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PHRM 864 > Final Exam > Flashcards

Final Exam Flashcards

1
Q

Neoplasm

A

new growth, may be benign or malignant

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2
Q

Tumor

A

nonspecific term meaning lump or swelling

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3
Q

Cancer

A

any malignant neoplasm

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4
Q

Hyperplasia

A

increase in organ or tissue size due to an increase in the number of cells (BPH)

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5
Q

Metaplasia

A

an adaptive, substitution of one type of adult tissue to another type of adult tissue

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6
Q

Dysplasia

A

an abnormal cellular proliferation is which there is loss of normal architecture

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7
Q

Anaplasia

A

loss of structural differentiation, cells dedifferentiate (leiomyoma)

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8
Q

What is the epithelial origin of carcinoma?

A

neoplasm of squamous epithelial cell origin

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9
Q

What is the benign version of a carcinoma?

A

papilloma

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10
Q

What is the epithelial origin of an adenocarcinoma?

A

neoplasm of glandular tissue

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11
Q

What is the benign version of an adenocarcinoma?

A

adenoma

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12
Q

What is the epithelial origin of a sarcoma

A

neoplasm with origin in mesenchymal tissues or derivatives (bone, muscle, fat)

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13
Q

What is the epithelial origin of lymphoma and leukemia

A

hematopoietic tissues

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14
Q

What is the epithelial origin of melanoma?

A

cancer of pigment producing cells in the skin or the eye

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15
Q

What is the epithelial origin of a blastoma?

A

in precursor cells called blasts, which are more common in children

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16
Q

What is the epithelial origin of a teratoma?

A

germ cell neoplasm made of several different differentiated cell/tissue types

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17
Q

What cells are affected in myeloid leukemias?

A

common myeloid progenitor

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18
Q

What cells are affected in lymphocytic leukemias?

A

common lymphoid progenitor

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19
Q

What cells are affected in lymphomas?

A

small lymphocytes (T,B)

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20
Q

Cancer is characterized by what three things?

A
  1. uncontrolled cellular growth (benign,cancer)
  2. tissue invasion (cancer)
  3. metastasis (cancer)
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21
Q

What are the hallmarks of cancer?

A
  • sustaining proliferative signaling
  • avoiding immune destruction
  • enabling replicative immortality
  • activating invasion and metastasis
  • inducing or accessing vasculature
  • genome instability and mutation
  • resisting cell death
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22
Q

What is an oncogene?

A

any gene in a healthy cell capable of promoting tumor growth

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23
Q

What is the genetic basis of cancer?

A

some cancers can result of mutation or deletion of a single potent tumor suppressor (retinoblastoma)

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24
Q

2-hit Hypothesis

A
  • assumption that hereditary retinoblastoma has a single deletion of the RB1 tumor suppressor
  • heterozygous mutations can increase susceptibility to cancers
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25
Q

What kind of genes are BRCA 1/2?

A

tumor suppressors

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26
Q

BRCA mutations in breast cancer increase susceptibility to what type of inhibitors?

A

PARP inhibitors (synthetic lethality)

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27
Q

PARP inhibitors

A
  • trap PARP to DNA, unable to uncouple from DNA
  • olaparib, rucaparib, niraparib
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28
Q

What happens during G0/G1?

A
  • cell is quiescent or accumulating building blocks required for division
  • cellular contents are duplicated
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29
Q

What happens during S phase?

A
  • each of the 46 chromosomes is duplicated by the cell
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30
Q

What happens during the G2 phase?

A
  • the cell “double checks” the duplicated chromosomes for error, making any needed repairs
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31
Q

What determines when the cells move from one phase of the cell cycle to the next?

A

cell cycle clock driven by cyclins paired with cyclin-dependent kinases

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32
Q

Non-cell specific agents

A

DNA damaging agents
- alkylators
- intercalaters

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33
Q

G1-specific agents

A

Mitogenic signaling
- kinase inhibitors
- hormone inhibitors

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34
Q

S-specific agents

A

DNA replication
- anti-metabolites
- anti-folates
- Topo I inhibitors

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35
Q

G2-specific agents

A

Sister Chromatid Separation
- Topo II inhibitors

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36
Q

M-specific agents

A

Chromosome Segregation
- microtubule inhibitors

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37
Q

Common Oncogenes

A
  • KRAS
  • PI3K
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38
Q

Common Tumor Suppressors

A
  • TP53, p16, RB1
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39
Q

Palbociclib Target

A

CDK4/6 (approved for BRACA 1/2)

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40
Q

Palbociclib Class of Drug

A

Kinase Inhibitor

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41
Q

Palbociclib Cell Cycle Target

A

G1

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42
Q

Palbociclib Dose Limiting Side Effects

A
  • neutropenia
  • N/V/D
  • fatigue
  • similar to traditional chemotherapies
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43
Q

Drugs that are more effective against cycling cells at many phases of the cell cycle are called what?

A
  • cell cycle non-specific
  • alkylating agents and DNA intercalation agents
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44
Q

Limitation of cell kill in phase specific drugs

A
  • higher drug doses may not result in greater tumor cell killing
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45
Q

Increased cell kills requires what?

A
  • prolonged exposure
  • one way to increase the number of cells present in the sensitive phase is to maintain therapeutic levels of a drug over a long period of time
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46
Q

Dose limiting toxicities of cancer chemotherapies?

A

Hematopoietic
- Infections
- hemostasis
- anemia

GI
- N/V
- Loss of appetite

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47
Q

Designing Chemotherapy Regimens

A
  • combination of drugs with different mechanisms of action
  • no additive toxicity for drugs with non-overlapping toxicity
  • increased cell killing
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48
Q

What is the CHOP regimen

A
  • Cyclophosphamide (alkylating agent)
  • Doxorubicin (anthracycline)
  • Vincristine (microtubule inhibitor)
  • Prednisone (steroid)
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49
Q

What are the causes altered drug metabolism?

A
  • increased transport of drugs out of the cell through efflux pumps (PgP, MRP)
  • reduced transport into the cell (loss of drug importer, decreased membrane permeability)
  • Decreased activation of prodrug
  • Increased detoxification of drug molecule
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50
Q

What causes changes in drug target or function?

A
  • increased expression of drug target through gene amplification (upregulation makes it harder to inhibit)
  • emergence of mutant, structurally altered taraget
  • emergence of cells bearing alterations in genes whose products are functionally redundant with the drug target
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51
Q

What causes physiological changes that promote resistance?

A
  • metastasis
  • massive stromalization
  • changes in cell state such as EMT
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52
Q

What causes cell survival mechanisms?

A
  • activation of anti-apoptoic regulators
  • increased repair of damage caused by chemotherapies
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53
Q

What is the most common reason for resistance to multiple chemos at once?

A

drug transport out of cell

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54
Q

What are the two major strategies to endocrine therapy?

A
  • stop steroid receptor function
  • decrease production of steroids
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55
Q

Tamoxifen MOA

A
  • selective estrogen receptor modulator
  • blocks estrogen-dependent breast cancer cell proliferation
  • estrogen agonist effects
  • acts as antagonist and agonists
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56
Q

SERM (Tamoxifen) Receptor Target

A

ER/PR +

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57
Q

SERM (Tamoxifen) Side Effects

A
  • hot flashes due to anti-estrogen effects
  • incidence of cancer increased 3-fold
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58
Q

SERM (Tamoxifen) Pre or Post menopausal?

A
  • pre and post menopausal
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59
Q

Tamoxifen Drug Interaction

A

Less effective in patients with a common CYP2D6 varient

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60
Q

Tamoxifen vs Raloxifene

A

Tamoxifen
- antiproliferative to Breast
- blocks bone resporption
- endometrial hyperplasia

Raloxifene
- no endometrial hyperplasia
- increases bone mass in osteoporosis

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61
Q

Selective Estrogen Receptor Down Modulator (Fluvestrant and Elacestrant) MOA

A
  • Fluvestrant has pure ER antagonist that has no agonist effects
  • Elacestrant acts as partial agonist at low doses and full SERD at high dose
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62
Q

SERD (Fluvestrant/Elacestrant) Receptor Target

A

ER

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63
Q

SERD Indication (Fluvestrant/Elacestrant)

A
  • ER+ metastatic breast cancer in postmenopausal women who have progressed on other anti-estrogen therapy
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64
Q

What does Aromatase convert?

A
  • Androstenedione to estrone
  • testosterone to estradiol
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65
Q

What do aromatase inhibitors block?

A
  • synthesis of estrogens
  • not the synthesis of androgens or progestrone
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66
Q

Non-steroidal aromatase inhibitors MOA

A
  • Letrozole and Anastrozole
  • potent and selective competitive inhibitor of aromatase activity
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67
Q

Indication of Non-steroidal aromatase inhibitors

A
  • treatment of breast cancer in postmenopausal women
  • first line or when started after 3-5 years of tamoxifen
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68
Q

Steroidal Aromatase inhibitor MOA

A
  • acts as false substrate that aromatase converts to reactive intermediate
  • binds irreversibly at active site and inactivates enzyme
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69
Q

Indication of Steroidal Aromatase Inhibitor

A

ER+ breast cancer in postmenopausal women who have progressed on anti-estrogen therapy

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70
Q

Which anti-estrogen compound directly inhibits the activity of the estrogen receptor throughout the body?

A

Fulvestrant (directly binds to ER)

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71
Q

Chronic administration of GnRH analogs ____ pituitary GnRH receptors and leads to pituitary _____

A

down regulates, desensitization

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72
Q

GnRH Analogs MOA

A
  • acute admin induces surge of LH and FSH (agonist effect)
  • chronic administration downregulates pituitary GnRH and decreases synthesis of estrogen
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73
Q

Toxicity of GnRH analogs

A
  • transient worsening of symptoms related to initial agonists
  • long term side effects include hot flashes, sexual dysfunction, gynecomastia
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74
Q

Indication of GnRH analogs in breast cancer

A
  • premenopausal breast cancer
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75
Q

Medications for postmenopausal women with ER+ disease

A
  • tamoxifen
  • Nonsteroidal aromatase inhibitors
  • steroidal aromatase inhibitor (exemestane)
  • pure anti-estrogens (fulvestrant)
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76
Q

Medications for premenopausal breast cancer

A
  • GnRH agonists
  • Surgical oophorectomy
  • Tamoxifen
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77
Q

Important enzyme in steroid hormone biosynthesis for prostate cancer

A

Type II 5-alpha reductase
- testosterone –> DHT in prostate cells

17 alpha-hydrolyse and C17,20 lyase
- conversion of pregnenolone and progesterone to DHEA and androstenedione

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78
Q

Importance of DHT in prostate cancer

A
  • DHT binds to androgen receptor (AR) in prostate cells
  • binding of AR to DHT leads to translocation to the nucleus and action of genes that drive cell
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79
Q

Degareliz/Relugolix versus Leuprolide/Goselerin

A
  • Degarelix/relugolix will not cuase flare of testosterone production
  • long term side effects are the same
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80
Q

Abiraterone MOA

A
  • inhibits the function of 17-alpha hydroylase and C17,20 lyase
  • inhibits the conversion of pregnenolone and progesterone to DHEA and androstenedion
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81
Q

Abiraterone side effect

A
  • increased levels of cholesterol
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82
Q

AR Receptor Antagonists

A
  • enzalutamide
  • apalutamide
  • darolutamide
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83
Q

AR Receptor Antagonist MOA

A
  • bind to AR to prevent AR translocation to the nucleus
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84
Q

AR Receptor Antagonist Target

A

androgen receptor

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85
Q

AR Indication

A
  • metastatic and non metastatic prostate cancer
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86
Q

What is unique about the action of Tamoxifen vs Fluvestrant?

A
  • it activates ER in the bone
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87
Q

Which compounds act directly on AR?

A

AR antagonists (enzalutamide)

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88
Q

What is cell signaling largely driven by?

A

the transfer of phosphate by a kinase to a target protein

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89
Q

What are the common targets of several kinases?

A
  • serine
  • tyrosine
  • threonine
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90
Q

What balances the activity of kinases by removing phosphates?

A

Phosphatases

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91
Q

Type I Kinase inhibitors

A

bind to the active conformation of the kinase

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92
Q

Type II kinase inhibitor

A

bind and stabilize the inactive conformation of the kinase

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93
Q

Type III kinase inhibitor

A

occupy the allosteric pocket outside of the ATP binding pocket

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94
Q

Competitive kinase inhibitors

A

bind kinase in a reversible fashion and must compete with ATP for binding

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95
Q

Covalent kinase inhibitors

A

covalently bind with reactive nucleophilic cysteine residue proximal to the ATP-binding site, resulting in the blockage of the ATP site and irreversible inhibition

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96
Q

Gefitinib Target

A

EGFR

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97
Q

Gefitinib MOA

A
  • Type I TKI
  • competitively inhibits the enzyme by binding to the ATP binding site in the kinase domain
  • inhibition of kinase activity turns off signal to proliferate
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98
Q

Gefitinib Indication

A
  • patients with metastatic NSCLC whose tumors have EGFR exon 19 or exon 21 (L8585R) mutations
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99
Q

Gefitinib Toxicities

A
  • fatigue
  • rash
  • diarrhea
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100
Q

Afatinib Target

A

All ErbB receptors (EGFR)

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101
Q

Afatinib MOA

A
  • covalent kinase inhibitor inhibitor
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102
Q

Common toxicities for drugs targeting EGFR

A

EGFR inhibitor associated rash

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103
Q

Common resistance mutation to Gefitinib

104
Q

Osimertinib MOA

A

covalent third generation EGFR inhbitor

105
Q

Osimertinib indication

A
  • effective against T790M mutant EGFR
106
Q

What two genes are genomically amplified in breast cancer?

A

HER2 and EGFR

107
Q

Lapatinib MOA

A
  • reversible inhibitor of EGFR and HER2
108
Q

Lapatinib targets

A

EGFR and HER2

109
Q

Side Effects of Lapatinib

A
  • N/V/D
  • decompensated heart failure
110
Q

Tucatinib MOA

A
  • TKI that preferentially binds to HER2
111
Q

Tucatinib Target

112
Q

FLT3 mutations

A
  • cytokine receptor important for hematopoietic cell survival and proliferation
  • mutations lead to increased proliferation and decreased apoptosis
  • acute myloid leukemia
113
Q

First generation FLT3 inhibitor

A
  • midostaurin (broad kinase inhibitor)
  • type I
114
Q

Second generation FLT3 inhibitor

A
  • crenolanib (more specific than first generation midostaurin)
  • type I
115
Q

Type II FLT3 inhibitors

A

Quizartinib (specifc for ITD mutations)

116
Q

What target is not driven by molecular diagnosticcs

A
  • VEGFR (tumor angiogenesis)
  • limited impact on disease
117
Q

Imatinib MOA

A

Type II small molecule inhibitor of the Abl tyrosine kinase to decreased proliferation and enhance apoptotic cell death in CML and GIST

118
Q

Imatinib Toxicities

A
  • n/v
  • fluid retention and edema
  • neutropenia and thrombocytopenia
119
Q

Treatment length for imatinib

120
Q

Ponatinib MOA

A
  • BCR-Abl inhibitor
  • effective against all the major mutant forms of BCR-Abl
121
Q

Indication for Ponatinib

A
  • inhibits the gatekeeper mutation of T315I that is resistant to all other BCR-Abl compounds
122
Q

Major drivers of Lung Cancer

A
  • Unknown
  • EGFR
  • KRAS
  • EML4-ALK
123
Q

EML4-ALK translocation

A
  • When ALK becomes inappropriately fused to ELM4 it becomes cytoplasmic and constitutively active
124
Q

Alectinib MOA

A

tyrosine kinase inhibitor of ALK

125
Q

Dabrafenib MOA

A

second generation BRAF-V600 inhibitor

126
Q

Indication of Dabrafenib

A
  • combination with trametinib for treatment of BRAF V600E/K mutant metastatic melanoma
127
Q

Trametinib MOA

A
  • inhibts the kinase activity of MEK1 and MEK2
  • Type III allosteric inhibitor
128
Q

Trametinib adverse reactiosn

A
  • rash
  • diarrhea
  • lymphedema
129
Q

Limitation of Trametinib use

A
  • not indicated for the treatment of patients who have received prior BRAF inhibitor therapy
130
Q

Bruton’s Tyrosine Kinase

A
  • important for normal B cell activity and B cell tumor growth
131
Q

What type of kinase inhibitor is Ibrutinib?

132
Q

BTK inhibitors

A

Ibrutinib
Acalabrutinib

133
Q

Acalabrutinib MOA

A
  • second generation covalent BTK inhibitor
  • also targets Cys481
  • more potent and selective than ibrutinib
134
Q

What type of kinase inhibitor is acalabrutinib

135
Q

Rapamycin Analogues

A
  • sirolimus
  • everolimus
136
Q

What do rapamycin analogues target

A

mTOR (serine-threonine kinase)

137
Q

Everolimus target

A

only mTORC1, not mTORC2

138
Q

Oncotype Dx

A

helps to predict recurrence and therefore can prevent overtreatment, do not drive indications for specific therapies

139
Q

What is the most dose-limiting toxicity of antimetabolites?

A

Myelosuppression

140
Q

What target DNA and RNA precursors

A

anti-metabolites target the synthesis of essential molecules in proliferating cells

141
Q

Purines

A

guanine, adenine

142
Q

Pyridines

A

thymine, cytosine

143
Q

MOA of pyrimidine analogs

A
  • interfere with pyrimidine nucleotide synthesis (5-FU, capecitabine)
  • Inhibition of DNA polymerase (Ara-C, Gemcitabine)
144
Q

Uridine analogs

A
  • primarily inhibit thymidine synthesis from uracil
145
Q

5-FU MOA

A
  • 5-FU is converted to FdUMP, which is an anlog of dUMP
  • FdUMP forms ternary complex with thymidylate synthase and tetrahydrofolate
  • this reaction cannot go to completion and thymidylate synthase is trapped
  • TMP cannot be produced
  • 5-FU also is converted into 5-UTP, which is incorporated into RNA and cannot be processed, affecting RNA stability
146
Q

5-FU resistance

A
  • downregulation of activating enzymes that convert 5-FU to FdUMP
  • upregulating thymidylate synthase
147
Q

5-FU susceptibility

A

~ 5% of the population has gene polymorphisms that result in deficiencyc of enzyme DPD which breaksdown 5-FU
- toxicity buildup

148
Q

Drug Rescue For 5-FU

149
Q

Drug Synergy of 5-FU

A

Leucovorate (increases the amount of covalent ternary complex with thymidylate synthase)

150
Q

Capecitabine MOA

A

orally active prodrug of 5-FU

151
Q

Cytosine Analogs MOA

A

primarily inhibit DNA synthesis

152
Q

Cytarabine (Ara-C)

A
  • Coverted to Ara-CTP intracellularly
  • Ara-CTP is a competitive inhibitor of DNA polymerase alpha
  • Cytidine deaminase converse cytarabine to non-toxic uracil arabinoside
  • decreased levels of cytidine deaminase in the CNS makes Ara-C highly toxic in meningeal leukemia and lymphoma
153
Q

Resistance mechanisms of cytarabine

A
  • downregulation of activating enzymes
  • upregulation of cytidine deaminase
  • downregulation of transporter to move drug into cells
154
Q

Gemcitabine vs Cytarabine

A
  • increased cell permeability
  • greater affinity for activating enzyme
  • better evasion of DNA repair enzymes
  • greater potency
155
Q

Synergy Cytarabine

A

Tetrahydrouridine (cytidine deaminase inhibitor) to increase efficaccy and decrease resistance

156
Q

Which drug is a nucleoside analog

A

Cytarabine

157
Q

Purine analogs

158
Q

6-MP MOA

A
  • inhibits multiple enzymes in the de novo purine biosynthesis pathway
  • blocks synthesis of purine nucleotides
159
Q

6-MP Metabolism

A
  • TPMT polymophisms increase risk of toxicity
160
Q

6-MP drug interactions

A

Xanthine oxidase inhibitors (allopurinol),
prevents the breakdown of 6-MP increasing toxicity

161
Q

Which drug does allopurinol not block the breakdown of

162
Q

Importance of Folic Acid

A
  • enters folate pool as dihydrofolate (FH2)
  • reduction to tetrahydrofolate by DHFR
163
Q

Inhibition of DHFR

A
  • reduces tetrahydrofolate pools
  • dihydrofolate (inactive folate) accumulates
164
Q

Methotrexate MOA

A

mimics folic acid, bind and inhibit DHFR

165
Q

Resistance to MTX

A
  • amplification of DHFR gene or mutation of DHFR
  • decreased polygultamation
166
Q

Pemetrexed

A
  • inhibitor of DHFR, thymidylate synthase, and glycinamide ribunucleotide formyltransferase
  • decreased risk of drug resistance
167
Q

Drug Rescue MTX

A

Leucovorin (increases intracellular pools of tetrahydrofolate and reverses toxic effects of DHFR inhibition)

168
Q

What are alkylating agents?

A

drugs that generate reactive electrophilic (electron deficient) intermediates that react with nucleophilic (electron rich) groups on DNA and proteins

169
Q

What is the most common site of alkylation

A

Guanine N7

170
Q

Most effective anti-cancer drugs are what?

A

bifunctional akylating agents that produce DNA intra- and interstrand linkages

171
Q

What part of the cell cycle do alkylating agents impact

A

not cell-cycle phase specific

172
Q

What in cells can react with alkylating agents and “quench” their activity?

A

Glutathione

173
Q

Side effects of alkylating agents

A
  • mutagenic and carcinogenic (second malignancies/leukemias)
  • normal cell populations rapidly proliferating (gut, bone marrow)
  • N/V, myelosuppresion, carcinogenic and teratogenic
174
Q

Chlorambucil

A

decrease nucelophilicity of nitrogen by adding aryl groups

175
Q

Cyclophosphamide MOA

A

chemically stable prodrug that requires hydroxylation of hepatic ccytochrome P450

176
Q

What byproduct does cyclophosphamide produce?

177
Q

Toxicities of cyclophosphamide

A
  • mild bone marrow toxicity
  • hemorrhagic cystitis
178
Q

Treating bladder toxicities caused by cyclophosphamide

179
Q

Mitomycin C (mutamycine)

A
  • aziridine containing natural product
  • funcctions as alkylating agent
  • bifunctional adducts
  • myelosuppression
180
Q

Platinum drugs

A
  • covalent crosslinkers, but not alkylating agents
  • often intrastrand
181
Q

Cisplatin MOA

A

aquo form is highly reacctive and a potent electrophile, reacts especially with thiols

182
Q

Dose limiting toxicity of ccisplatin

A

nephrotoxicity (proximal tubule

183
Q

other toxcities of cisplatin

A
  • severe N/V
  • minimal bone marrow toxicity
  • peripheral neuropathy dose related
  • ototoxicity
184
Q

Drug resistancce of cisplatin

A
  • increased intracellular concentration of non-protein thiols, especially glutathione
  • increased expression of cellular GST
185
Q

Mechanism of Action of Topoisomerase I Inhibitors

A
  • bind to and form ternary drug-enzyme-DNA complex, blocks DNA religation
186
Q

What phase of the cell cycle is most sensitive to Topo I

187
Q

Drug resistance to Topo I Inhibitors

A
  • Glutathione S-transferase overexpression (most important)
  • PGP overexpression
  • MRP overexpression
  • topoisomerase downregulation or mutation to prevent inhibitor binding
188
Q

Topo I Inhibitor Drugs

A

topotecan
irinotecan

189
Q

Ininotecan Mutation

A

SN-38 polymorphisms that cause low expression of UGT1A1, causing increased toxicity of Irinotecan

190
Q

Topo II Inhibitor MOA

A

inhibits Topo II to relieve torsional strain and untangles DNA

191
Q

What type of compounds are Topo 2 Inhibitors

A

only ones that produce double stranded DNA breaks

192
Q

Topo 2 Inhibitor Drugs

A

Anthracyclines (doxorubicin)
Etoposide

193
Q

Topo 2 Inhibitor mechanisms of toxicity

A
  • intercalators (AC)
  • free radical causes DNA damage
  • inhibition of Topo II presumed to be most important therapeutically
194
Q

What causes the cardiotoxicity seen with anthracycliens

A

free radical damage

195
Q

What part of the cell cycle do AC topo II inhibitors impact

A

non-cell cycle dependent

196
Q

Toxicities of doxorubicin

A
  • cardiotoxicity
  • severe local tissue damage if extravasated
  • read color
197
Q

Which topo II AC has less cardiotoxicity?

A

epirubicin

198
Q

Drug that mediates toxicity of anthracyclines

A
  • Dexrazoxane
  • protects against AC induced cardiotoxicity
199
Q

Etoposide MOA

A

Topo 2 inhibitor that does not intercalate

200
Q

What part of the cell cycle does etoposide topo 2 inhibitors impact

201
Q

Resistance to Topo II Inhibitors

A
  • Glutathione S transferase overexpression (doxorubicin only)
  • pgp overexpression
  • MRP overexpression
  • topo 2 downregulation or mutation
  • increased DNA damage repair
202
Q

What part of the cell cycle does bleomycin impact

A

G2 and M phases

203
Q

What is a dose limiting toxicity of bleomycin

A
  • pulmonary (myelosuppression is minimal)
  • skin rash
  • bleomycin is inactivated by bleomycin aminohydrolyase, which is in high concentrations everywhere but skin and lung
204
Q

What is dynamic instability?

A
  • shrinking and growing of microtubules
  • polymerization (build)
    -depolymerization (fall apart)
205
Q

What is bleomycin

A

Topo 2 intercalator

206
Q

Vinca alkaloids MOA

A

prevent microtubule assembly

207
Q

Taxanes MOA

A

prevent microtubule disassembly

208
Q

What drug requires a specific transporter to get into cells?

A

Vinca alkaloids (PGP)

209
Q

Vinca Alkaloids dose limiting toxicity

A

peripheral neuropathy
(myelosuppression rare)

210
Q

Eribulin vs vincristine

A

lower rate of neurotoxicity

211
Q

Microtubule Stabilzers

A

Taxanes and epothilones

212
Q

Taxanes MOA

A

blocks depolymerization and segregation of sister chromatids to daughter cells

213
Q

Resistance of Taxanes

214
Q

Dose limiting side effects of paclitaxel

A
  • myelosuppression
  • sensory neuropathy is reversible
215
Q

Cabazitaxel vs Paclitaxel

A
  • poor binding to PGP and MDR
  • more efficacious in multi drug resistant tumors
216
Q

Epothilones vs Taxanes

A
  • not cross resistant with taxanes
  • poor PGP substrate
217
Q

Epothilones toxicity

A
  • neurotoxicity like taxanes (reversible)
218
Q

mAb nomenclature: o

219
Q

mAb nomenclature: xi

220
Q

mAb nomenclature: zu

221
Q

mAb nomenclature: u

A

fully human

222
Q

Binding of several antibodies to a receptor on the surface of a cancer cell can lead to what?

A

CDC and antibody-dependent cellular toxicity (ADC)

223
Q

Trastuzumab MOA

A

recombinant humanized monoclonal antibody specific for HER2

224
Q

Trastuzumab Target

A

binds to HER2 receptor and induces recepter internalization and degredation

225
Q

Trastuzumab Toxicities

A
  • flu like symptoms
  • cardiomyopathy
  • risk of hypersensitivity reactions
226
Q

Pertuzumab MOA

A

recombanized humanized monoclonal antibody specific for HER2

227
Q

Pertuzumab Target

A

binds to HER2 and inhibitors dimerization (decreases signal)

228
Q

Indication of Pertuzumab

A

used in combination with Trastuzumab

229
Q

Cetuximab MOA

A
  • competitively inhibits binding of EGF and TGF-alpha
  • blocks phosphorylation and activation of receptor associated kinases
  • leads to inhibition of cell growth and induction of apoptosis
230
Q

Where does cetuximab and panitumumab bind to?

A

extracellular domain of the EGF receptor

231
Q

Toxicities of Cetuximab

A
  • severe infusion reactions in first dose
  • acneiform rash
  • asthenias
  • fever
232
Q

Bevacizumab MOA

A
  • Binds to VEGF and blocks interaction with endothelial receptors
  • blocks endothelial cell proliferation and new blood vessel formation
233
Q

Is VEGF mutated in cancer?

A

no!, not an oncogene

234
Q

Can bevacizumab be used as a monotherapy?

A

No, no evidence of efficacy as a single agnet

235
Q

Bevacizumab vs Ramucirumab

A
  • bevacizumab binds to the ligand
  • ramucirumab binds to the receptor
236
Q

What does rituximab target?

A

CD20 in B-cell non-hodgkin’s lymphoma

237
Q

What does daratumumab target?

A

Cd38 in multiple myeloma

238
Q

Trastuzumab Emtansine (T-DM1, Kadcyla) MOA

A

ADC consisting of cytotoxic agent emtansine linked to mAb trastuzumab

239
Q

Adverse effects of trastuzumab emtansine

A
  • AEs of trastuzumab
  • thrombocytopenia
  • hepatotoxicity
240
Q

Trastuzumab/Derextecan MOA

A

ADC consisting of Topo I inhibitor and mAb

241
Q

What is negative selection

A

strong affinity of immature T cell ans self MHC molecules that causes apoptosis

242
Q

What is positive selection

A

binding is just right where T cells survive

243
Q

Central tolerance

A
  • all high avidity self reactive T cells have been
  • need to empower T cells to kill cancers, which are often very different from self
244
Q

Strategies to overcome central tolerance

A
  • redirect T cells to cancer using genetic means
  • redirect T cells to cancer using recombinant proteins
  • lower the threshold to allow for targeting neo agents
245
Q

BiTE target

246
Q

BiTE drug

A

blinatumomab

247
Q

Blinatumomab MOA

A

bind CD3 to physically bring an activated T cell in proximity with CD19

248
Q

are BiTE drugs chimeric antibodies

249
Q

what do CTLA-4 and PD1 act as?

A

brakes or checkpoints on the immune system

250
Q

Ipilimumab MOA

A

bind CTLA-4 receptor and reverses the CTL inhibition

251
Q

What may be required with Ipilimumab?

A

high dose corticosteroids

252
Q

Pembrolizumab MOA

A

bind PD-1 receptor blocks interaction with PDL-1 which is expressed on T cells

253
Q

Sipulcel-T

A

PAP-GM-CSF to stimulate a patient’s own immune system to attack the cancer

254
Q

Side effects Sipulcel-T

A

flu like symptoms

possible increased risk of stroke

255
Q

CAR-T cell target

PHRM 864 (11 decks)

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