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Pharmacology > Cancer IV > Flashcards

Cancer IV Flashcards

1
Q

Selective Estrogen-Receptor Modulators:

Drug?

A

Selective Estrogen-Receptor Modulators:

Tamoxifen

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2
Q

Tamoxifen:

  1. MOA: ____ inhibitor of ____ binding to the ____.
  2. _____ rather than cytocidal. What does this mean?
  3. Metabolites?
A

Tamoxifen:

  1. MOA: competitive inhibitor of estradiol binding to the ER
  2. Cytostatic rather than cytocidal. Halts cells at G0 or G1.
  3. Metabolites = N-desmethyltamoxifen and 4-hydroxytamoxifen both are futher metabolized to 4-hydroxy-N-desmethyltamoxifen
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3
Q

Tamoxifen:

  1. Use?
  2. Common side effects?
A

Tamoxifen:

  1. Use - ER-positive metastatic breast cancer or following primary tumor excision as adjuvant therapy
  2. Common SE: vasomotor symptoms (hot flashes), atrophy of the lining of the vagina, hair loss, N/V. Also increases risk of endometrial cancer and increases risk for thromboembolic events
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4
Q

Selective estrogen-receptor down regulators (SERDs):

Drug?

A

SERDs:

Fulvestrant

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5
Q

Fulvestrant:

  1. MOA: This is a steroidal ___ that binds to the ___ with high affinity, inhibits _____, and increases _____. This leads to increased ____ turnover and disruption of ____ localization. Agonist activity?
  2. Route of administration? Plasma T1/2?
A

Fulvestrant:

  1. MOA: This is a steroidal antiestrogen that binds to the ER with high affinity, inhibits dimerization, and increases degradation. This leads to increased ER turnover and disruption of nuclear localization. NO agonist activity.
  2. Intramuscularly; T1/2 = 40 days
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6
Q

Fulvestrant:

  1. Use?
  2. Side effects?
A

Fulvestrant:

  1. ER positive metastatic breast cancer after progression on first-line antiestrogen therapy such as tamoxifen
  2. SE = Nausea, asthenia, pain, vasodilation (hot flashes), and headache
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7
Q

Resistance to Tamoxifen:

  1. Loss or modification of _____ ____
  2. Overexpression of?
  3. Regulation of ____ ____ pathway
  4. Altered ____ expression
  5. Co-regulatory _____ balance modification
A

Resistance to Tamoxifen:

  1. Loss or modification of estrogen receptor
  2. Overexpression of EGFR, HER2, MAPK
  3. Regulation of signal transduction pathway
  4. Altered microRNA expression
  5. Co-regulatory protein balance modification
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8
Q

Role of Anastrozole?

A

Aromatase inhibitor

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9
Q

Anastrozole:

  1. MOA: non-_____, ______ inhibitor that binds ____ to the ___ of CYPs, thus suppressing ____ activity and leading to _____ deprivation.
  2. Main metabolite?
  3. Excretory pathway?
A

Anastrozole:

  1. MOA: non-_steroidal_, aromatase inhibitor that binds reversibly to the heme of CYPs, thus suppressing aromatase activity and leading to estrogen deprivation
  2. Metabolite is a triazole
  3. Excretory pathway is via the liver
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10
Q

Anastrozole:

  1. Treatment?
  2. Due to profound suppression of estrogen, there is a substantial risk of?
  3. Comparison to tamoxifen in terms of side effects?
A

Anastrozole:

  1. Treats postmenopausal women with hormone-receptor positive breast cancer
  2. Substantial risk of osteoporotic fractures
  3. Fewer thromboembolic events and fewer episodes of vaginal bleeding
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11
Q

Resistance to Aromatase inhibitors (anastrozole)

  1. Insensitivity to _____.
  2. Ineffective _____ of aromatase
  3. ______ of estrogen ______ of aromatase
  4. Use of non-estrogen ____ ____
A

Resistance to aromatase inhibitors (anastrozole)

  1. Insenstivity to estrogen
  2. Ineffective inhibition of aromatase
  3. Sources of estrogen _independent _of aromatase
  4. Use of non-estrogen signaling pathways
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12
Q

Gonadotropin Releasing Hormone Agonists:

2 drugs?

A

GnRH agonists:

a. Leuprolide
b. Gosrelin

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13
Q

Leuprolide and Gosrelin:

  1. MOA: ____ ____ cause a surge in levels of ___ and ___, followed by inhibition of ____ release, resulting in reduction of ____ production of __________ to castration levels
  2. Use?
  3. Common side effects?
A

Leuprolide and Gosrelin:

  1. MOA: GnRH__ agonists cause a surge in levels of LH and FSH, followed by inhibition of gonadotropin release, resulting in reduction of testicular production of testosterone to castration levels
  2. Use: palliative therapy of hormonally responsive tumors
  3. SE: vasomotor flushing, loss of libido, gynecomastia, increased wt, loss of bone mineral density, and loss of muscle mass
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14
Q

Role of Flutamide?

A

Androgen receptor blocker

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15
Q

Flutamide:

  1. MOA: non-_____ _____ receptor blocker that inhibits ____ binding and ____ receptor ___ translocation.
  2. Excretion?
  3. Side effects?
A

Flutamide:

  1. MOA: non-_steroidal androgen_ receptor blocker that inhibits ligand binding and androgen receptor nuclear translocation
  2. Excretion via urine
  3. SE: vasomotor flushing, gynecomastia, mastodynia (breast pain), decreased libido/potency. May also cause diarrhea, nausea, and reversible liver abnormalities
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16
Q

Biological response modifiers:

Immunostimulants, differentiating agents, and agents enable host to?

A

Biological response modifiers:

These enable host to tolerate immunosuppressive anticancer drugs

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17
Q

Immunostimulants:

Name 2.

A

Immunostimulants:

a. Interferon alpha-2a
b. Interferon alpha-2b

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18
Q

Interferons:

  1. Anticancer effects due to what 2 things?
  2. Uses?
  3. Administration?
  4. Toxicity? At prolonged or high dose?
A

Interferons:

  1. Anticancer effects due to enhancement of immune responses and direct antiproliferative effects
  2. Hairy cell leukemia, CML, malignant melanoma, follicular lymphoma, and AIDS related Kaposi’s sarcoma
  3. Administered IM or SUBQ
  4. Tox: flu-like symptoms, anorexia, wt loss, diarrhea, ab. pain, dizziness, cough; High dose: BM suppression, thyroid dysfunction, alopecia, cardiotox, and neurotoxicity
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19
Q

Differentiating Agents:

2 drugs?

A

Differentiating agents:

a. Retinoids
b. Tretinoin

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20
Q

Retinoids and Tretinoin:

  1. Binds to?
  2. Used in?
A

Retinoids and Tretinoin:

  1. Binds to retinoic acid receptor
  2. Used in acute promyelocytic leukemia
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21
Q

Retinoids and Tretinoin:

Acute promyelocytic leukemia is the result of ____ translocation of ___ gene ( on chromosome ____) with the _____ gene (on chromosome ___). ATRA (tretinoin) acts on this to stimulate terminal _____. These cells then naturally progress to an _____ state.

A

Retinoids and Tretinoin:

Acute promyelocytic leukemia is the result of reciprocal translocation of RAR gene (on chromosome 17) with the PML gene (on C15). ATRA acts on this to stimulate terminal differentiation. These cells then naturally progress to an apoptotic state

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22
Q

Retinoids and Tretinoin:

Toxicities?

A

Retinoids and Tretinoin:

Tox: Retinoic acid syndrome: dyspnea, fever, weight gain, hypotension, and pulmonary infiltrates and pleural or pericardial effusions

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23
Q

Protein tyrosine kinase inhibitors:

3 drugs.

A

Protein tyrosine kinase inhibitors:

a. Imatinib (gleevec)
b. Gefitinib
c. Erlotinib

24
Q

Imatinib:

  1. Main MOA?
  2. Inhibits the _____ and ___ tyrosine kinases. Also approved to treat?
A

Imatinib:

  1. competitive inhibitor of Bcr-Abl tyrosine kinase - competes with ATP for binding (for CML caused by the philly chromosome)
  2. Inhibits the PDGF-R and c-kit tyrosine kinases. Also approved to treat Gastrointestinal stromal tumor (GIST)
25
Q

Imatinib:

  1. Resistance occurs from mutations in? What else?
  2. Toxicities?
A

Imatinib:

  1. Resistance occurs from mutation in kinase domain; over-expression, downstream signaling molecule activation, drug entry, and efflux
  2. Tox: N/V, edema, muscle cramps in leukemia, neutropenia, and thrombocytopenia
26
Q

Gefitinib and Erlotinib:

  1. ____ tyrosine kinase inhibitors
  2. Gefitinib is for treatment of?
  3. Gefitinib responders tend to be?
A

Gefitinib and Erlotinib:

  1. EGFR tyrosine kinase inhibitors
  2. Gefitinib: non-small cell lung carcinoma which has failed standard chemo
  3. Gefitinib responders tend to be females, nonsmokers, asian, and with bronchoalveolar history
27
Q

Gefitinib and Erlotinib:

  1. Erlotinib is for treatment of?
  2. Erlotinib SE?
A

Gefitinib and Erlotinib:

  1. Erlotinib: locally advanced or metastatic non-small cell lung cancer
  2. SE: diarrhea, rash, increased liver enzymes, and rarely - interstitial lung disease
28
Q

Gefitinib and Erlotinib:

Gefitinib side effects?

A

Gefitinib and Erlotinib:

Gefitinib: diarrhea, rash, acne, dry skin, nausea, and vomitting

29
Q

Antibody drugs?

A

Antibodies:

a. Trastuzumab
b. Bevacizumab
c. Cetuximab
d. Rituximab

30
Q

Trastuzumab:

  1. What is this?
  2. Binds to receptor and inhibits? promotes?
A

Trastuzumab:

  1. This is a humanized monoclonal Ab directed against HER2/Neu
  2. Binds to receptor and inhibits cell growth; promotes antibody-dependent cell death
31
Q

Trastuzumab:

  1. Approved for first line therapy of? What combination?
  2. Toxicity?
  3. Should monitor?
A

Trastuzumab:

  1. First line of therapy for metastatic HER2 overexpressing breast cancer in combination with paclitaxel or as monotherapy following chemo relapse
  2. Tox: cardiotoxicity (esp in combo with doxorubicin), flu like symptoms, pulmonary toxicity, hypersensitivity
  3. Monitor LVEF (LV ejection fraction)
32
Q

Bevacizumab:

  1. ____ inhibitor.
  2. MOA?
A

Bevacizumab:

  1. angiogenesis inhibitor
  2. MOA: binds to VEGF and prevents VEGF binding to VEGFR
33
Q

Bevacizumab:

  1. Approved for? Combination with?
  2. Toxicity? No _____.
A

Bevacizumab:

  1. Approved for metastatic colon or rectal cancer (in combo with 5-fluorouracil) and metastatic NSCLC (non-small cell lung cancer)
  2. Tox: GI perforation, impaired wound healing, pulmonary hemorrhage, thromboembolism, nephrotic syndrome, and hypertension, decreased appetitie, epistaxis, headache, and asthenia; No myelo-suppression
34
Q

Cetuximab:

  1. ___ antagonist at ____, inhibits cell ____ and promotes apoptosis.
  2. Approved only for?
A

Cetuximab:

  1. Competitive antagonist at EGFR, inhibits cell growth and promotes apoptosis
  2. Approved only for metastatic, EGFR-positive, KRAS wildtype, colorectal cancer
35
Q

Cetuximab:

  1. Resistance observed in instances of?
  2. Toxicities?
A

Cetuximab:

  1. Resistance in instances of up-regulation of ERBB2 expression
  2. Tox: sever infusion reactions, severe rash and interstitial lung disease
36
Q

Rituximab:

  1. Binds to ___ on surface of ___ cells and triggers?
  2. Injury is limited to?
A

Rituximab:

  1. Binds to CD20 on surface of B cells and triggers an immune attack
  2. Injury is limited to B cells only (however both malignant and normal)
37
Q

Rituximab:

  1. Use?
  2. Toxicity?
A

Rituximab:

  1. Treat low grade, B-cell non-hodgkins lymphoma
  2. Tox: severe infusion related hypersensitivity, tumor lysis syndrome, mucocutaneous reactions, and hepatitis B reactivation
38
Q

Review:

  1. Between tyrosine kinase inhibitors and antibody directed targets which has greater specificity?
  2. What medication interacts intracellularly with the bcr-abl domain?
  3. What interacts with the Her2 receptor?
A

Review:

  1. Antibody medications have greater specificity
  2. Bcr-abl = imatinib
  3. Her2 = tratuzumab
39
Q

Review:

  1. What medication interacts with the EGFR tyrosine kinase receptor?
  2. What blocks VEGF?
  3. What is a competitive anatognist at EGFR?
A

Review:

  1. EGFR = gefitinib and erlotinib
  2. VEGF = Bevacizumab
  3. EGFR antagonist = cetuximab
40
Q

Glucocorticoids:

  1. What are the antitumor properties of glucocorticoids?
  2. Used in combination therapy for ____ in kids as well as ____ ____ for both adults and children
  3. Side effects?
A

Glucocorticoids:

  1. Activate glucocorticoid receptor and initiate apoptosis
  2. Used in combination therapy for ALL in kids as well as malignant lymphoma for adults and kids
  3. SE: glucose intolerance, immunosuppression, osteoporosis, and psychosis
41
Q

Vorinostat:

  1. Second line therapy for?
  2. This is a ____ ___ inhibitor inducting cell cycle arrest and apoptosis
  3. Most common side effect? Others?
A

Vorinostat:

  1. Second line therapy for cutaneous T-cell lymphoma (aka Sezary syndrome)
  2. This is a histone deacetylase inhibitor inducing arrest and apoptosis
  3. Fatigue is the most common side effect; rare - pulmonary embolus and DVT, thombocytopenia and anemia, N/V, diarrhea, hyperglycemia, hypokalemia, and hypomagnesia
42
Q

Bortezomib:

  1. This is a _____ inhibitor that binds to ___ core of ____ proteosome and down regulates _____ leading to cell death.
  2. Dose limiting side effects?
A

Bortezomib:

  1. This is a proteasome inhibitor that binds to 20S core of 26S proteasome and down regulates NF-kB leading to cell death
  2. SE: GI, heme, lymph, and renal side effects
43
Q

Bortezomib:

  1. Use?
  2. Other more serious side effects (2)? One of which can be reduced - how?
A

Bortezomib:

  1. Use = multiple myeloma after 2 failed Rx
  2. Neuropathy (12-30%), high rate of shingles which can be reduced by prophylactic acyclovir
44
Q

Reasons for cancer chemotherapy failure:

4 reasons?

A

Reasons for cancer chemotherapy failure:

a. Unfavorable cell kinetics
b. Unfavorable pharmacokinetics
c. unfavorable drug delivery
d. Intrinsic and acquired drug resistance

45
Q

Reasons for cancer chemotherapy failure:

Unfavorable cell kinetics:

  1. Many drugs are only effective against?
  2. Thus what are resistant?
A

Reasons for cancer chemotherapy failure:

Unfavorable cell kinetics:

  1. Effective against rapidly proliferating malignancies
  2. Solid tumors, slow growers, are frequently resistant bc most of them are in the Go resting state
46
Q

Acquired Drug Resistance Mechanisms:

  1. Increase in DNA ____
  2. Alteration in _____ ___
  3. Decrease in drug _____
A

Acquired Drug Resistance Mechanisms:

  1. Increase in DNA Repair
  2. Alteration in target site
  3. Decrease in drug activation
47
Q

Acquired Drug Resistance Mechanisms:

Increase in drug ____ (3 things)

A

Acquired Drug Resistance Mechanisms:

Increase in drug:

a. inactivation
b. sequestration
c. efflux

48
Q

Acquired Drug Resistance Mechanisms:

Increase in DNA repair:

  1. Types of drugs that damage cellular DNA?
  2. Example that causes increased repair activity?
A

Acquired Drug Resistance Mechanisms:

Increase in DNA repair:

  1. Alkylating agents damage cellular DNA
  2. Example: CENU produces alkylating agent that alkylates guanine O6 (leading to crosslinks and inactivation) –> MGMT is an enzyme that can remove the alkylating moiety from the guanin and increased expression of MGMT causes resistanct to CENU (chloroethylnitrosureas: carmustine, lomustine, and methyl-CCNU-semustine) drugs
49
Q

Acquired Drug Resistance Mechanisms:

Alteration in target site:

  1. What kind of drugs target enzymes are important for metabolism?
  2. Example?
A

Acquired Drug Resistance Mechanisms:

Alteration in target site:

  1. Anti-metabolite drugs target these enzymes and thus mutation of these enzymes reduce affinity of the drug
  2. Example: DHFR provides THF for DNA synthesis. Methotrexate reversibly binds DHFR to inhibit it. And mutations in DHFR reduces its affinity to methotrexate and still catalyzes conversion of FH4 to FH2
50
Q

Acquired Drug Resistance Mechanisms:

Decrease in drug activation:

  1. Some drugs need to be _____ by cellular enzymes and thus alteration causes?
  2. Example?
A

Acquired Drug Resistance Mechanisms:

Decrease in drug activation:

  1. Some drugs need to be activated by cellular enzymes and thus alteration causes decreased activation and resistance
  2. 6-MP needs to be converted to TIMP by HGPRT to be active. Decreased expression of HGPRT decreases the conversion of 6MP to TIMP
51
Q

Acquired Drug Resistance Mechanisms:

Increase in drug inactivation:

  1. Conjugation of DNA _____ agents by _____ spontaneously or mediated by _____ ___ ________ (GST) will inactivate these drugs.
  2. Type of drugs effected?
A

Acquired Drug Resistance Mechanisms:

Increase in drug inactivation:

  1. Conjugation of DNA alkylating agents by glutathione spontaneously or mediated by glutathione s-transferase will inactivate these drugs
  2. Nitrogen mustards (cyclophosphamide, cholambucil, isofamide, mechlorethamine, and melphalan)
52
Q

Acquired Drug Resistance Mechanisms:

Increase in drug sequestration:

  1. What does increased sequestration do?
  2. Example of drug?
A

Acquired Drug Resistance Mechanisms:

Increase in drug sequestration:

  1. Causes a reduction of active intracellular drug concentration
  2. Cisplatinum
53
Q

Acquired Drug Resistance Mechanisms:

Increase in drug efflux:

What are three efflux pumps?

A

Acquired Drug Resistance Mechanisms:

Increase in drug efflux:

a. MDR (multidrug resistance)/ PgP (P-glycoprotein)
b. MRP (multidrug resistance protein)
c. BCRP/MXR (breast cancer resistance protein)

54
Q

Acquired Drug Resistance Mechanisms:

Increase in drug efflux:

  1. Pgp specific for what drugs?
  2. MRP1 specific for?
  3. Overlap of Pgp and MRP?
A

Acquired Drug Resistance Mechanisms:

Increase in drug efflux:

  1. Pgp: Verapamil, Paclitaxel, and colchicine
  2. MRP1: methotrexate and glutathione conjugated DDP
  3. Pgp and MRP: Etopiside and vinblastine
55
Q

Acquired Drug Resistance Mechanisms:

Increase in drug efflux:

  1. Overlap of Pgp and BCRP?
  2. All 3 efflux mechanisms efflux what drugs?
A

Acquired Drug Resistance Mechanisms:

Increase in drug efflux:

  1. Pgp and BCRP: Prazosin, topotecan, mitoxantrone
  2. All: daunorubicin, doxorubicin, and epirubicin
56
Q

Helpful hints:

  1. Monoclonal antibodies end in?
  2. Small molecules end with? (indicates protein inhibitory properties)
  3. In the middle, contains what stem for circulatory system target? tyrosine kinase inhibitor? proteasome inhibitors?
A

Helpful hints:

  1. Monoclonal abs: “mab”
  2. Small molecules: “ib”
  3. Circulatory: “ci” ; tyrosine kinase: “tin” ; proteasome: “zom”
57
Q

Helpful hints:

  1. -zomib?
  2. -tinib?
  3. What is an EMT?
A

Helpful hints:

  1. -zomib = proteasome inhibitor
  2. -tinib = tyrosine kinase inhibitor
  3. Epithelial-mesenchymal transition: allows a polarized epithelial cell to assume a mesenchymal cell phenotype (with enhanced migratory capacity, invasiveness, resistance to apoptosis, and increased production of ECM proteins)

Pharmacology (24 decks)

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