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M2 Hematology > 23. New Cancer Drugs, Resistance PHARM > Flashcards

23. New Cancer Drugs, Resistance PHARM Flashcards

1
Q

why do many cancer drugs cause problems with a pt’s normal cells?

A

many target all rapidly dividing cells and there are toxic to gut lining, bone marrow, and hair follicles.

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2
Q

how are we hoping to avoid systemic toxicities of cancer drugs?

A

by selecting molecular targets that are specific to the cancer cells (oncogenes or tumor suppressors)

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3
Q

what is the oncogene that is characteristic of CML? what is the drug that targets it?

A

CML: the BCR-ABL translocation. drug = imatinib

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4
Q

what is the oncogene in non-small cell lung cancer? what drug targets it?

A

epidermal growth factor receptor (EGFR) overexpression. drug = erlotinib (& others)

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5
Q

what is the oncogene in breast cancer? what drug targets it

A

Her2/neu overexpression. drug = trastuzumab

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6
Q

what are tumor suppressor genes?

A

normal genes which are lost or altered and therefore cause malignancy.

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7
Q

examples of tumor suppressor types/genes?

A
  • point mutations (p53, BRCA)
  • chromo/DNA deletion
  • gene silencing
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8
Q

what kind of mutation is an oncogene?

A

gain of function mutation, leading to overexpression and tumorigenesis

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9
Q

imatinib: mechanism?

A

inhibits the tyrosine kinase domain of the BCR-ABL oncoprotein. blocks phosphorylation of downstream proteins

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10
Q

imatinib: effectiveness in CML patients?

A

can be used in both chronic and blast phase as a single agent. complete remission can occur.

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11
Q

what is imatinib also used for?

A

treating gastrointestinal stromal tumors (GIST) which overexpress the c-kit tyrosine kinase receptor

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12
Q

imatinib: kinetics? adverse effects? interactions?

A

orally well absorbed, hepatic (CYP3A4) metabolism
cardiac toxicity
interactions with CYP inhibitors

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13
Q

trastuzumab: what does it do?

A

recognizes the Her2/neu receptor, blocks it so that growth factor cannot bind.

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14
Q

what cancers is the her2/neu receptor expressed in?

A

over-expressed in some breast cancers. poor prognosis.

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15
Q

drugs that end in -MAB: what are they likely to be?

A

monoclonal antibodies

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16
Q

trastuzumab: when is it used alone? what if it is combined with chemo?

A
  • single agent activity in advanced, estrogen-resistant breast cancers.
  • when combined with chemo, enhanced clinical responses are observed
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17
Q

Trastuzumab: class?

A

anti-Her2/neu antibody

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18
Q

trastuzumab: action?

A

blocks action of Her2/neu receptor in breast cancer.

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19
Q

trastuzumab: adverse effects?

A

cardiac toxicity, dyspnea, allergic reactions

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20
Q

erlotinib: what pathway does it block?

A

the EGFR pathway: ligand-activated, works through a series of phosphorylations

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21
Q

what patients are ideal for erlotinib?

A

lung cancer patients: a subset have an activating mutation of EGFR and are sensitized to EGFR inhibitors

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22
Q

what can happen to EGFR despite treatment with erlotinib?

A

further mutation and molecular resistance, elevated signaling through alternate pathways

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23
Q

erlotinib: what cancers is it active against?

A

lung, pancreatic.

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24
Q

erlotinib: what class?

A

small molecule epidermal growth factor receptor inhibitor

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25
Q

erlotinib: kinetics?

A

hepatic (CYP3A4) metabolism

26
Q

erlotinib: adverse effects?

A

rash, diarrhea, dyspnea

27
Q

erlotinib: interactions?

A

smoking, CYP3A4 inhibitors

28
Q

what is angiogenesis?

A

formation of new blood vessels by a cancer that promotes tumor cell growth

29
Q

what are some angiogenic factors?

A

bFGF, EGF, PDGF

30
Q

what can inhibit those angiogenic factors?

A

anti-VEGF, endostatin, angiostatin

31
Q

why are anti-angiogenic factors so promising?

A
  • resistance is infrequent
  • activity does not depend on targeting tumor cells
  • chronic therapy could prevent vascularization of tumors
32
Q

bevacizumab: what class?

A

anti-angiogenic (anti-vascular endothelial growth factor antibody)

33
Q

bevacizumab: mechanism?

A

recognizes vascular endothelial growth factor (VEGF) and blocks its angiogenic activity

34
Q

bevacizumab: what cancers does it treat?

A

colon, lung. also useful in macular degeneration and retinal diseases

35
Q

bevacizumab: complications?

A

possibility for bleeding, allergic reactions, less wound healing, GI perforation

36
Q

what is the major difference between normal and tumor cells?

A

tumor cells are genetically unstable, which allows some cells to escape chemo by mutating.

37
Q

what is intrinsic resistance?

A

when a tumor displays resistance to chemo from the onset of treatment.

38
Q

what is acquired resistance?

A

when the tumor is initially sensitive, but then commences regrowth despite ongoing treatment

39
Q

what are some mechanisms of acquired resistance?

A
  • oncogene mutation
  • oncogene amplification
  • increased metabolism
  • decreased drug concentration
  • alternative signaling pathways
  • stem cell quiescence
  • incr plasma protein binding
40
Q

what are threee types of cancer therapy resistance?

A
  • pharmacokinetic
  • cytokinetic
  • cellular resistance
41
Q

describe pharmacokinetic resistance

A

systemic or tumor mass level resistance.

poor absorption, incr drug clearance, poor tumor vascularity, anatomic sanctuaries (testes, brain)

42
Q

describe cytokinetic resistance

A

based on growth rate

tumor is in the wrong phase of cell cycle for specific drug, low growth fraction

43
Q

describe cellular resistance

A

changes to tumor cells
gene amplicafication or overexpression, chromo rearrangements, point mutations, changes in chromatin.
–> increased genomic instability

44
Q

what accounts for multidrug resistance?

A

some resistance mechanisms are specific to the drug or class of drugs…. in the case of multidrug resistance, cells become resistant to many different classes of agents.

45
Q

what are ATP-binding cassette transporters?

A

ABC transporters: transmembrane proteins which pump drugs out of the cell. we are looking for pump blockers to minimize this effect

46
Q

three examples of ABC transporters?

A
  • P-glycoprotein (PGP)
  • multidrug resistance protein (MRP1)
  • ABCG2
47
Q

Overexpression of PGP, MRP1 and ABCG2 causes increased efflux of drugs including what?

A

vinca alkaloids, antracyclines, taxanes, etoposide, teniposide, camptothecins, imatinib, mitoxantrone

48
Q

why do we assess for PGP transport activity when developing new drugs?

A

to screen out drugs that would be inactive in cells that overexpress PGP

49
Q

what drugs would not be subject to efflux even in the presence of an efflux protein (PGP, MRP1, ABCG2)?

A

cisplatin, carboplatin, 5-fluorouracil, AraC, cyclophosphamide, bleomycin

50
Q

describe how decreased expression of topoisomerase II leads to multidrug resistance

A

DNA agents like doxorubicin and etoposide interact with Topo II. with less of TopoII, there is less substrate for them.

51
Q

describe how increased repair of DNA leads to multidrug resistance

A

repair is responsible for resistance to several cancer drugs (esp alkylating agents and cisplatin).

52
Q

describe how Glutathione-S-transferase induction (GST) leads to multidrug resistance

A

GST catalyzes conjugation of electrophilic compounds to glutathione. enhances detoxification and elimination. acts on cisplatin, anthracyclines and alkalating agents.

53
Q

describe how failure to induce apoptosis leads to multidrug resistance

A

may be due to decreased expression of pro-apoptotic mediators, or increased expression of antiapoptotic mediators. p53 is in here somewhere as well.

54
Q

describe collateral sensitivity.

A

way to decrease drug resistance. resistance to one drug causes changes that make the cell MORE sensitive to a second drug

55
Q

describe combination therapy

A

way to decrease drug resistance. use of non-cross-resistant drugs (both substrates and non-substrates of ABC transporters)

56
Q

describe dose escalation

A

way to decrease drug resistance. used with or without bone marrow transplant

57
Q

constant infusion, adjuvant therapy: what are these?

A

ways to decrease drug resistance

58
Q

Cancer cells isolated from a patient exhibit relative resistance to vincristine, doxorubicin, daunorubicin and etoposide but not to 5-fluorouracil or cisplatin. The mechanism of resistance is most likely to involve what?

A

overexpression of PGP

59
Q

Most cases of Chronic Myelogenous Leukemia (CML) are associated with a chromosomal abnormality that can be preferentially targeted using what drug?

A

imatinib

60
Q

Attempts to limit tumor growth include inhibiting angiogenesis thus blocking the tumors access to a blood supply. Bevacizumab inhibits the activity of which angiogenic protein?

A

VEGF

M2 Hematology (15 decks)

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