Lecture 7 - Anticancer Meds Flashcards
1
Q
Cancer
A
also known as a malignant tumor or malignant neoplasm, is a group of diseases involving abnormal cell growth with the potential to invade or to spread to other parts of the body
2
Q
____ have a higher chance of getting cancer and a higher chance of dying earlier
A
men
3
Q
List the 3 top cancers for men and women in Canada
A
Men:
1) Prostate
2) Colorectal
3) Lung
Women:
1) Breast
2) Lung
3) Colorectal
4
Q
Cancer is primarily a disease of ____ age
A
old
5
Q
Malignant
A
if tumor invades surrounding tissue (cancerous)
6
Q
Benign
A
if tumor has no effect on surrounding tissue (non-cancerous)
7
Q
Metastatic
A
if individual cells break away and start a new tumor elsewhere (cancerous)
8
Q
Describe the path to cancer
A
-Clonal proliferation
-Starts from a single cell
-Expansion in steps
-Pre-malignant states
(Polyp, MDS, MGUS)
-Serial accumulation of mutations
(Clonal evolution, resistance)
9
Q
List some hallmarks of cancer
A
- Self sufficiency in growth signals
- Insensitivity to anti-growth signals
- Evading apoptosis
- Limitless reproductive potential
- Sustained angiogenesis
- Tissue invasion and metastases
- Genomic instability
10
Q
Is cancer a genetic disease?
A
Yes
11
Q
Cancer arises from the accumulation of _____ changes (somatic mutations)
*Genetic selection at the level of single cells
A
genetic
12
Q
Most cancers incur a minimum of ______ different gene mutations
A
5 (6-9)
13
Q
We don’t inherit cancer but we do inherit _______ to cancer
A
dispositions (susceptibility)
14
Q
_______ is a hallmark of cancer cells
A
Aneuploidy
15
Q
What is aneuploidy?
A
The presence of an abnormal number of chromosomes in a cell
16
Q
2 components of Etiology of cancer
A
Nature:
-What we inherit
Nurture
-Environmental factor (what we do to our body) ex. smoking, UV radiation, etc.
17
Q
You need an _____ and an elongated promoter to lead to cancer
A
initiator
18
Q
Tumor initiators = ______
A
mutagens
19
Q
Tumor Promoters = _____ ______
A
proliferation inducers
20
Q
List some tumor initiators (mutagens)
A
- X rays
- UV light
- DNA alkylating agents
21
Q
List some tumor promoters (proliferation inducers)
A
- Phorbol esters
- Inflammation
- Alcohol
- Estrogens and Androgens
- Epstein-Barr Virus
22
Q
Cell cycle phases:
G1 (gap phase)
A
the cell grows and prepares to synthesize DNA
23
Q
Cell cycle phases:
S (synthesis phase)
A
in which the cell synthesizes DNA
24
Q
Cell cycle phases:
G2 (second gap phase)
A
in which the cell prepares to divide
25
Cell cycle phases:
| M (mitosis phase)
cell division occurs
26
Cell cycle phases:
| G0 (arrest/quiescent)
cell is in resting state
27
Cell cycle phases:
| Checkpoint 1
G1/S checkpoint:
| Cell monitors size and DNA integrity
28
Cell cycle phases:
| Checkpoint 2
G2/M checkpoint:
| Cell monitors DNA synthesis and damage
29
Cell cycle phases:
| Checkpoint 3
M checkpoint:
| Cell monitors spindle formation and attachment to kinetochores
30
What protein complexes are involved in the cell cycle?
- Cyclins
| - Cyclin dependent kinases (Cdks)
31
Are Cdk (cyclin dependent kinases) levels stable?
yes
32
Are cyclin levels stable?
no they change throughout the cell cycle
33
The ability to drive through the checkpoint are reliant on ??
cyclins and cdks (oncogenes)
*cdk = cyclin dependent kinase
34
Cdks must bind to the correct ___ in order to function
cyclin
35
What do kinases do?
enzymes that add phosphate groups to proteins to convert them from an "off" to an "on" state
36
Describe the pathogenesis of cancer:
_____ are activated
___ ______ ____ are inactivated
Oncogenes are activated
Tumor suppressor genes are inactivated
37
Oncogene = ?
gas pedal
38
Tumor suppressor genes = ?
brakes
39
What is p53?
a class tumor suppressor
40
What is Rb?
also a classic tumor suppressor
41
Rb binds to a protein called ____
E2F1
*when bound to Rb, E2F1 can't function
42
_______ = drives cell cycle forward and bypasses checkpoints
Oncogenes
43
______ = an amplified oncogene
HER2/neu
*a growth factor receptor
44
25-30% of ____ cancers over-express HER2/neu
breast
45
____ is used as a treatment for breast cancers that over-express HER2/neu
Herceptin
46
___ = a frequently mutated oncogene
Ras
47
Translocations can be ? (2)
- Balanced
| - Reciprocal
48
Aneuploidy can be ? (4)
- Pseudodiploid
- Hyperdiploid
- Complex
- Random loss or gain
- Loss of tumor suppressor function
- Proto-oncogenic gain of function (into oncogene)
49
What is the Philadelphia chromosome?
- Translocation between chromosome 22 and chromosome 9
- Classic oncogenic rearrangement associated with a variety of leukemias
- BCR-ABL tyrosine kinase fusion
- Imatinib (Gleevec) is an Abl-kinase targeted tyrosine kinase inhibitor (TKi) used in the treatment of the Ph+ CML and other tumors
50
When is chemotherapy most effective?
when growth fraction is high
51
Describe early stages of tumour growth?
- high growth fraction
| - short doubling times
52
Describe late stages of tumour growth?
- low growth fraction
| - long doubling times
53
Benign = ?
non-cancerous
| "polyp"
54
Malignant = ?
cancerous
55
Malignant epithelial = ?
carcinoma
56
Malignant mesenchyme = ?
sarcoma
57
Malignant hematopoietic = ?
leukemia, lymphoma, myeloma
58
Hyperplasia
increased number of cells
59
Hypertrophy
increased size of cells
60
Dysplasia
disorderly proliferation
61
Neoplasia
abnormal new growth
62
Anaplasia
lack of differentiation
63
Tumor
originally meant any swelling, but now equated with neoplasia (abnormal new growth)
64
Metastasis
growth at a distant site
65
Bening tumor ends in "___"
"oma"
ex. adenoma
ex. fibroma
ex. lipoma
66
Malignant cancer ends in ______ or ______
carcinoma or sarcoma
ex. adenocarcinoma
ex. fibrosarcoma
ex. liposarcoma
ex. leukemia and lymphoma (don't follow the rule wtf)
67
Describe the stages of tumor progression
- Hyperplasia
- Dysplasia
- Carcinoma in situ (not cross the basal lamina)
- Cancer (malignant tumors) - Metastasis
68
_____ = non-invasive
benign
69
_____ = invasive/metastatic
malignant
70
How do we classify cancers?
Grade - How bad do the cells look?
Stage - Where has the cancer spread?
```
T = Tumour
N = Nodes (Lymph)
M = Metastases
```
71
Grade 1 Cancer
Well differentiated
72
Grade 2 Cancer
Moderately differentiated
73
Grade 3 Cancer
Poorly differentiated
74
Grade 4 Cancer
Anaplastic (now all the cells look really different)
75
As the cancer stage increases, survival rates ____
decrease
76
If cancer spreads to another part of the body, it keeps it's old _____
name
For ex. if kidney cancer spreads to the lungs, it is called kidney cancer which has metastasized to the lung
77
List some cancer factors affecting outcome
- Growth fraction
- Doubling time
- Type
- Stage
- Resistance
78
List some patient factors affecting outcome
- Overall health
- Bone marrow capacity
- Liver function
- Kidney function
- Age
- Compliance
79
Describe radiation
- Ionization and excitation of atoms that kills cells
- Cell killing, nausea, vomiting, fatigue, somnolence
- Late effect; fibrosis and gliosis
- Skin and mucosal reactions are accentuated by other modalities like chemotherapy
-Definitive, adjuvant, palliative
80
Purpose of primary chemotherapy
shrink of eliminate tumor
81
Purpose of neoadjuvant chemotherapy
make tumor more amenable to other therapies
82
Purpose of adjuvant chemotherapy
eradicate micro metastasis
83
Purpose of palliation chemotherapy
symptom control
84
What does CR Response to chemotherapy mean?
complete disappearance for at least 1 month
85
What does PR Response to chemotherapy mean?
50% of > reduction in tumor size or markers and no new disease for 1 month
86
What does SD Response to chemotherapy mean?
no reduction or growth
87
What does Progression Response to chemotherapy mean?
25% increase in tumor size
88
What are some cell cycle specific agents?
- antimetabolites
| - vinca alkaloids
89
What are some cell cycle non-specific agents?
- doxorubicin
| - cisplatin
90
Drugs that act only on a specific portion of the cell cycle (CCS) drugs will be least effective at treating cancers who have ____ growth fractions
low
91
It is common to follow treatment with a _____ drug with a ____ drug so that cancer cells are recruited into the cell cycle, where CCS drugs can be more effective
follow treatment with a NCCS drug with a CCS drug
92
CCS:
| Plant alkaloids target which phase?
G2-M
93
CCS:
| DNA synthesis inhibitors target which phase?
S
94
CCS:
| They are ____ dependent (duration and timing more important than dose)
scheduele
95
CCS:
| Only ___ cells killed
proliferating (high growth factor tumors preferentially eliminated)
96
NCCS:
| What cells are killed?
Both proliferating and non-proliferating cells are killed (attack both high and low growth factor tumors)
97
NCCS:
| They are ___ dependent (total dose is more important than schedule)
dose
98
Why are cancer chemotherapeutics typically given in cycles?
to allow normal cells time to recover from the treatment
99
Fractional kill hypothesis:
In order to reduce the impact of the recovery/resistance problem, the key principles to antineoplastic drug therapy are:
? (3)
- Use high doses (including increasing doses during treatment; called DOSE ESCALATION)
- Minimize recovery intervals (cell kill hypothesis)
- Employ sequential scheduling during combination therapy
100
What are some critical factors to treatment?
- Early start to the treatment
- Treatment must continue past the time when cancer cells can be detected using conventional techniques
- Appropriate scheduling of treatment courses and care to ensure sufficient log-kill is obtained are also crucial factors that enable success
101
List 3 types of chemotherapy treatments
1) Inhibitors of cell growth (Growth Factor Proteins ex. hormones)
2) Inhibitors of DNA Duplication
3) Inhibitors of Cell Division
102
Describe the wide range of drugs for chemotherapy
1) Non cell cycle dependent (Genotoxic agents)
2) Cell cycle dependent
- Cytoskeletal inhibitors
- Topoisomerase inhibitors
- Antimetabolites
- Hormonal therapy
3) Others
103
What drugs are cell-cycle independent?
- Platinating agents
| - Alkylating agents
104
What drugs target S phase?
- Vinca alkaloids
- 5-fluorouracil
- Methotrexate
- Hydroxyurea
- Doxorubicin
- Cytarabine
- Gemcitabine
- Etoposide
105
What drugs target G2 phase?
-Bleomycin
106
What drugs target M phase?
- Taxanes
- Vinca alkaloids
- Etoposide
107
look at slide 82 for a review man
omg if i have time man
108
Genotoxic agents are ?
non cell-cycle specific
| NCCS
109
Anti-metabolites target __ phase
S
110
Cytoskeletal inhibitors target _____ phase
mitosis
111
Topoisomerase inhibitors target ___ phase
G2
112
Steroid hormones target ___ phase
G1
113
```
Genotoxic Agents (NCCS):
MOA
```
- affect the function of nucleic acids
- bind directly to DNA
- inhibit DNA replication enzymes
- DNA damage leads to apoptosis
* *prevent the separation of strands
* *Induce mispairing that renders them non-functional
114
```
Genotoxic Agents (NCCS):
Include _____ and ______ agents
```
Include alkylating and intercalating agents
115
```
Genotoxic Agents (NCCS):
List the most common genotoxic agents
```
1) Platinum based chemotherapeutic agents:
- cisplatin
- carboplatin
- xaliplatin
2) Doxorubicin analogs
3) Cyclophosphamide-pro drug, orally active, less side effects in normal cells
116
Describe Antimetabolites (S phase - CCS):
- Structurally similar to natural metabolites
- Prevents cells from carrying out vital functions and they are unable to grow and survive
- Interfere with the production of nucleic acids, RNA and DNA
- If new DNA cannot be made, cells are unable to divide !!!
117
Antimetabolites (S phase - CCS):
| List some
1) Folate antagonists
ex. Methotrexate
2) Purine antagonists
ex. Thiopurine methyltransferase
3) Pyrimidine antagonists
ex. 5-Fluorouracil
118
Antimetabolites (S phase - CCS):
Describe folate antagonists
Ex. Methotrexate
- Folate antagonists inhibit dihydrofolate reductase, an enzyme involved in the formation of purine and pyrimidine nucleotides for DNA synthesis
* Without DNA replication, cell growth is blocked
119
Antimetabolites (S phase - CCS):
Describe the next generation Folate Antagonist
Permetrexed:
- Inhibits DHFR
- Inhibits thymidylate synthase (TS)
- Inhibits glycinamide ribonucleotide formyl transferase (GRFT)
*More effectively inhibits DNA and RNA synthesis
120
Antimetabolites (S phase - CCS):
Describe folinic acid
Folinic Acid (Leucovorin):
- Used with methotrexate and antifolates to reduce (rescue therapy) myelosuppresion (often the most significant dose limiting adverse rx)
- THF analog that can be used as a methyl donor
- DHFR insensitive
121
Antimetabolites (S phase - CCS):
Purine Antagonists:
MOA
Purine antagonists prevent continued replication of DNA, and therefore cell division:
6-Mercaptopurine (6-MP) - looks like Adenine
6-Thioguanine (6-TG) - looks like Guanine
122
Antimetabolites (S phase - CCS):
Purine Antagonists:
Describe thiopurine methyltransferase (TPMT)
- Metabolism of thiopurine drugs such as azathioprine, 6-Mercaptopurine and 6-Thioguanine
- TPMT catalyzes the S-methylation of thiopurine drugs
- Defects in the TPMT gene leads to decreased methylation and decreased inactivation of 6MP leading to enhanced bone marrow toxicity which may cause myelosuppresion, anemia, bleeding tendency, leukopenia & infection
123
Antimetabolites (S phase - CCS):
Purine Antagonists:
What does TPMT polymorphism result in?
As TPMT is a deactivation pathway, the result is more active drug, increased toxicity (similar to an overdose situation)
124
Antimetabolites (S phase - CCS):
Pyrimidine antagonists:
MOA
-Block synthesis of pyrimidine containing nucleotides
(dCTP and dTTP in DNA; CTP and UTP in RNA)
-Stop DNA/RNA synthesis and inhibit cell division
125
Antimetabolites (S phase - CCS):
Pyrimidine antagonists:
List some pyrimidine Antagonists used in cancer therapy
1) 5-Fluorouracil (5-FU)
| 2) Cytarabine (cytosine arabinoside, ARA-C)
126
Antimetabolites (S phase - CCS):
Pyrimidine antagonists:
MOA of 5-FU
inhibit thymidylate synthase
which prevents cell growth probs
127
What is the mitotic spindle?
attaches to kinetochores, helps align chromosomes and then separates them
128
What is MAD and BUB?
Part of the spindle checkpoint that halt the cell cycle until all chromosomes are aligned at the middle of the cell
129
```
Cytoskeletal inhibitors (Mitosis phase):
List 2 drugs affecting this category
```
Taxanes:
- Paclitaxel
- Docetaxel
Vinca alkaloids:
- Vincristine
- Vimblastin
- Vindesine
130
```
Cytoskeletal inhibitors (Mitosis phase):
How do they work?
```
- Affect the mechanics of cell division
| - Without proper microtubule formation, cell division is not possible
131
Cytoskeletal inhibitors (Mitosis phase):
How do Taxanes (Paclitaxel, Docetaxel) work?
- affect anaphse
| - affect depolymerization
132
Cytoskeletal inhibitors (Mitosis phase):
How do Vinca alkaloids (Vincrinstine, Vimblastin, Vindesine) work?
- affect metaphase
| - affect polymerization
133
Cytoskeletal inhibitors (Mitosis phase):
Main side effect of taxanes?
female infertility by ovarian damage
134
Topoisomerase 1 inhibitors (G2 phase):
What do Topoisomerase inhibitors do?
Topoisomerase (Top1) inhibitors interfere with the action of topoisomerase enzymes (Top 1 and 2), which are enzymes that control the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.
Blocks the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome = apoptosis and cell death
135
Topoisomerase 1 inhibitors (G2 phase):
List some
Topotecan
| Irinotecan
136
Topoisomerase 2 inhibitors (G2 phase):
List some
Etoposide
| Teniposide
137
Steroid hormones (G1 phase):
Describe the MOA
1) Steroid hormone enters target cell
2) Hormone binds to receptor, induces conformational change
3) Hormone-receptor complex binds to DNA, induces start of transcription
4) Many mRNA transcripts are produced, amplifying the signal
5) Each transcript is translated many times, further amplifying the signal
138
Steroid hormones (G1 phase):
Hormone Therapy
Objective ?
starve cancer cells from hormonal signals necessary for growth
139
Steroid hormones (G1 phase):
Hormone Therapy
Approach ?
- hormone blocking drugs at target cells
| - prevent hormone production
140
Steroid hormones (G1 phase):
List some types of hormonal antagonists
1) Selective estrogen receptor modulators (SERMs)
2) Aromatase Inhibitors (AIs)
3) Selective androgen receptor modulators (SARMs)
141
Steroid hormones (G1 phase):
SERMs:
ER = ?
positive breast cancer cells
142
```
Steroid hormones (G1 phase):
SERMs:
```
List some
- Tamoxifen
- Raloxifene
- Toremifene
*If you're ER negative, these drugs won't work for you ?
143
```
Steroid hormones (G1 phase):
SERMs:
```
MOA
inhibition of estrogen's growth stimulating effects
144
```
Steroid hormones (G1 phase):
SERMs:
```
Describe Tamoxifen Chemotherapy
- Anti-estrogen affinity is dependent on primary metabolite, endoxifen (100x more active)
- CYP2D6 enzyme is responsible for metabolism of tamoxifen
* Can't give endoxifen alone
* Have to give tamoxifen and then have the other rxns in liver happen, and have tamoxifen converted into endoxifen
145
```
Steroid hormones (G1 phase):
SERMs:
```
Tamoxifen main DDI ?
Antidepressants
- paroxetine
- fluoxetine
- bupropion
146
```
Steroid hormones (G1 phase):
Aromatase Inhibitors:
```
List some
Exemestane
Anastrozole
Letrozole
147
```
Steroid hormones (G1 phase):
Aromatase Inhibitors:
```
MOA
Prevents conversion of hormones into estrone and estradiol
148
Steroid hormones (G1 phase):
Specific Androgen Receptor Modulators (SARMs):
List some
Flutamide
Bicalutamide
*Competitively bind AR
149
Principles of drug selection for combination therapy?
- active when used alone
- different mechanisms of action (including different mechanisms for the development of resistance) and/or different chemical classes
- NCCS vs CCS or active in different stages of cell cycle
- different toxicities
150
Combination therapy can result in?
- Synergistic effects (ex. Cytarabine and 6-Thioguanine)
- Decreased development of resistance
- Broader cell kill in cancers that consist of a heterogenous tumour cell population
151
List some adverse effects of chemotherapy drugs
Bone marrow depression
- Anemia
- Bleeding
- Infections
- Secondary cancers (Procarbazine)
Teratogenesis
Carcinogenesis
Resistance
152
How can we tell there is resistance to Methotrexate?
Increased concentrations of DHRF enzyme in cancer cells (gene amplification)
153
What is P-glycoprotein?
- First multi drug resistance mechanism to be characterized
- P-glycoprotein is transmembrane ATP-dependent efflux pump
- Actively transports many types of chemotherapy from cells
- Overexpression in cancers causes drug resistance
- P-glycoprotein inhibitors tested in clinical trials
154
List 5 forms of resistance mechanisms to chemotherapy
1) Increased expression of target proteins
2) Failure of the drugs to enter cancer cell or increased intracellular drug ejection rate
3) Drugs fail to reach target cells
4) The target molecule is no longer present
5) The target molecule is altered (mutation/deletion)
155
List 3 drugs involved in Monoclonal Antibody Therapy?
- Rituximab
- Trastuzumab
- Cetuximab
156
Monoclonal Antibody Therapy:
| Describe Rituximab
- binds to CD20 antigen (receptor) present on the cell surface of B-lymphocytes
- binding to CD20 targets the cell to complement-activated phagocytosis and antibody-dependent apoptosis
- inhibit proliferation of lymphocytes and lymphoma cells
157
Monoclonal Antibody Therapy:
| Describe Trastuzumab
-binds to human epidermal growth factor receptor protein-2 (HER2)
158
Monoclonal Antibody Therapy:
| Describe Cetuximab
-chimeric (mouse/human) monoclonal antibody against epidermal growth factor receptor protein (EGFR)
159
List 2 antibody-drug conjugates
Brentuximab vedotin
Trastuzumab emtansine
