1
Q
What is combination chemotherapy?
A
- Combination: use multiple different drugs at the same time or in specific sequence
2
Q
What is adjuvant chemotherapy?
A
Adjuvant: use drugs after surgery to remove residual or metastatic cells
3
Q
What is neoadjuvant chemotherapy?
A
Neoadjuvant: use drugs before surgery to reduce tumor mass and to initiate chemotherapy sooner
4
Q
Compare and contrast cell-specific and cell-nonspecific drugs.
A
- Specific: target a unique phase in the cell cycle (vinca alkaloids poison mitotic spindle)
- Nonspecific: kill cells regardless of phase (DNA damaging drugs)
5
Q
What order of reaction is cell killing?
A
First order.
6
Q
What percentage of cells are killed with 1 log kill drugs, 2 log kill drugs, and 3 log kill drugs?
A
- 1 log kill drug = 90% cells killed
- 2 log kill drug = 99% cells killed
- 3 log kill drug = 99.9% cells killed
7
Q
Why are intermittent therapies used to treat cancer?
A
Intermittent therapies are used to kill as many cancer cells possible without killing the patient
8
Q
What are drug transporters, the gene encoding them, and how do they cause drug resistance?
A
- Drug Transporters: ATPases that transport small molecules out of the cell
- P-glycoprotein encoded by mdr1 gene
- Upregulation causes more drug to be pumped out
9
Q
Describe the four principles of combination chemotherapy.
A
- Non-overlapping toxicities
- Targets are in different phases of cell cycle
- Have different mechanisms of action
- Have different mechanisms of resistance
10
Q
What is the main function of alkylating agents?
A
covalently binds to DNA
11
Q
What are examples of alkylating agents, the general mechanism of action, and side effects?
A
- Examples: Nitrogen mustards, cisplatin, temozolomide (TMZ)
- MOA: effectively attacks DNA of dividing cells
- Side Effects: non-specifically attacks normal dividing cells
- Hair follicles: hair loss
- RBCs: anemia
- WBCs: immunosuppression
- Epithelial cells of GI tract: GI issues
12
Q
What is the overall function of antimetabolites?
A
inhibits synthesis of DNA
13
Q
What is the mechanism of action of the antimetabolite methotrexate? Why is leucovorin used as a “rescue”?
A
- MOA: folate analog that binds dihydrofolate reductase (DHFR)
- DHFR is critical enzyme in purine and thymidine synthesis
- Leucovorin is THF that is selectively uptaken by specific expressed transporter only in normal cells to ensure survivability of normal cells during chemotherapy treatment
14
Q
What is the mechanism of action of the antimetabolite 5-fluorouracil?
A
MOA: uracil analog that binds thymidylate synthase, preventing conversion of dUMP to dTMP
15
Q
- Describe how the conversion of dUMP to dTMP occurs. What enzyme is used?
- Describe how the conversion of DHF to THF occurs. What enzyme is used?
A
16
Q
What is the mechanism of action of hydroxyurea?
A
MOA: inhibits ribonucleotide reductase, prohibiting conversion of ribose to deoxyribose for use in DNA synthesis
17
Q
What is the main mechanism of action in antitumor antibiotics?
A
disrupts DNA structure and function
18
Q
What are several examples of antitumor antibiotics and what is their mechanism of action?
A
- Examples: anthracyclines, dactinomycin, and bleomycin
- MOAs
- Intercalation into DNA – structure is flat so they can slide between base pairs of DNA, preventing DNA and RNA polymerases from acting
- Generation of ROS – causes DNA cleavage
- Binding to cell membranes – hydrophobic regions disrupt processes
19
Q
What does the upregulation of L-asparaginase do in cancer cells? What is the enzyme it counteracts and the two amino acids being interconverted.
A
- Function of L-asparaginase is to convert asparagine to aspartate intracellularly
- Function of Asparagine synthetase is to convert aspartate to asparagine intracellularly
- In cancer cells, existing low levels of Asparagine synthetase and induced high levels of L-asparaginase → insufficient [asparagine] → decrease in protein synthesis and cell growth
20
Q
What is the main function of antimitotic agents?
A
block microtubule functions
21
Q
What are the three different types of the antimitotic agents, microtubule inhibitors? What are the two contrasting mechanisms of action? What phase of the cell cycle do these drugs work in?
A
- Vinca alkaloids
- MOA: prevents assembly of microtubules by binding to tubulin dimers that go into structure
- Taxanes
- MOA: prevents disassembly of microtubules by binding to assembled microtubules
- Estramustine
22
Q
What are the two different types of the antimitotic agents, topoisomerase inhibitors? What is one example of each? What are the two contrasting mechanisms of action? What phase of the cell cycle do these drugs work in?
A
- Occurs in S phase
- Topoisomerase II inhibitors
- Example: etoposide
- MOA: topoisomerase II induces ds breaks to unwind DNA and inhibitors prevent resealing by the enzyme
- Topoisomerase I inhibitors
- Example: topotecan
- MOA: collision between replication fork and topoisomerase I – DNA complex → ds breaks → cell death
23
Q
What is the main function of hormonal agents?
A
affect signaling through steroid receptors
24
Q
What is one example and the mechanism of action of glucocorticoids, a type of hormonal agent?
A
- Prednisone
- MOA: used for liquid tumors to bind to intracellular receptors and affect gene transcription
25
What is the mechanism of action of progestin, a type of hormonal agent? What is one cancer it is used to treat?
* MOA: agonists for PRs; triggers cell differentiation of immature cancer cells
* Used to treat endometrial cancer
26
What are two examples of drugs and their mechanism of action of antiestrogens, a type of hormonal agent?
* Tamoxifen, fulvestrant
* MOA: inhibits ERs
27
What is the mechanism of action of aromatase inhibitors, a type of hormonal agent? Who is it given to? What is one example of a drug used?
* Anastrozole
* Given to post-menopausal women
* MOA: acts by inhibiting aromatase which prevents conversion of antrostenedione to estrone in the adrenal gland
28
What is the mechanism of action of antiandrogens, a type of hormonal agent? What is one example of a drug? What type of cancer is it used to treat?
* Enzalutamide
* MOA: androgen receptor antagonists
* Used to treat prostate cancer
29
What is the mechanism of action of overstimulation of LHRH and GnRH receptors?
Overstimulation of LHRH and GnRH receptors with LHRH and GnRH analogues → negative feedback inhibition → internalization and desensitization of receptors → decrease in testosterone and estrogen
30
What is the main function of signaling inhibitors?
block critical signaling pathways
31
What are six different drugs used that inhibit RTKs? What does each selectively inhibit?
* Gleevec – selective inhibitor of Bcr-Abl
* Gefitinib – selective inhibitor of EGFRs
* Erlotinib – selective inhibitor of EGFRs for palliative care treatment
* Trastuzumab – selective inhibitor of HER2
* Cetuximab – selective inhibitor of EGFRs
* Rituximab – selective inhibitor of CD20 antigen
32
What is one example of a angiogenesis inhibitor? What RTK does it selectively inhibit?
Bevacizumab – selective inhibitor of VEGF
33
What is one example of a proteasome inhibitor?
Bortezomib – specific and reversible inhibitor of proteasomes that degrades pro-apoptotic proteins
34
What are -nib, -mab, and -mib classes of drugs?
* -nib class of drugs act on RTKs
* –mab class of drugs are monoclonal antibodies that bind to extracellular receptor or to the hormone
* monoclonal because only antibody produced by immune cell
* –mib class of drugs act on intracellular receptors
35
What are the functions and locations of epithelium?
* Epithelium
* Functions: absorption, secretion, transport, excretion, protection, sensory reception
* Locations: cells of organs, covering of all surfaces, glands, and sensory organs/structures
36
What are the functions and locations of connective tissue?
* Connective Tissue
* Functions: support, protection, movement
* Locations: tendons, ligaments, fascia, supportive fibrous, muscle, nerve, blood vessels, adipose tissue, bone, cartilage, dermis
37
What are the functions and locations of hematopoietic tissue?
* Hematopoietic Tissue
* Functions: immune and other defense/surveillance mechanisms, oxygen transport
* Locations: blood, bone marrow cells, and cells of related organs (lymph node, spleen, marrow)
38
What are the 5 different characteristics common to all epithelia?
* Closely aggregated cells
* Cell-to-cell adhesion
* Polarized – apical and basolateral surfaces
* Attachment to basement membrane
* Avascular
39
What are the four important criteria for classifying epithelia?
* Number of layers
* Shape of cells
* Modifiers
40
Identify the types of epithelia based on number of layers.
* Simple: single layer
* Stratified: two or more layers (look at most superficial layer)
* Pseudostratified: all cells attached to basement membrane with nuclei at varying heights
* Transitional/Urothelium: stretchy layers
41
What are the two different type of modifiers of epithelia?
* Ciliated – moves substances across surface
* Keratinized – exists on surface of skin for protection
42
For Simple Squamous epithelia,
* What do they look like?
* Where are they found?
* What is their function?
* Simple Squamous
* Fried egg structure
* Found in lining of cavities (mesothelium) and lining of blood vessels (endothelium)
* Function: filtration, exchange, barrier
43
For Simple Cuboidal epithelia,
* Where are they found?
* What is their function?
* Simple Cuboidal
* Found in glands and tubules
* Function: absorption, secretion, barrier, and conduit
44
For Simple Columnar epithelia,
* Where are they found?
* What is their function?
* What modifications can they have?
* Simple Columnar
* Found in GI tract
* Function: absorption and secretion
* Can be ciliated (respiratory tract and fallopian tube)
45
For Stratified Squamous epithelia,
* Where are they found?
* What is their function?
* Stratified Squamous
* Found in mouth, skin, and vagina
* Can have keratin (epidermis)
* Function: barrier and protection
46
For Stratified Cuboidal epithelia,
* Where are they found?
* What is their function?
* Stratified Cuboidal
* Found in gland ducts
* Function: conduit (transports between gland and lumen)
47
For Stratified Columnar epithelia,
* Where are they found?
* What is their function?
* Stratified Columnar
* Found in large exocrine gland ducts and anorectal junction
* Function: barrier and conduit
48
For Transitional/Urothelium epithelia,
* Where are they found?
* What is their function?
* How can they be identified?
* Transitional/Urothelium (changes based on the degree of stretch)
* Found in urinary tract
* Function: barrier and dispensability (stretch)
* Can be identified by the rounded snout on the apical surface
49
For Pseudostratified columnar epithelia,
* How do they appear?
* Where are they found?
* What is their function?
* How can they be modified?
* Pseudostratified Columnar
* All cells attached to basement membrane with nuclei at varying heights
* Found in: respiratory system and male reproductive tract
* Function: secretion, absorption, and conduit
* Can be ciliated
50
Identify the epithelia.
Simple Squamous
51
Identify the type of epithelia
Pseudostratified Columnar
52
Identify the type of epithelia.
Stratified Squamous
53
Identify the type of epithelia.
Simple Cuboidal
54
Identify the type of epithelia.
Transitional/Urothelium
55
Identify the type of epithelia.
Stratified Cuboidal
56
Identify the type of epithelia.
Simple Columnar
57
Identify the type of epithelia.
Stratified Columnar
58
Define Cell Adhesion proteins.
* Cell Adhesion Proteins: keep cells in epithelium attached together to allow for protection, barrier, communication
59
What is the complex involved in cell adhesion proteins and what are its 4 main constituents?
* Terminal bar/junctional complex
* Zona occludens
* Zona adherens
* Macula adherens (desmosomes)
60
Define polarity in terms of epithelial tissue.
The ability to discern the lateral domain, basal domain, and the apical domain from each other.
61
What is the function of lateral domain and define lateral infoldings?
Lateral domain (cell junctions)
* Occluding- selective permeability, barrier, preservation of domains
* Anchoring
* Communicating
* Lateral infoldings – allow increase area for communication
62
What is the function of the apical domain?
* Apical domain (lumen side)
* Surface specializations (cilia, etc.)
63
What is the function of the basal domain and what is another name for basal domain?
* Basal domain
* Basement membrane, anchoring junctions
64
What are the three types of motility/surface area mechanisms used in our body?
* What are their functions?
* Microvilli – cytoplasmic processes containing a core of actin filaments
* Increase surface area/absorption
* Stereocilia (microvilli of unusual length)
* Increase surface area/absorption
* Cilia
* Cytoplasmic processes containing bundle of microtubules
65
What are the 4 cellular adaptive processes?
* Hypertrophy
* Hyperplasia
* Atrophy
* Metaplasia
66
Define hypertrophy and where does hypertrophy occur?
* Hypertrophy
* Occurs in terminally differentiated cells due to more structural proteins
* Increase in size of cells
67
Define hyperplasia.
* Hyperplasia
* Increase in number of cells in an organ due to outside stimulus (i.e. breast during pregnancy due to hormones)
* Can occur simultaneously with hypertrophy
68
Define atrophy. What processes are decreased in atrophy?
* Reduction in number of cells due to decreased protein synthesis and increased protein degradation
69
Define metaplasia.
* Metaplasia
* Reprogramming of stem cells to differentiate to adapt to and resist stimulus
70
Identify the type of necrosis.
* In its appearance, what are its microscopic features?
* What are features of its gross appearance?
* Liquefactive necrosis
* Gross: produces a gelatinous and purulent (aka pus)
* Microscopic: infiltration of ghost cells and debris by neutrophils (multilobed)
71
Identify the type of necrosis.
* In its appearance, what are its microscopic features?
* What are features of its gross appearance?
* Caseous necrosis
* Gross: cottage cheese appearance
* Microscopic: cell debris walled off by WBCs
72
Identify the type of necrosis.
* In its appearance, what are its microscopic features?
* What are features of its gross appearance?
* Coagulative necrosis
* Gross: occurs after an ischemic event and the architecture is preserved (wedge shape)
* Microscopic: ghost cells maintain cell outline
73
Identify the type of necrosis.
* In its appearance, what are its microscopic features (necrotic)?
* What are features of its gross appearance?
* Fibrinous necrosis
* Microscopic: autoimmune deposits of antigen-antibody onto blood vessel walls
* Inflammation of blood vessels (vasculitis) causes pinkish tint
* No gross appearance as it cannot be visualized grossly
74
What does normal fibrinous tissue look like?
75
Identify the type of necrosis.
* In its appearance, what are its microscopic features (necrotic)?
* What are features of its gross appearance?
* Gangrenous necrosis
* Gross: skin looks black and dead
* Microscopic: initially coagulative necrosis (dry) and then liquefactive necrosis (wet)
76
Differentiate necrosis from apoptosis.
* Necrosis is initiated by exogenous stimuli leading to the denaturation of cellular components
* Has inflammation
* Apoptosis is initiated by intracellular signals and leads to phagocytosis
* Does not have inflammation response
* Caused by deprivation of GFs or from radiation/chemotherapy
77
What are the three protective mechanisms of inflammation?
* Three protective mechanisms of inflammation
* Eliminate necrotic tissue
* Destruction of etiologic agent
* Initiate repair
78
What are the five signs of inflammation?
SHARP
* Tumor – **S**welling
* Calor – **H**eat
* Function is **A**ltered
* Rubor – **R**edness
* Dolor – **P**ain
79
For acute inflammation,
* What is the gross appearance?
* What is the microcopic appearance?
* What occurs to the blood vessels?
* What is an example?
* Exudation of fluid (high protein, thick fluid)
* Neutrophilic infiltration (multilobed)
* Vasodilation with increased vascular permeability
* Example: acne
80
For chronic inflammation,
* What occurs to the blood vessels?
* What occurs on a microscopic level?
* Provide an example.
* Chronic inflammation
* Scarring of angiogenic vasculature
* Leukocyte infiltration (mononuclear)
* Example: rheumatoid arthritis (autoimmune)
81
Define differentiation.
* Differentiation – extent to which neoplastic cells resemble normal cells morphologically and functionally.
82
Differentiate neoplasia from hyperplasia, metaplasia, and dysplasia by defining each one of them.
* Neoplasia: irreversible and uncontrolled growth from a clonal cell
* Hyperplasia: increase in number of cells
* Metaplasia: replacement of one cell type with another
* Dysplasia: “disordered growth” from loss of uniformity and loss of organization of individual cells
83
What are the two factors important for classifying neoplasms?
* By type of cell type in which the neoplasm originates
* By primary site, or the location in the body in which the neoplasm originates
84
Define what a neoplasm with only the suffix -oma implies.
* **-Oma** implies benign (exceptions include lymphoma, melanoma, seminoma)
85
Define carcinoma.
* **Carcinoma** – malignant and usually sqamous epithelial
86
Define adenocarcinoma.
* **Adenocarcinoma** – malignant and from cuboidal and columnar cells (they function as absorbing and secreting)
87
Define sarcoma.
* **Sarcoma** – malignant and mesenchymal/connective tissue
88
Define lymphoma/leukemia
* **Lymphoma/Leukemia** – malignant and lymphoid (lymphoma)/hematpoietic (leukemia)
89
Define the prefix Leiomyo.
* **Leiomyo** – smooth muscle prefix
90
What are the four characteristics of benign?
Characteristics of Benign
* Welly differentiated
* Slow growth
* Non-invasive
* No metastasis
91
What are the four characteristics of malignant?
Characteristics of Malignant
* Poorly differentiated
* Rapid growth
* Invasive
* Metastasis
92
What are the six features of malignant neoplasms?
Malignant Neoplasms
* Pleomorphism – nuclei vary in shape and size
* Nuclear changes – hyperchromasia (dark chromatin), prominent nucleoli (increased rRNA – lots of protein synthesis), and increased Nucleus/Cytoplasm ratio
* Increased mitotic activity and abnormal mitoses
* Loss of polarity – inability to differentiate between basal and apical cells
* Giant cells
* Anaplasia – lack of differentiation, encompasses many of the above features
93
What are the definitions of the following:
* Idiopathic
* Iatrogenic
* Congenital
* Acquired
* Nosocomial
* Multifactorial
* Idiopathic – no identifiable cause
* Iatrogenic – occur as a result of medical treatment
* Congenital – disease existing at birth or before birth, occurs during development of fetus
* Acquired – develops in postnatal period
* Nosocomial – due to being in a hospital environments
* Multifactorial – combination of causes (genetic and environmental)
94
Define in-situ in terms of tumors.
* In-situ – confined to a structure and is pre-malignant
95
Define well differentiated and what kind of grade is usually indicated with a well-differentiated tumor?
* Well differentiated – mimics normal structures; low grade
96
Define poorly differntiated and what sort of grade is indicated in poorly differentiated tissue?
* Undifferentiated – loss of all differentiating/distinguishing features in the tissue; high grade
97
What is the difference between grading and staging?
* Grading is based on histologic appearance (mitotic spindles, differentiation of tissue)
* Staging is based on tumor size, presence in lymph nodes, and presence of metastasis
* Presence of metastasis automatically makes cancer a stage four
SPM
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