7 - Anticancer Flashcards
1
Q
What is cancer?
A
- Malignant tumour or malignant neoplasm
- Group of diseases involving abnormal cell growth w/ potential to invade or spread to other parts of the body
- Cell division in overdrive
2
Q
What is the path to cancer?
A
- Clonal proliferation
- Starts from single cell
- Expansion in steps
- Pre-malignant states (polyp, MDS, MGUS)
- Serial accumulation of mutations
3
Q
What are the hallmarks of cancer?
A
- Aneuploidy (abnormal # of chromosomes)
- Self-sufficiency in growth signals
- Insensitivity to anti-growth signals
- Evading apoptosis
- Limitless reproductive potential
- Tissue invasion and metastases
- Genomic instability
4
Q
Cancer arises from accumulation of _____
A
Genetic changes (somatic mutations) -- Most cancer incurs a minimum of 5 (often 6-9) different gene mutations
5
Q
Is cancer hereditary?
A
No, but can inherit dispositions to cancer (BRCA 1/2 mutations)
6
Q
What do the genes that are mutated in cancer code for?
A
Proteins that are involved in regulating the cell cycle
7
Q
What are tumour initiators? Give examples
A
- Mutagens
- Ex: X rays, UV light, DNA alkylating agents
8
Q
What are tumour promoters? Give examples
A
- Proliferation inducers
- Ex: phorbol esters, inflammation, alcohol, estrogens, androgens, and Epstein-Barr virus
9
Q
What happens to the cell cycle in cancer?
A
Becomes dysregulated (cells divide when they’re not supposed to or in a place they’re not supposed to)
10
Q
What are the phases of the cell cycle? What occurs in each phase?
A
1) G1/gap phase - cell grows and prepares to synthesize DNA
2) S/synthesis phase - cell synthesizes DNA
3) G2/second gap phase - cell prepares to divide
4) M/mitosis phase - cell division occurs
5) G0/arrest phase - cell is in resting state
11
Q
What proteins are present during the cell cycle? How do their amounts vary?
A
- Cyclins and cyclin dependent kinases
- Cyclin dependent kinase levels stay stable, but cyclin levels change throughout the cell cycle
12
Q
What is the relationship between cyclin dependent kinases and cyclins?
A
- Cdks must bind the correct cyclin in order to function
- Cause cascade of kinases adding phosphates to other proteins to activate them, that eventually leads to transcription of genes
13
Q
What is an oncogene?
A
Gene that when mutated, gains a function or is expressed at abnormally high levels and/or high activity (often kinases, transcription factors, or growth factors/receptors)
14
Q
What is a tumour suppressor gene?
A
- Encodes for a protein that is involved in suppressing cell division
- When mutated is no longer functional (can lead to cancer)
15
Q
What is the normal function of oncogenes? What happens to them for cancer to occur?
A
- Normal function = cell growth and gene transcription
- Activated for cancer to occur
16
Q
What is the normal function of tumour suppressor genes? What happens to them for cancer to occur?
A
- Normal function = DNA repair, cell cycle control, and cell death (maintain genomic integrity)
- Inactivated for cancer to occur
17
Q
Chemotherapy is most effective when growth fraction is ____
A
High
18
Q
Is a polyp benign or malignant?
A
Benign
19
Q
What are the types of malignant cancers?
A
- Epithelial (carcinoma)
- Mesenchyme (sarcoma)
- Hematopoietic (leukemia, lymphoma, myeloma)
20
Q
Define hyperplasia
A
Increased # of cells
21
Q
Define hypertrophy
A
Increased size of cells
22
Q
Define dysplasia
A
Disorderly proliferation
23
Q
Define neoplasia
A
Abnormal new growth
24
Q
Define anaplasia
A
Lack of differentiation
25
Define tumour
Originally meant any type of swelling, but now equated w/ neoplasia
26
Define metastasis
Growth at distant site
27
What will a benign tumour end in?
-oma (ex: adenoma, fibroma, lipoma)
28
What will a malignant cancer end in?
Carcinoma or sarcoma; leukemia and lymphoma
29
What are the stages of tumour progression?
- Hyperplasia
- Dysplasia
- Carcinoma in situ (not cross the basal lamina)
- Cancer (malignant tumours)
- Metastasis
30
What are characteristics of benign neoplasms?
- Non-invasive
- Well-defined borders
- Well differentiated
- Regular nuclei
- Rare mitoses
31
What are characteristics of malignant neoplasms?
- Invasive/metastatic
- Irregular borders
- Poorly differentiated
- Irregular, larger nuclei
- More frequent and/or abnormal mitoses
32
What are some predictors of the behaviour of a tumour?
- Grade (how bad do the cells look)
- Stage (where has the cancer spread)
- TNM
- Tumour
- Nodes (lymph)
- Metastases
33
What are the various grades of cancer?
- Grade 1 = well differentiated
- Grade 2 = moderately differentiated
- Grade 3 = poorly differentiated
- Grade 4 = anaplastic
34
What are the stages of colon cancer?
Duke's A, B, C, or D (A has highest chance of survival after 5 years; D has lowest chance)
35
What are some possible therapeutic routes?
- Surgery
- Radiotherapy
- Chemotherapy (hormonal therapy, specific inhibitors)
- Immunotherapy
- Biologic therapy (vaccines, gene therapy)
- Combination of the above
36
What can be done to detect cancer?
- Blood work
- Palpation
- Symptomatic
- Coincidental
- CT scan
- PET/CT
- SPECT/CT
- MRI
- Staging
- Response
37
What determines the tx for cancer?
- Type of tumour
- Location and amount of disease
- Health status of px
- Tx used in combination
38
What is the objective of cancer tx?
- Kill cancer cells and/or lead them to apoptosis
| - Contain and/or limit cell growth
39
What are some cancer factors that affect outcome of tx?
- Growth fraction (% of cells not in G0) - determines efficacy of CCS drugs
- Doubling time - affects course scheduling
- Type and stage - determines cure vs. palliation
- Resistance - can limit tx and/or force a switch in medication
40
What are some patient factors that affect outcome of tx?
- Overall health
- Bone marrow capacity (determines dose and duration of tx)
- Liver and kidney function (determine drug selection and/or dosage)
- Age
- Compliance
41
What is the major dose-limiting toxicity for most drugs?
Bone marrow suppression
42
Which cells are affected by cytotoxicity?
- Cancer cells
- Bone marrow
- GI mucosa (common SE = N/V)
- Hair follicles
- Taste buds
- Fetus
- Radiation recall reaction
43
What is the radiation recall reaction? Which drugs cause it?
- Erythema and desquamation of the skin at sites of prior (or simultaneous) radiation therapy (rash and skin peeling)
- Most commonly associated w/ anthracycline antibiotics, but can occur w/ any cytotoxic drug
44
What is radiation?
Ionization and excitation of atoms that kill cells
45
What are side effects of radiation?
N/V, fatigue, somnolence
46
What is used in external beam radiation?
Gamma photons or neutron beams
47
What are the purposes of chemo?
- Primary = shrink or eliminate tumour
- Neoadjuvant = make tumour more amenable to other therapies
- Adjuvant = eradicate micro metastasis
- Palliation = symptom control
48
What are the various response to chemo?
- CR = complete disappearance for at least 1 month
- PR = 50% or more reduction in tumour size or markers and no new disease for 1 month
- SD = no reduction or growth
- Progression = 25% increase in tumour size
49
Do tumour cells grow faster than normal cells?
Not always
50
Which drugs are cell cycle specific agents?
- Antimetabolites
- Vinca alkaloids
- Cytoskeletal inhibitors
- Topoisomerase inhibitors
- Hormonal therapy
51
Which drugs are cell cycle non-specific agents?
Doxorubicin and cisplatin
52
What is involved in the most effective chemotherapy?
- Multiple agent regimens
- Optimization of PK/PD
- Optimization to genetics of px and cancer
53
Phase specific agents (CCS) are ______ dependent. What does this mean?
- Schedule dependent
| - More effective when given in divided doses at repeated intervals and more effective in tumours w/ high growth fraction
54
Phase non-specific agents (NCCS) are ___ dependent
Dose or concentration dependent
55
Chemotherapy follows _____ kill
Exponential log kill (never reaches zero)
56
How are cancer chemotherapeutics normally given? What is the problem w/ this? What can be done to prevent this?
- Typically given in cycles to allow normal cells time to recover from tx
- Problem = stopping drug therapy also allows any remaining cancer cells to recover and develop resistance
- Can employ anti-neoplastic drug therapy
57
What are the key principles of anti-neoplastic drug therapy?
- Use high doses (including increasing doses during tx; called dose escalation
- Minimize recovery intervals
- Employ sequential scheduling during combination therapy
58
What are the critical factors for cancer tx?
- Early start to tx
- Tx must continue past the time when cancer cells can be detected using conventional techniques
- Appropriate scheduling of tx courses and care to ensure that a sufficient log-kill is obtained
59
What are the various mechanisms of chemotherapy?
- Inhibit cell growth (growth factor proteins, ex: hormones)
- Inhibit DNA duplication
- Inhibit cell division
60
Which part of the cell cycle can vary greatly between px?
Duration of G0 and G1 phases
61
When will CCS drugs be least effective?
Cancers w/ low growth fractions (ie: most cells in G0)
62
Is it common to use both NCCS and CCS drugs in cancer tx?
Yes, common to follow NCCS w/ a CCS drug to recruit the cancer cells into the cell cycle, where CCS drugs can be more effective
63
Which phase of the cell cycle do plant alkaloids work on?
G2 -> M
64
Which phase of the cell cycle do DNA synthesis inhibitors and anti-metabolites work on?
S
65
Which cells do CCS drugs kill?
Proliferating cells
66
Which phase of the cell cycle do NCCS drugs work?
Any phase, including G0
67
Which cells do NCCS drugs kill?
Proliferating and non-proliferating (both high and low growth factor tumours)
68
Which phase of the cell cycle do cytoskeletal inhibitors work on?
Mitosis
69
Which phase of the cell cycle do topoisomerase inhibitors work on?
G2 phase
70
Which phase of the cell cycle do steroid hormones work on?
G1 phase
71
What are the functions of genotoxic agents (NCCS)?
- Affect function of nucleic acids
- Bind directly to DNA and inhibit DNA replication enzymes
- DNA damage leads to apoptosis
72
What are the most commonly used genotoxic agents?
- Cisplatin
- Carboplatin
- Oxaliplatin
- Doxorubicin analogs
- Cyclophosphamide
73
What are common SE of genotoxic agents?
- Hematopoietic effects
- GI
- Hair loss
- Renal toxicity
- Ototoxicity w/ cisplatin
- Heart effects w/ doxorubicin-based compounds
- Bladder effects w/ cyclophosphamide compounds
74
What are the functions of antimetabolites?
- Prevent cells from carrying out vital functions, making them unable to grow and survive
- Interfere w/ production of nucleic acids, RNA, and DNA
75
What is methotrexate? What does it do?
- Folate antagonist
- Inhibits dihydrofolate reductase, an enzyme involved in formation of purine and pyrimidine nucleotides for DNA synthesis
76
What are indications for methotrexate?
- Acute lymphocytic leukemia
- Large cell lymphoma
- Head and neck cancers
- Breast/bladder cancer
- Rheumatoid arthritis
77
What is used as an adjuvant in anti-folate therapy? Why?
- Folinic acid used w/ methotrexate and anti-folates
| - Reduce myelosuppression
78
What do purine antagonists prevent?
Continued replication of DNA and therefore cell division
79
What are indications for purine antagonists?
- Acute lymphocytic or myelocytic leukemia
- Lymphoblastic leukemia
- IBD
- Organ transplant
80
What is the function fo thiopurine S-methyltransferase (TMPT)?
Catalyzes the S-methylation of thiopurine drugs, leading to an inactive metabolite
81
What does a defect in the TMPT gene cause?
Decreased methylation and decreased inactivation of 6MP => enhanced bone marrow toxicity
82
What are the polymorphisms of the TMPT gene?
- WT (wild type)/WT normal allele = extensive metabolizer
- WT/MUT (mutant allele) = intermediate metabolizer
- MUT/MUT = poor metabolizer, making them intolerant to thiopurines (causes more active drug and increased toxicity)
83
What do pyrimidine antagonists do?
- Block synthesis of pyrimidine containing nucleotides
| - Stop DNA/RNA synthesis and inhibit cell division
84
Which pyrimidine antagonists are used in cancer therapy?
- 5-FU (inhibits thymidylate synthase, which converts dUMP to dTMP)
- Cytarabine
85
What are indications for 5-FU?
- Colorectal cancer
- Breast cancer
- Pancreatic cancer
- Stomach cancer
- Genito-urinary tract cancers
- Esophageal cancer
- Liver cancer
- Skin cancer
86
What do cytoskeletal inhibitors do?
- Affect mechanisms of cell division
| - Prevent proper microtubule formation, making cell division impossible
87
What are indications for cytoskeletal inhibitors?
- Breast cancer
- Testicular
- Hodgkin's disease and other lymphomas
- Childhood leukemias
- Rhabdomyosarcoma
- Neuroblastoma
88
What are side effects of Vinca alkaloids?
- Loss of white blood cells and blood platelets
- GI problems
- High BP
- Excessive sweating
- Depression
- Muscle cramps
- Hyponatremia
- Constipation
- Hair loss
89
What are side effects of taxane?
- N/V, loss of appetite
- Thinned or brittle hair
- Tingling in hands or toes
- Bruising or bleeding
- Fever, chills, cough, dizziness, SOB
- Female infertility
90
What are topoisomerase inhibitors do?
- Interfere w/ action of topoisomerase enzymes, which control changes in DNA structure by catalyzing the breaking and rejoining of phosphodiester backbone of DNA strands during normal cell cycle
- Block ligation step of cell cycle, generating single and double stranded breaks that harm integrity of genome => apoptosis and cell death
91
What is the MOA of steroid hormones?
- Enter target cells and bind to receptor, inducing conformational change
- Hormone-receptor complex binds to DNA, inducing start of transcription
- Many mRNA transcripts are produced, amplifying the signal
92
What is the objective of hormonal therapy?
Starve cancer cells from hormonal signals necessary for growth
93
What are the indications for hormone therapy?
Breast, ovarian, prostate, and endometrial cancers
94
What are the types of hormonal antagonists?
- SERMs (selective estrogen receptor modulators)
- AI (aromatase inhibitors)
- SARMs (selective androgen receptor modulators)
95
Which drugs are SERMs?
- Tamoxifen
- Raloxifene
- Toremifene
96
What is the function of SERMs?
Occupy hormone receptor binding space, blocking estrogen from binding => prevents gene transcription and inhibits growth stimulating effects
97
What is the anti-estrogen affinity of tamoxifen dependent on?
The primary metabolite endoxifen (tamoxifen is metabolized by CYP2D6 into endoxifen)
98
What effect does a CYP2D6 polymorphism have on tamoxifen?
Reduces endoxifen formation, so lowers activity and drug effectiveness
99
What are DDIs w/ tamoxifen?
Anti-depressants b/c can reduce endoxifen levels even w/ functional CYP2D6 allele
100
When are SERMs and AIs indicated?
- Advanced or metastatic breast cancer
- High risk population for invasive breast cancer
- SERM = recent use in lung tumour and GBM (brain tumours)
101
Which drugs are aromatase inhibitors?
- Exemestane
- Anastrozole
- Letrozole
102
What do aromatase inhibitors do?
Block formation of estrogen, so prevent conversion of immature hormone into finalized active hormone
103
What do SARMs do?
Prevent binding of testosterone to androgen receptor, so prevent gene transcription and tumour cell growth
104
Which drugs are SARMs?
- Flutamide
| - Bicalutamine
105
Which 2 anti-cancer drugs exert a synergistic effect?
Cisplatin and etoposide
106
What are benefits to combination cancer therapy?
- Synergistic effects
- Decreased development of resistance
- Broader cell kill in cancers w/ heterogeneous tumour cell population
107
What are common side effects of chemotherapy drugs?
- Bone marrow depression => anemia, bleeding, infections, secondary cancers
- Teratogenesis
- Carcinogenesis
- Resistance (often px don't die from primary tumour, they die from recurrence of resistant tumour)
108
What are some cellular mechanisms for drug resistance?
- Drug target alterations (up-regulation of enzyme target, enhanced drug metabolism)
- Multi-drug resistance (drug efflux via P-glycoprotein transporters, drug conjugation by glutathione)
- Enhanced survival (suppression of apoptosis, enhanced DNA repair systems)
109
What are some non-cellular mechanisms for drug resistance?
- Pharmacological sanctuaries
| - Altered in vivo growth kinetics
110
How can cancer cells develop resistance to methotrexate?
Increased concentrations of DHFR enzyme
111
How can cancer cells develop resistance to tamoxifen?
Downregulation/mutation of estrogen receptor so tamoxifen doesn't work, but cell is still getting growth effects
112
How can cancer cells develop resistance to 5-fluorouracil?
- Down-regulate thymidylate synthase, so 5-FU loses its target
- Will still give px off-site SE, so SE doesn't necessarily mean the drug is working in the cancer cell
113
What are the mechanisms for chemotherapy resistance?
- Increased expression of target proteins
- Failure of drugs to enter cancer cells or increased rate of removal of drug from cancer cell
- Drug fails to reach target cells
- Target molecule altered or no longer present
* * Often more than one of these
114
What is a P-glycoprotein?
- Transmembrane ATP-dependent efflux pump
- Actively transports many types of chemotherapy from cells
- Overexpression in cancers causes drug resistance
115
What is a major cause of multi-drug resistance?
Failure of DNA damaged cells to undergo apoptosis
116
What drugs are used for monoclonal antibody therapy?
- Rituximab
- Trastuzumab
- Cetuximab
117
What does rituximab do? What are some side effects?
- Binds to CD20 antigen receptor present on surface of B cells => complement-activated phagocytosis and Ab-dependent apoptosis
- Inhibit proliferation of lymphocytes and lymphoma cells
- SE = severe hypersensitivity reactions, anaphylactic shock
118
What does trastuzumab do? What is it indicated for? What are some side effects?
- Binds to human epidermal growth factor receptor protein-2 (HER2), which is overexpressed in some cancers
- Indicated for HER2+ metastatic breast cancer and early stage HER2+ breast cancer
- SE = allergic reaction, heart muscle damage, pulmonary toxicity
119
What does cetuximab do? What is it indicated for? What are some side effects?
- Acts against epidermal growth factor receptor protein (EGFR), which is overexpressed in some cancers
- Indicated for metastatic colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer
- SE = acne, fever, chills, hypotension, wheezing
120
What is imatinib?
Selective tyrosine kinase inhibitor, so prevents phosphorylation of specific proteins involved in cell growth and differentiation
121
What does gefitinib do?
- Interrupts mutated or overactive EGFR receptor signaling
- Used in breast and lung cancer
- Can be used in combo w/ methotrexate
122
What does erlotinib do?
Reversible EGFR tyrosine kinase inhibitor
123
What are antibody-drug conjugates?
Combination of monoclonal antibodies w/ cytotoxic small molecule drugs (allows for discrimination btwn healthy and diseased tissues)
124
Which drugs are antibody-drug conjugates?
- Brentuximab vedotin
| - Trastuzumab emtansine
125
Which drug is an angiogenesis inhibitor?
Bevacizumab (avastin)
126
What are the 2 possible approaches to gene therapy for cancer?
- Injecting cancer cells w/ special genes that make tumour more receptive to effects of anti-cancer drugs
- Introducing multi-drug resistant gene into bone marrow to make stem cells more immune to toxic SE of anti-cancer drugs
