Lecture 5: Cancer Chemotherapy I Flashcards
1
Q
What is squamous cell carcinoma of the lung caused by?
A
- Cigarette smoking
- Squamous cell carcinoma causes keratin pearls
2
Q
Is adenocarcinoma caused by smoking?
A
NO
3
Q
What is malignant melanoma?
A
- Local invasion and lymph node metastasis
- Deeper → worse prognosis
4
Q
What are the most new cases of malignant cancer for males and females?
A
Males: prostate
Females: breast
pancreatic cancer is very rare but one of the most lethal cancers
5
Q
Which cancer(s) have the highest death rate?
A
Lung and Bronchus
6
Q
What induces mesothelioma directly?
A
Asbestos
mesothelioma → cancer covering outside lung
7
Q
Asbestos increases the risk of what cancer?
A
Increases the risk of squamous cell carcinoma in conjunction with cigarette smoking
8
Q
Does smoking increase the risk of mesothelioma?
A
NO
9
Q
What are the key disposing factors of Hepatocellular carcinoma?
A
- Chronic Hepatitis B
- Chronic Hepatitis C
- Alcoholism
- Aflatoxin exposure
epithelium have a glandular appearance
10
Q
Most cancer therapies are designed to be ____ toxic to malignant tumor cells
A
directly
try to kill tumor cells w/o injuring good normal cells
11
Q
What do most cancer therapies affect?
A
- affect DNA or RNA synthesis and protein synthesis downstream to affect tumor cell proliferation or survival.
- also affect normal cells and thus, both abnormal and normal cell proliferation is blocked, leading to toxicities
12
Q
What is a major goal of cancer therapy?
A
to remove or destroy all malignant cells and convert the malignancy into a chronic disease (i.e. palliation)
chronic disease could be HTN, diabetes, etc
13
Q
What is a big problem with chemotherapy?
A
Tumor cell resistance
14
Q
Because of tumor cell resistance how is chemotherapy given?
A
pt give a combination of chemotherapeutic regimens
15
Q
Tumor cells acquire additonal ____ to resist drugs
A
mutations
16
Q
Multidrug resistance from tumor cells can occur by what?
A
amplification of P- glycoprotein (MDR1) that pumps the drug out of the cell.
This is an ABC family co-transporter, that induces the efflux of drugs from cells in an ATP-dependent manner
17
Q
Because tumor cells acquire additional mutations to resist drugs, what is done to minimize that?
A
resistance is minimized by short-term, intermittent therapy with drug combinations
try to treat with alternative combinations of drugs so you can try and kill the mutated tumor early on
18
Q
What are the 4 key complications of cancer therapeutics?
A
- Bone marrow suppression
- Stomatitis
- Nausea and severe vomiting
- Hair loss
19
Q
What are 3 specific complications (side effects) of cancer therapeutics?
A
- Cyclophosphamide- severe cystitis
- Doxorubicin- cardiotoxicity
- Bleomycin- pulmonary fibrosis
HIGH YIELD
cystitis: inflammation of the bladder and hemorrhage
20
Q
Which drugs cause major and mild myelosuppression?
A
Major: Cyclophosphamide and Doxorubucin
Mild: Bleomycin
21
Q
Side effects of Cisplatin
A
- Ototoxicity
- Nephrotoxicity
- Nausea/vomiting
22
Q
Side effect of Doxorubucin
A
cardiotoxicity
23
Q
Side effect of Bleomycin
A
Pulmonary toxicity
24
Q
Side effects of Cyclophosohamide
A
Hemorrhagic cystitis
25
Side effect of **Oxaliplatin/Vincrisitne/ Taxanes**
peripheral neuropathy
## Footnote
taxol for breast cancer
microtubule inhibitor, can change stability of the tubule
26
What are the hallmarks of cancer? (what a malignant cells need to have
1. Sustaining proliferative signaling ( K-RAS)
2. Evading growth supressors (cell cycle-P53)
3. Activating invasion and metastasis
4. Enabling replicative immortality ( Telomerase/TERT)
5. Inducing angiosgenesis (VEGF)
6. Resisting cell death
27
True or false: Tumor cells interact w/ host
True, normal cells play a role and how they are responding to tumor cells
28
What is the greatest focus of therapeutic intervention?
Avoiding immune destruction
29
Adenoma to Carcinoma Sequence in Colon Cancer development
APC + APC + RAS (Adenoma) + P53 + Telemorase (Carcinoma)
30
What is Adenomatous polyposis?
A precursor for colonic adenocarcinoma
## Footnote
colonoscopy: look for polpys
31
What is familial polyposis?
A genetic cause of colonic adenocarcinoma. Mutation of APC gene: 5q-autosomal dominant disease
## Footnote
mutation of APC, 100% will get colon cancer bc its 1 allele
32
Conversion of normal human fibroblasts and epithelial cells into malignant tumor cells requires 4 genes. What are they?
| turning fibroblasts into tumor cells
The 4 genes activated:
1. Ras
2. SV40 large T antigen
3. SV40 small t antigen
4. TERT (telomerase)
## Footnote
when these 4 are mixed, in turns into tumor cells
33
List how each of these genes plays a role in being converted into a malignant state
1. Ras
2. SV40 large T antigen
3. SV40 small t antigen
4. TERT (telomerase)
1. Ras → stimulates signal transduction
2. SV40 large T antigen → blocks the cell cycle inhibitors p53 and Rb
3. SV40 small t antigen → blocks the activity of protein phosphatase 2A (PP2A)
4. TERT (telomerase) → allows for cell replicative immortality
## Footnote
Transduction of 4 individual genes into normal human cells can convert them into a malignant state.
most cancers have activated RAS and elevated TERT
34
What are specific chromosomal translocation leading to malignancy for **Chronic Myelogenous leukemia (CML)**?
Chr:9:22 Bcr-Abl Philadelphia chromosome
Classic finding: Splenomegaly
35
What are specific chromosomal translocation leading to malignancy for **Burkitt's Lymphoma**?
Chr:8:14
Myc amplification, pro growth
36
# Chemoterapeutic agents
What is a treament for Chronic Myleogenous leukemia (CML)
Imatinib: an inhibitor of Abl kinsae
## Footnote
has profound ability to induce remission
37
Imatinib MOA
Binds to Abl kinase in its inactive conformation and prevents its activation thus it has less toxicity
## Footnote
leukemic cells can become resistant to Imatinib through new mutations in Abl in the Bcr-Abl fusion protein
38
What are the new generations of Abl inhibitors to treat CML?
Dasatinib and Nilotinib (more potent and efficacious than Imatininb in treating CML)
39
What is breast cancer?
Invasive ductal carcinoma (invades lymph nodes very easily)
40
What are key genetic changes that underlie the development of breast carcinoma?
* Luminal-> *ER+ and HER2*-=BRCA2 and PIK3CA mutation
* HER2 enriched->*HER2+*= TP53 mutation and HER2 amplification
* Basal like-> *ER- and HER2-*= TP53 mutation and BRCA1 inactivation
41
What can identify metastatic carcinoma to a lymph node?
immunostaining can identify the malignant cells
## Footnote
how pathologists find tumor and characterize what it is
42
Explain therapeutic targeting of EGF receptors in epithelial cancers.
1. EGFR inhibitors are used for what cancers?
2. EC domain of EGFR?
3. IC domain of EGFR?
1. EGFR inhibitors are particularly utilized in **breast, lung, and colon cancers.**
2. *Blocking monoclonal antibodies* directed to the extracellular domain of EGFR
3. *Chemical inhibitors of the tyrosine kinase* activity of the EGFR intracellular domain
## Footnote
-resistance has been observed to both the antibody and chemical EGFR inhibitors
43
Examples of Combination Chemotherapeutic regimens
| slide 24
Combination Chemotherapeutic regimens are usually different drugs that inhibit diff things + antibodies mixed together
44
# Key chemotherapeutic agents: targets and mechanism of action
Protein kinase inhibitors antibodies MOA
| low yield
block activites of signaling pathways
45
# Key chemotherapeutic agents: targets and mechanism of action
Immune checkpoint inhibitors MOA
| low yield
block immune evasion
46
# Key chemotherapeutic agents: targets and mechanism of action
Hormone antagonists MOA
| low yield
inhibits receptor fxn and expression
47
# Key chemotherapeutic agents: targets and mechanism of action
Expothilones, Taxanes, Vinca Alkaloids, Estramustine MOA
| low yield
Inhibit fxn of microtubules
48
# Key chemotherapeutic agents: targets and mechanism of action
ATRA, Arsenic trioxide, Histone Deacetylase inhibitors MOA
| low yield
induce differentiation
49
How do chemotherapeutic agents target the cell cycle?
1. Messes up DNA, RNA, and protein synthesis
2. Trap cells in S-phase where DNA is replicated
3. Blocls M phase with tubulin needed for chromosome segmentation and for cells to divide
50
What are the cell cycle specific drugs?
* Antimetabolites
* Bleomycin
* Etoposide
* Vinca alkaloids
51
What are the cell cycle non-specific drugs?
Alkylating agents
Antibodies
Cisplatin
Nitosoureas
52
Anti-metabolites chemotherapeutic agents are structurally related to what? What do they interfere with and how?
* Compounds are structurally related to normal compounds
* Interfere with the availability of purine or pyrimidine nucleotide precursors
* This interference occurs by inhibiting synthesis or by competing with normal precursors during DNA or RNA synthesis.
## Footnote
enzymes picks them up thinking they are normal cmpds
53
Anti-metabolites chemotherapeutic agents have maximal cytotoxic effecs during what phase of the cell cycle?
S-phase (dna replication)
54
True or false: Methotrexate (MTX) is usually used in combination regimens
True
## Footnote
MTX is a folate-related molecule important in pregnancy and closing the neural tube. low folate-anemia (need for RBC production)
55
MTX is used in which cancers?
ALL, Burkitt’s lymphoma, breast cancer and other solid tumors
56
-5-FU anti-metabolite is used for which cancer(s)?
used in slowly growing tumors including colon, breast, ovarian, pancreatic and gastric cancers
57
-5-FU is coadministered with what?
**Leucovorin** to enhance inhibition of thymidylate synthase
58
MOA of MTX anti-metabolites
MTX **targets dihydrofolate reductase**, which is necessary to create reduced folate isoforms, FH2, FH4, and N5, N10- methylene-FH4 that are required to generate dTMP
## Footnote
blocks synth of folate isoforms that are required to generate dTMP
59
-5-FU anti-metabolite MOA
5-FU **targets thymidylate synthase** which generates dTMP from dUMP, a reaction that also requires N5, N10-methylene-FH4
## Footnote
TS generates dTMP from dUMP requires N5, N10-methylene-FH4
60
Leucovorin (N5-formyl-FH4) anti-metabolite MOA
converted to N5, N10- methylene-FH4 and **bypass the effects of MTX, which can cause key side effects including megaloblastic anemia**
61
Function of Capecitabine
| Antimetabolite
## Footnote
Low yield
Metabolized to 5-FU can show less toxicity due to more selective conversion to 5-FU within the tumor.
62
Function of Cytarabine
| Anti-metabolite
## Footnote
Low yield
acts as a pyrimidine analog, inhibits RNA processing, used to treat AML, inhibits DNA polymerase
63
Function of Azacitidine
| Anti-metabolte
## Footnote
Low yield
Is a pyrimidine analog, inhibits RNA processing, used to treat AML
64
Function of Gemcitabine
| Antimetabolite
## Footnote
Low yield
Used in pancreatic cancer and non-small cell lung cancer therapy, metabolites block DNA synthesis
65
Which of the following chemotherapies has a side effect of pulmonary fibrosis?
a. Cyclophosphamide
b. Doxorubicin
c. Bleomycin
c. Bleomycin
66
Which of the following describes Familial polyposis?
a. APC, 5Q autosomal dominant disease
b. BCR-ABL translocation
c. Myc amplification
d. None of the above
a. APC, 5Q autosomal dominant disease
67
Which of the following corresponds to the translocation (9:22)(q34:q11) Abl-BCR ?
a. CML
b. AML
c. Burkits lymphoma
d.Follicular lymphoma
a. CML
68
Which of the following EGFR targeted therapeutic treatment binds extracellularly?
a. Cetuximab
b. Osimertinib
c. Gefitinib
d. Afatinib
a. Cetuximab
69
What gets administered with methotrexate to prevent megablastomic anemia?
a. 5FU
b. Leucovorin
c. Cytarabine
d. Azacitidine
b. Leucovorin
