Cancer IV Flashcards
1
Q
Selective Estrogen-Receptor Modulators:
Drug?
A
Selective Estrogen-Receptor Modulators:
Tamoxifen
2
Q
Tamoxifen:
- MOA: ____ inhibitor of ____ binding to the ____.
- _____ rather than cytocidal. What does this mean?
- Metabolites?
A
Tamoxifen:
- MOA: competitive inhibitor of estradiol binding to the ER
- Cytostatic rather than cytocidal. Halts cells at G0 or G1.
- Metabolites = N-desmethyltamoxifen and 4-hydroxytamoxifen both are futher metabolized to 4-hydroxy-N-desmethyltamoxifen
3
Q
Tamoxifen:
- Use?
- Common side effects?
A
Tamoxifen:
- Use - ER-positive metastatic breast cancer or following primary tumor excision as adjuvant therapy
- 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
4
Q
Selective estrogen-receptor down regulators (SERDs):
Drug?
A
SERDs:
Fulvestrant
5
Q
Fulvestrant:
- 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?
- Route of administration? Plasma T1/2?
A
Fulvestrant:
- 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.
- Intramuscularly; T1/2 = 40 days
6
Q
Fulvestrant:
- Use?
- Side effects?
A
Fulvestrant:
- ER positive metastatic breast cancer after progression on first-line antiestrogen therapy such as tamoxifen
- SE = Nausea, asthenia, pain, vasodilation (hot flashes), and headache
7
Q
Resistance to Tamoxifen:
- Loss or modification of _____ ____
- Overexpression of?
- Regulation of ____ ____ pathway
- Altered ____ expression
- Co-regulatory _____ balance modification
A
Resistance to Tamoxifen:
- Loss or modification of estrogen receptor
- Overexpression of EGFR, HER2, MAPK
- Regulation of signal transduction pathway
- Altered microRNA expression
- Co-regulatory protein balance modification
8
Q
Role of Anastrozole?
A
Aromatase inhibitor
9
Q
Anastrozole:
- MOA: non-_____, ______ inhibitor that binds ____ to the ___ of CYPs, thus suppressing ____ activity and leading to _____ deprivation.
- Main metabolite?
- Excretory pathway?
A
Anastrozole:
- MOA: non-_steroidal_, aromatase inhibitor that binds reversibly to the heme of CYPs, thus suppressing aromatase activity and leading to estrogen deprivation
- Metabolite is a triazole
- Excretory pathway is via the liver
10
Q
Anastrozole:
- Treatment?
- Due to profound suppression of estrogen, there is a substantial risk of?
- Comparison to tamoxifen in terms of side effects?
A
Anastrozole:
- Treats postmenopausal women with hormone-receptor positive breast cancer
- Substantial risk of osteoporotic fractures
- Fewer thromboembolic events and fewer episodes of vaginal bleeding
11
Q
Resistance to Aromatase inhibitors (anastrozole)
- Insensitivity to _____.
- Ineffective _____ of aromatase
- ______ of estrogen ______ of aromatase
- Use of non-estrogen ____ ____
A
Resistance to aromatase inhibitors (anastrozole)
- Insenstivity to estrogen
- Ineffective inhibition of aromatase
- Sources of estrogen _independent _of aromatase
- Use of non-estrogen signaling pathways
12
Q
Gonadotropin Releasing Hormone Agonists:
2 drugs?
A
GnRH agonists:
a. Leuprolide
b. Gosrelin
13
Q
Leuprolide and Gosrelin:
- MOA: ____ ____ cause a surge in levels of ___ and ___, followed by inhibition of ____ release, resulting in reduction of ____ production of __________ to castration levels
- Use?
- Common side effects?
A
Leuprolide and Gosrelin:
- 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
- Use: palliative therapy of hormonally responsive tumors
- SE: vasomotor flushing, loss of libido, gynecomastia, increased wt, loss of bone mineral density, and loss of muscle mass
14
Q
Role of Flutamide?
A
Androgen receptor blocker
15
Q
Flutamide:
- MOA: non-_____ _____ receptor blocker that inhibits ____ binding and ____ receptor ___ translocation.
- Excretion?
- Side effects?
A
Flutamide:
- MOA: non-_steroidal androgen_ receptor blocker that inhibits ligand binding and androgen receptor nuclear translocation
- Excretion via urine
- SE: vasomotor flushing, gynecomastia, mastodynia (breast pain), decreased libido/potency. May also cause diarrhea, nausea, and reversible liver abnormalities
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
17
Q
Immunostimulants:
Name 2.
A
Immunostimulants:
a. Interferon alpha-2a
b. Interferon alpha-2b
18
Q
Interferons:
- Anticancer effects due to what 2 things?
- Uses?
- Administration?
- Toxicity? At prolonged or high dose?
A
Interferons:
- Anticancer effects due to enhancement of immune responses and direct antiproliferative effects
- Hairy cell leukemia, CML, malignant melanoma, follicular lymphoma, and AIDS related Kaposi’s sarcoma
- Administered IM or SUBQ
- Tox: flu-like symptoms, anorexia, wt loss, diarrhea, ab. pain, dizziness, cough; High dose: BM suppression, thyroid dysfunction, alopecia, cardiotox, and neurotoxicity
19
Q
Differentiating Agents:
2 drugs?
A
Differentiating agents:
a. Retinoids
b. Tretinoin
20
Q
Retinoids and Tretinoin:
- Binds to?
- Used in?
A
Retinoids and Tretinoin:
- Binds to retinoic acid receptor
- Used in acute promyelocytic leukemia
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
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
23
Q
Protein tyrosine kinase inhibitors:
3 drugs.
A
Protein tyrosine kinase inhibitors:
a. Imatinib (gleevec)
b. Gefitinib
c. Erlotinib
24
Q
Imatinib:
- Main MOA?
- Inhibits the _____ and ___ tyrosine kinases. Also approved to treat?
A
Imatinib:
- competitive inhibitor of Bcr-Abl tyrosine kinase - competes with ATP for binding (for CML caused by the philly chromosome)
- Inhibits the PDGF-R and c-kit tyrosine kinases. Also approved to treat Gastrointestinal stromal tumor (GIST)
25
Imatinib:
1. Resistance occurs from mutations in? What else?
2. Toxicities?
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
Gefitinib and Erlotinib:
1. ____ tyrosine kinase inhibitors
2. Gefitinib is for treatment of?
3. Gefitinib responders tend to be?
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
Gefitinib and Erlotinib:
1. Erlotinib is for treatment of?
2. Erlotinib SE?
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
Gefitinib and Erlotinib:
Gefitinib side effects?
Gefitinib and Erlotinib:
Gefitinib: diarrhea, rash, acne, dry skin, nausea, and vomitting
29
Antibody drugs?
Antibodies:
a. Trastuzumab
b. Bevacizumab
c. Cetuximab
d. Rituximab
30
Trastuzumab:
1. What is this?
2. Binds to receptor and inhibits? promotes?
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
Trastuzumab:
1. Approved for first line therapy of? What combination?
2. Toxicity?
3. Should monitor?
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
Bevacizumab:
1. ____ inhibitor.
2. MOA?
Bevacizumab:
1. _angiogenesis_ inhibitor
2. MOA: binds to VEGF and prevents VEGF binding to VEGFR
33
Bevacizumab:
1. Approved for? Combination with?
2. Toxicity? No \_\_\_\_\_.
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
Cetuximab:
1. ___ antagonist at \_\_\_\_, inhibits cell ____ and promotes apoptosis.
2. Approved only for?
Cetuximab:
1. _Competitive_ antagonist at _EGFR_, inhibits cell _growth_ and promotes apoptosis
2. Approved only for metastatic, EGFR-positive, KRAS wildtype, colorectal cancer
35
Cetuximab:
1. Resistance observed in instances of?
2. Toxicities?
Cetuximab:
1. Resistance in instances of up-regulation of ERBB2 expression
2. Tox: _sever infusion reactions, severe rash_ and interstitial lung disease
36
Rituximab:
1. Binds to ___ on surface of ___ cells and triggers?
2. Injury is limited to?
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
Rituximab:
1. Use?
2. Toxicity?
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
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?
Review:
1. Antibody medications have greater specificity
2. Bcr-abl = imatinib
3. Her2 = tratuzumab
39
Review:
1. What medication interacts with the EGFR tyrosine kinase receptor?
2. What blocks VEGF?
3. What is a competitive anatognist at EGFR?
Review:
1. EGFR = gefitinib and erlotinib
2. VEGF = Bevacizumab
3. EGFR antagonist = cetuximab
40
Glucocorticoids:
1. What are the antitumor properties of glucocorticoids?
3. Used in combination therapy for ____ in kids as well as ____ \_\_\_\_ for both adults and children
3. Side effects?
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
Vorinostat:
1. Second line therapy for?
2. This is a ____ \_\_\_ inhibitor inducting cell cycle arrest and apoptosis
3. Most common side effect? Others?
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
Bortezomib:
1. This is a _____ inhibitor that binds to ___ core of ____ proteosome and down regulates _____ leading to cell death.
2. Dose limiting side effects?
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
Bortezomib:
1. Use?
2. Other more serious side effects (2)? One of which can be reduced - how?
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
Reasons for cancer chemotherapy failure:
4 reasons?
Reasons for cancer chemotherapy failure:
a. Unfavorable cell kinetics
b. Unfavorable pharmacokinetics
c. unfavorable drug delivery
d. Intrinsic and acquired drug resistance
45
Reasons for cancer chemotherapy failure:
Unfavorable cell kinetics:
1. Many drugs are only effective against?
2. Thus what are resistant?
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
Acquired Drug Resistance Mechanisms:
1. Increase in DNA \_\_\_\_
2. Alteration in _____ \_\_\_
3. Decrease in drug \_\_\_\_\_
Acquired Drug Resistance Mechanisms:
1. Increase in DNA _Repair_
2. Alteration in _target site_
3. Decrease in drug _activation_
47
Acquired Drug Resistance Mechanisms:
Increase in drug ____ (3 things)
Acquired Drug Resistance Mechanisms:
Increase in drug:
a. inactivation
b. sequestration
c. efflux
48
Acquired Drug Resistance Mechanisms:
Increase in DNA repair:
1. Types of drugs that damage cellular DNA?
2. Example that causes increased repair activity?
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
Acquired Drug Resistance Mechanisms:
Alteration in target site:
1. What kind of drugs target enzymes are important for metabolism?
2. Example?
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
Acquired Drug Resistance Mechanisms:
Decrease in drug activation:
1. Some drugs need to be _____ by cellular enzymes and thus alteration causes?
2. Example?
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
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?
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
Acquired Drug Resistance Mechanisms:
Increase in drug sequestration:
1. What does increased sequestration do?
2. Example of drug?
Acquired Drug Resistance Mechanisms:
Increase in drug sequestration:
1. Causes a reduction of active intracellular drug concentration
2. Cisplatinum
53
Acquired Drug Resistance Mechanisms:
Increase in drug efflux:
What are three efflux pumps?
Acquired Drug Resistance Mechanisms:
Increase in drug efflux:
a. MDR (**_m_**ulti**_d_**rug **_r_**esistance)/ PgP (_P_-**_g_**lyco**_p_**rotein)
b. MRP (**_m_**ultidrug **_r_**esistance **_p_**rotein)
c. BCRP/MXR (**_b_**reast **_c_**ancer **_r_**esistance **_p_**rotein)
54
Acquired Drug Resistance Mechanisms:
Increase in drug efflux:
1. Pgp specific for what drugs?
2. MRP1 specific for?
3. Overlap of Pgp and MRP?
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
Acquired Drug Resistance Mechanisms:
Increase in drug efflux:
1. Overlap of Pgp and BCRP?
2. All 3 efflux mechanisms efflux what drugs?
Acquired Drug Resistance Mechanisms:
Increase in drug efflux:
1. Pgp and BCRP: Prazosin, topotecan, mitoxantrone
2. All: daunorubicin, doxorubicin, and epirubicin
56
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?
Helpful hints:
1. Monoclonal abs: "mab"
2. Small molecules: "ib"
3. Circulatory: "ci" ; tyrosine kinase: "tin" ; proteasome: "zom"
57
Helpful hints:
1. -zomib?
2. -tinib?
3. What is an EMT?
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)
