate, bypasses block of DHFR, sometimse used in intervals of recovery

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17
Q

6-mercaptopurine

A
  • purine antagonists
  • metabolites that inhibit de novo purine synth
  • interfere with DNA/RNA synthesis
  • S phase specific
  • metabolically inactivated by xanthine oxidase (in milk)
  • interacts with allopurinol (xanthine oxidase inhibitor, often used in conjunction with chemo to reduce uric acid accumulation/kidney toxicity associated with tumor cell death)
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18
Q

How do cells develop resistance to purine antagonists

A

-activated by conversion to NMPs/NTPs via HGPRT; cells down-regulate HGPRT enzyme

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19
Q

6-thioguanine

A
  • purine antagonists
  • metabolites that inhibit de novo purine synth
  • interfere with DNA/RNA synthesis
  • S phase specific
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20
Q

fluorouracil (5-FU)

A
  • pyrimidine antagonist
  • metabolite fdUMP inhibits thymidylate synthetase, causes thymineless death
  • metabolites incorporated into newly synth. DNA/RNA
  • S phase specific
  • synergistic toxicity when admin with leucovorin (binds thymidylate synthetase even more strongly)
  • variable abs orally, generally IV
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21
Q

capecitabine

A

-oral prodrug of fluorouracil
-contains hydrophobic chain, helps enter cells. MUST BE CONVERTED to 5FU via thymidine phosphorylase
-may be preferentially activated in tumor tissues
Use: colon ca, refractory breast ca

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22
Q

cytarabine

A
  • sub to ribose ring
  • araC converted to araCMP then araCTP , with inhibits DNA synthesis, incorporated into DNA causing mutations and breaks
  • metabolic activation requires deoxycytidine kinase
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23
Q

resistance to cytarabine

A

mutational loss of deoxycytidine kinase

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24
Q

daunorubicin/doxorubicin

A

-antitumor antibiotics:anthracyclines
-3 member ring
-widely used with broad spectrum
-DNA intercalation, interferes with DNA topoisomerase II binding, DNA scission
dose limiting: irreversible cardiac toxicity at high doses

25
Q

bleomycin

A
  • antitumor antibiotics
  • DNA strand scission
  • broad spectrum
  • no sig. myelosuppression, useful in combo (ABVD in hodgkin’s lymphoma)
  • causes anaphylactic reactions- small test doses
26
Q

ABVD

A

combo used for Hodgkin’s Lymphoma; adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine

27
Q

vinblastine

A
  • mitotic spindle poison; vinca alkaloids
  • M phase specific
  • inhibitor of microtubule polymerization
  • S.E: N/V, dose limiting bone marrow suppression
  • Hodgkin’s lymphoma (ABVD) & other lymphomas
28
Q

how do cells dev resistance to vinblastine

A

tubulin gene mutations

29
Q

vincristine

A
  • mitotic spindle poison; vinca alkaloid
  • also arrests mitosis via binding to microtubules
  • no acute SE, milder non-dose limiting BM suppression, dose limiting neurotoxicity.
  • acute childhood leukemia
  • part of MOPP for hodgkin’s
30
Q

resistance to vincristine

A

tubulin gene mutations

31
Q

paclitaxel

A
  • mitotic splindle poison
  • plant alkaloid
  • enhances tubulin polymerization
  • M phase specific
  • ovarian/ adv
32
Q

Topotecan

A
  • Topoisomerase I inhibitor
  • bind to cleavable complex of DNA topoisomerase I and DNA, block religation of single-strang break
  • Double strand breaks occur with DNA replication
  • S phase specific
  • ovarian/lung ca.
  • dose limiting tox: myelosuppression
33
Q

irinotecan

A
  • Topoisomerase I inhibitor
  • bind to cleavable complex of DNA topoisomerase I and DNA, block religation of single-strang break
  • Double strand breaks occur with DNA replication
  • S phase specific
  • colon ca
  • dose limiting tox: diarrhea
34
Q

etoposide

A

DNA topoisomerase II inhibitor

  • forms ternary complex with topoisomerase II and DNA
  • interferes with religation of double-strand break
  • DNA stand scission
  • anthracycline antibiotics can do this as well
35
Q

Cisplatin

A
  • platinum coordination complex
  • non cell-cycle specific
  • may fxn by inhibiting DNA synthesis
  • useful in combo
  • ovarian/testicular ca.
    toxicity: nephrotoxicty, acoustic nerve dysfunction
36
Q

tamoxifen

A
  • competitive inhibitor of estrogen binding to receptor, technically a selective estrogen response modulator (SERM)
  • partial agonist of estrogen receptor
  • efficacy varies in different tissues due to multiple receptor forms
  • low toxicity, SE (hot flashes)
  • employed effectively in cancers of estrogen-responsive tissues: breast, uterine, endometrium
  • increased risk of thrombosis and endometrial cancer
37
Q

Estrogen receptor status

A

presence of estrogen receptors in breast ca tissues predicts benefit from tamoxifen rx. (40 percent are ER positive)

38
Q

prophylactic tamoxifen

A

has been suggested as an effective means of prevention for high risk women (50% risk reduction) but not increased lifespan

39
Q

Tamoxifen postmenopausal

A

reduces risks of bone fractures

40
Q

raloxifene

A

SERM given for prevention of breast ca in patients with osteoporosis

41
Q

letrozole

A

-aromatase inhibitor
-inhibit conversion of androgens to estrogen
-effectively block estrogen production in postmenopausal women
-not used in pre-menopausal women because of compensatory gonadotropin/ovarian estrogen production
-more effective than tamoxifen in treatment of ER+ breast ca. in post-menopausal women
-no increased incidence of uterine ca. or thrombosis
SE: joint pain, loss of bone density (rx with biphosphonates)

42
Q

anastrazole

A

-aromatase inhibitor
-inhibit conversion of androgens to estrogen
-effectively block estrogen production in postmenopausal women
-not used in pre-menopausal women because of compensatory gonadotropin/ovarian estrogen production
-more effective than tamoxifen in treatment of ER+ breast ca. in post-menopausal women
-no increased incidence of uterine ca. or thrombosis
SE: joint pain, loss of bone density (rx with biphosphonates)

43
Q

exemestane

A

-aromatase inhibitor
-inhibit conversion of androgens to estrogen
-effectively block estrogen production in postmenopausal women
-not used in pre-menopausal women because of compensatory gonadotropin/ovarian estrogen production
-more effective than tamoxifen in treatment of ER+ breast ca. in post-menopausal women
-greatly reduces risk of breast ca. in high risk post menopausal women
-no increased incidence of uterine ca. or thrombosis
SE: joint pain, loss of bone density (rx with biphosphonates)

44
Q

leuprolide

A
  • synth peptide analog of GnRH, GnRH agonist
  • cont., high dose rx (vs. physiological:pulsatile) lowers androgen level in men and estrogen levels in pre-menopausal women (androgen ablation)
  • as effective as estrogen therapy or orchiectomy in rx of prostate ca. with fewer side effects
45
Q

flutamide

A
  • androgen receptor antagonist
  • alone ineffective against prostate ca due to rapid androgen receptor mutation
  • used in conjunction with leuprolide to block effects of the initial pulse of androgen levels and associated “flare” of prostate ca. at start of therapy
46
Q

prednisone

A
  • induces apoptosis in leukemia cells
  • used in several multidrug regimens for leukemia, lymphoma, and myeloma
  • does not cure leukemia, but useful for inducing remission in ALL or undifferentiated childhood leukemia
  • palliative agen in other cancers (reduce inflammation/nausea)
47
Q

targeted agents

A
  • include kinase inhibitors and antibodies

- inhibit function of activated oncogenes or PRO necessary for tumor cell proliferation

48
Q

kinase inhibitors

A

-small molecule inhibitors of oncogenic PRO kinases that are activated and drive tumor cell proliferation/survival

49
Q

chimeric antibodies

A
  • target tumor cell-specific cell surface receptors of angiogenic factors
  • kill cells by direct and immune system-mediated mechanisms (some with conjugated toxins)
  • leads to the activation of proteolytic cascade of complement and formation of a membrane attack complex (MAC). Cell is phagocytosed/cytolyzed
50
Q

erlotinib

A
  • target: EGF receptor protein tyrosine kinase that is overexpressed in cancers (lung/brain/head & neck)
  • small molecule EGFR kinase inhibitor approved for NSCLC and head and neck cancers
51
Q

cetuximab

A
  • target: EGF receptor protein tyrosine kinase that is overexpressed in cancers (lung/brain/head & neck)
  • chimeric EGFR antibody approved for use in colon cancer and head/neck ca.
52
Q

resistance to erlotinib

A

once cell has mutated EGFR, develops resistance

53
Q

iapatinib

A

target: HER2 protein tyrosine kinase (EGF-receptor related) that is overexpressed in various cancers
- smalll molecule EGFR and HER2 kinase inhibitor used in breast ca

54
Q

trastuzumab

A

target: HER2 protein tyrosine kinase (EGF-receptor related) that is overexpressed in various cancers
- humanized HER2 antibody in HER+ refractory metastatic breast ca.
- recognizes the cell surface antigen HER2 which is dramatically elevated in 25% of breast tumors
- direct tumor cell effects and immune system-mediated effects

55
Q

pertuzumab

A

target: HER2 protein tyrosine kinase (EGF-receptor related) that is overexpressed in various cancers
- humanized HER2 antibody approved for use in combination with tratuzumab and docetaxel to treat HER2+ metastatic breast ca.

56
Q

imatinib

A

target: activated bcr/abl protein tyrosine kinase arising from gene rearrangement/fusion in CML
- small molecule inhibitor of abl PRO tyrosine kinase and activated bcr/abl fusion
- approved for CML with bcr/abl mutation

57
Q

resistance to imatinib

A

-works well unless dev. an abl mutation, decreased drug binding

58
Q

brentuximab vedotin

A

target: CD30 surface antigen on some hodgkin/non-hodkin lymphoma cells
- chimeric IgG conjugated to highly toxic mitotic spindle poison vedotin with cleavable linker
- accelerated FDA approval for HL and anaplastic large cell lymphoma
- -upon binding to CD 30 positive tumor cells, the antibody conjugated vedotin is internalized and proteolytically cleaved to release toxin

Mandie's Pharm test I (10 decks)

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