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Foundations Exam 3 > Neoplasia > Flashcards

Neoplasia Flashcards

1
Q

Three phases of cancer formation?

A

1) preneoplastic epigenetic changes
2) cancer transformation (initiation)
3) Progression

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2
Q

Mass of detectable tumors? Mass of fatal tumors?

A
  • At least 1 gram

- Usually 1 kg

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3
Q

What three major classes of genes are usually mutated in cancer?

A
  • DNA repair genes
  • Tumor suppressor genes
  • Protoncogenes
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4
Q

What are three different ways oncogenes can stimulate cells?

A
  • overexpression
  • expression at the wrong place/time
  • unresponsive to negative regulation
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5
Q

What receptor is overexpressed by KSHV (Kaposi’s)?

A

G protein receptor that signals without ligand

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6
Q

With HTLV-1 (human T cell lymphotrophic virus), which growth factor receptor is overexpressed? in which cells?

A

IL-2 receptor in infected T cells

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7
Q

Which EGF receptor is overexpressed in breast cancer, ovarian cancer, etc? Consequence?

A

ERBB2 (Her-2-Neu)

Hypersensitivity to EGF signaling

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8
Q

What drug targets ERBB2?

A

Herceptin

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9
Q

In CML, a chromosome translocation produces what hybrid oncogene product? Consequence?

A

Bcr-Abl – Abl inhibitory domain is lost and cell is constitutively activated

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10
Q

What drug inhibits Abl kinase?

A

imatinib (Gleevec)

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11
Q

What is B-Raf? In melanomas, colorectal cancers, and thyroid cancers, what mutation is observed in B-Raf? Consequence?

A
  • protoncogene; member of Raf threonine/serine protein kinase family
  • Regulator downstream of Ras
  • V600E
  • signals on its own bypassing upstream receptors
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12
Q

What drug/drug type is used to treat melanomas with the BRAF V600E mutation?

A

protein kinase inhibitor = VEMURAFENIB

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13
Q

What pathway is regulated by PTEN (phosphatase and tensin homolog)?
What is the function of this pathway?

A
  • phosphatidylinositol-3-kinase (PI3K)/Akt pathway
  • PTEN phosphatase protein is a tumor suppressor
  • important for cell activation and apoptosis resistance
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14
Q

What fusion gene can be formed by translocation with the ALK (anaplastic lymphoma kinase) gene? How does this fusion gene product function and in what cancers is it often found?

A
  • ALK gene codes for tyrosine kinase receptor of insulin super family
  • EML4-ALK fusion gene
  • Dimerizes without the need for a ligand and constitutively signals
  • Lung cancers, particularly NSC adenocarcinomas in young, non-smokers
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15
Q

What protein kinase inhibitor can be used to treat EML4-ALK positive lung cancers?

A

crizotinib

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16
Q

What is an example of a common GAP (GTPase activating protein)?

A

NF-1

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17
Q

What gene regulates B-catenin? What is the function of B-catenin?

A
  • APC (adenomatous polyposis coli) = tumor suppressor protein that acts as antagonist in the Wnt pathway
  • APC docks on B-cat that isn’t bound to E cadherin and B-cat is degraded
  • Wnt frees B-cat from APC to act as TF to activate various proliferating genes (wound healing)
  • TF involved in cell-cell contact signaling
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18
Q

Defective APC is most commonly found in what cancers?

A

colorectal cancers and benign intestinal polyps

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19
Q

What is the normal function of let7 miRNA? Deleted/underexpressed in what cancer type?

A
  • Targets 3’ UTR of Ras and downregulates Ras protein expression
  • lung cancer
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20
Q

What 4 types of cancer respond only occasionally to chemotherapy?

A
  • Non-small lung cancer
  • melanoma
  • pancreatic and hepatocellular carcinoma
  • renal and prostate cancer
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21
Q

What are two anti-mitotic drugs?

A
  • paclitaxel

- vincristine

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22
Q

How does paclitaxel work?

A
  • Promotes tubulin polymerization and blocks disassembly required for mitosis
  • Cells are arrested in mitosis
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23
Q

Three unusual side effects of paclitaxel?

A

neuropathy, hypersensitivity, arrhythmias

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24
Q

How does vincristine work?

A

Binds tubulin and inhibits microtubule formation (opposite of paclitaxel)

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25
Q

Unusual vincristine side effect? Cause?

A

neurotoxicity because microtubules are important in neuronal transport

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26
Q

What drugs are substrates for CYP450?

A

paclitaxel (anti-mitotic) - inactivated
doxorubicin (antibiotic)
cyclophosphamide (pro-drug, alkylating agent)
ondansetron (anti-emetic)

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27
Q

Two antibiotics used in chemotherapy? Natural source?

A

doxorubicin
dactinomycin
Soil microbe Streptomyces

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28
Q

What cancers are often treated with doxorubicin?

A

hematologic cancers and solid tumors

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29
Q

How does doxorubicin work?

A

Inhibits topoisomerase II, intercalates DNA, binds cell membranes, and generates free radicals

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30
Q

How does dactinomycin work?

A

Binds dsDNA by intercalating between G-C bp – inhibits RNA synthesis (RNA needed all the time)

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31
Q

Unusual side effects of doxorubicin? Treatment for more severe side effect?

A
  • Cardiotoxicity, red urine

- dezroxane = iron chelator

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32
Q

How is doxorubicin eliminated?

A

Biphasic - peak half-lives at 3 and 30 hours (CYP450 in liver)

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33
Q

What is one alkylating agent used in cancer treatment?

A

Cyclophosphamide (nitrogen mustard)

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34
Q

How does cyclophosphamide work?

A
  • transfers alkyl groups to cellular constituents
  • Damages and cross-links DNA
  • Targets REPLICATION - fork stops at alkyl groups
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35
Q

Secondary use for cyclophosphamide?

A

immunosuppression in transplant patients

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36
Q

How is cyclophosphamide metabolized?

A

Pro-drug activated by P450 proteins in liver

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37
Q

Two anti-metabolites used in cancer treatment?

A

Methotrexate and 5-fluorouracil, also 6-MP

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38
Q

Methotrexate inhibits which enzyme and synthesis of which products?

A

Dihydrofolate reductase - THF, thymidylate, nucleotides, amino acids

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39
Q

Dual functions of 5-FU?

A
  • incorporated into RNA/DNA – inhibits RNA functioning/processing
  • inhibits thymidylate synthase – inhibits biosynthesis of pyrimidines
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40
Q

Two things to consider with methotrexate?

A
  • can accumulate in ascetic, pleural, peritoneal fluid
  • significant interactions with drugs that bind to plasma proteins (salicylate, sulfonamides, phenytoin), which can displace metho from normal binding proteins and cause increased tox
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41
Q

What enzyme degrades 5-FU? Clinical application?

A
  • PRO-DRUG
  • Dihydropyrimidine dehydrogenase
  • individuals w/ compromised enzyme function can experience drug tox
42
Q

What is dexamethasone used in some cancer therapies?

A
  • immunosuppressant

- allows greater access to tumor by drugs by suppressing tumor-associated immune cells

43
Q

What are two hormonal agents used in treating breast cancer?

A

Tamoxifen and anastrozole

44
Q

What four factors determine the degree of myelosuppression in chemo patients?

A
  • dose/schedule
  • age
  • prior therapy
  • nutritional state and liver/kidney health
45
Q

How are chemotherapy regimens applied to allow blood counts to recover?

A

6 week cycles

46
Q

What can be administered to patients to inhibit myelosuppression? How do they help?

A
  • granulocyte colony-stimulating factor (filgastrim)
  • granulocyte-monocyte colony stimulating factor (sargramostim)
  • enhance neutrophil recovery after chemo
47
Q

Where is the vomiting receptor center/chemoreceptor trigger zones in brain? Vomiting sensors rich in what 4 receptor types?

A
  • medulla

- histamine, 5-HT3, dopamine, cholinergic

48
Q

What is the 5-HT3 receptor antagonist prototype?

A

Ondansetron

49
Q

Why is ondansetron used in chemo patients?

A

anti-emetic

50
Q

Pharmacokinetics of ondansetron?

A
  • Metabolized by P450 pathway

- effects persist after it disappears from circulation suggesting prolonged interaction with receptor

51
Q

What is prednisone? Why is it used in cancer patients?

A
  • adrenocorticoseroid; potent lympholytic
  • suppress nausea; decrease BC discomfort by reducing tumor inflammation
  • combo therapy in leukemia/lymphoma regimens
52
Q

What Ab fragment targets Her-2/neu in some breast cancer patients?

A

trastuzumab/heceptin

53
Q

What Ab fragment targets EGFR in some cancer patients?

A

cetuximab/erbitux

54
Q

How does tamoxifen work?

A
  • inhibitor/partial agonist of estrogen receptor (late stage hormone responsive BC, prevention of BC in high risk patients)
  • estrogenic activity in the uterus
55
Q

How does anastrozole work?

A
  • non-steroidal inhibitor of aromatase (estrogen synthesis enzyme)
  • binds specifically to heme group of Cyp19/aromatase
56
Q

Side effects of tamoxifen?

A
  • hot flashes, NV, hair loss, vaginal lining atrophy

- 2-3 fold increase in endometrial cancer risk

57
Q

Tamoxifen and anastrozole are given orally. Differences in half lives and clinical implications?

A
  • Tam has 7-14 day half life
  • Ana has short half life
  • Don’t have to take Tam as often
58
Q

What is the primary drug for lung cancer? Two combination drugs?

A

Cisplatin; paclitaxel and etoposide

59
Q

How does the platinum derivative Cisplatin work?

A

Cross-links and alkylates DNA

60
Q

Two unusual adverse effects of Cisplatin?

A

Renal toxicity (hydration) and electrolyte disturbances (check biochem notes)

61
Q

Etoposide and doxorubicin both target which enzyme? Why is etoposide preferable in treating lung cancer?

A
  • topoisomerase II

- doxorubicin is not taken up as well in the lungs as etoposide

62
Q

What is the most common GI malignancy?

A

colorectal cancer

63
Q

What is the primary drug for GI cancer?

A

5-FU (thymidylate synthase)

64
Q

What is the Folfox regimen used for?

A

In 5-FU resistant cancers, Folfox contains folinic acid which synergizes with 5-FU to inhibit thymidylate synthase (second line therapy)

65
Q

What is Bevacizumab/avastin used for?

A
  • monoclonal Ab that binds VEGF
  • Blocks VEGF binding to VEGFR
  • Inhibits angiogenesis
66
Q

What role does asparaginase play in cancer treatment?

A
  • Used to deprive leukemic cells of asparagine, which they do not synthesize and absorb from the bloodstream
67
Q

What fusion chromosome is associated with adult CML? Consequence?

A
  • Bcr-Abl oncogene (Philadelphia chromosome)

- highly active Tyr kinase that drives cells to grow and avoid apoptosis

68
Q

What Ab inhibits the Bcr-Abl oncogene in CML?

A

Imatinib (complete response in half of patients)

69
Q

How is Hodgkin’s lymphoma treated? Efficacy?

A

ABVD = doxorubicin, bleomycin, vinblastine, dacarbazine
Response in 80-90%
Cures in 60%
Combined with radiation

70
Q

How is non-Hodgkin’s lymphoma treated?

A
  • worse prognosis than Hodgkin’s

- CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone

71
Q

What is the first line of therapy in androgen-dependent prostate cancer?

A
  • Androgen deprivation therapy (ADT) using gonadotropin releasing hormone (GnRH) agonists or androgen receptor inhibitors
72
Q

What is an example of a GnRH agonist and how do they work?

A
  • Leuprolide

- Resemble GnRH and trigger a surge in LH resulting in FSH release

73
Q

What is an important side effect to consider when treating with GnRH agonists? How can it be managed?

A
  • Initially, GnRH agonists - LH – FSH - cause a increase in testosterone release
  • BUT eventually cells become desensitized and stop producing LH/FSH, decreasing testosterone production
  • Androgen receptor inhibitors can be used to manage initial testosterone increase
74
Q

Two classes of AR inhibitors? Examples?

A
  • steroidal

- non-steroidal = FLUTAMIDE

75
Q

How do AR inhibitors work?

A

Bind to AR and prevent it from translocating to the nucleus and binding DNA

76
Q

What are three side effects of flutamide?

A
  • non-steroidal AR inhibitors

- ND, reversible liver damage

77
Q

Why does chemotherapy work poorly for brain cancers?

A

Most drugs do not cross BBB (work being done on drug delivery = implantable wafer)

78
Q

What is the nitrosurea drug most useful in treating brain cancer?

A

Carmustine

79
Q

How do nitrosurea drugs work (carmustine)?

A

alkylation of DNA on O6-guanine

80
Q

What four transporter proteins play a role in drug resistance? Transporter type?

A
  • MRP1, MRP2, P-glycoprotein, BCRP (breast cancer)

- ABC, ATP-binding cassette transporter proteins (efflux pumps)

81
Q

What 5 anti-neoplastic drugs are P-glycoprotein substrates?

A
  • vincristine, etoposide, taxol, doxorubicin, dactinomycin
82
Q

What anti-neoplastic drug ia NOT P-glycoprotein substrates?

A

Methotrexate

83
Q

What are three resistance mechanisms against alkylating agents?

A
  • increased DNA repair
  • Increased permeability of drug
  • Increased glutathione production (inactivates drug)
84
Q

What are three resistance mechanisms against methotrexate?

A
  • decreased polyglutamate-methotrexate formation (highly active form of drug)
  • Increased DHFR synthesis
  • Mutations in DHFR
85
Q

What is a resistance mechanism against the pro-drug 5-FU?

A

changes in the enzymes that convert 5=FU to its active nucleotide form

86
Q

What are two resistance mechanisms against paclitaxel?

A
  • mutations in Beta-tubulin (target protein)

- increased expression of anti-apoptotic survival proteins (survivin)

87
Q

In acute promyelotic leukemia, what mechanism prevents terminal differentiation of cancer cells?

A
  • 15:17 translocation generates PML-RARA (retinoic acid receptor alpha) fusion gene
  • Fusion receptor product does not respond to physiological retinoic acid which causes differentiation of normal promyelocytes
88
Q

How can acute promyelocytic leukemia be treated?

A

PML-RARA responds to high doses of all-trans retinoic acid = terminal differentiation

89
Q

Successful tumors must attract a blood supply to grow past __ mm

A

1 mm

90
Q

What antibody is used against VEGF in cancer treatment?

A

bevacizumab

91
Q

What are 2 ways stromal cells may participate in the epithelial-mesenchymal transition?

A
  • macrophages in tumor secrete proteases
  • Tumor factors stimulate mesenchymal stem cells in tumor stroma to secrete CCL5 chemokines which stimulates invasive behavior
92
Q

What are melanomas derived from embryologically? What TF gives then inherent invasive activity?

A

Neural crest cells; Slug

93
Q

What enzymes contribute to metastasis by degrading ECM?

A

matrix metalloproteases

94
Q

MOST CIRCULATING CANCER CELLS DO NOT SUCCESSFULLY IMPLANT

A

ovarian cancer ascites and shunting to venous circulation example

95
Q

Three routes of spread of cancer?

A

Body cavities, lymphatics, blood

96
Q

What two cancer types commonly metastasize to bone? Chemokine-receptor pathway?

A

Breast, prostate

- SDF-1 is made by bone and attracts breast/prostate cancer cells that express CXCR4 chemokine receptor

97
Q

What is one potential advantage of tumors preferentially using glycolysis?

A

Metabolite = lactate which may be a building block for fat, DNA, protein in tumors

98
Q

Why do tumors light up on PET scans using a glucose analog?

A

Because they increase GLUT1 transporters to import glucose for glycolysis

99
Q

How do E5, E6, and E7 HPV proteins promote cancer?

A
  • E6 binds p53 and accelerates degradation
  • E7 binds and inhibits Rb
  • Both E6 and 7 impede apoptosis
  • E5 prevents endosome acidification = EGFR inappropriately stimulates proliferation
100
Q

What are 3 ways the HTLV Tax protein contributes to cancer development?

A
  • activates IL-2 receptor gene
  • promotes p53 degradation
  • activates other oncogenes
101
Q

What two cell types are infected by EBV?

A

epithelial and B cells

102
Q

What is the major oncogene in EBV?

A

LMP1

Foundations Exam 3 (3 decks)

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