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Pharmacology 2 > Anticancer > Flashcards

Anticancer Flashcards

1
Q

How does a cell become cancerous?

A

When cell division becomes unregulated, can become benign (tumor has no effect on surrounding tissue-non-cancerous), malignant (tumor invades surrounding tissue-cancerous) or metastatic (cells break away and start a new tumor elsewhere-cancerous)

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2
Q

What are some hallmarks of cancer?

A

Self-sufficiency (operates independent) in growth signals
Insensitivity to anti-growth signals
Evading apoptosis
Limitless reproductive potential
Sustained angiogenesis (forms new blood cells)
Tissue invasion and metastatses
Genomic instability

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3
Q

How is cancer a genetic disease?

A

Not a hereditary disease but can pass a predisposition to develop
Arises from an accumulation of genetic changes (somatic mutations, single cells) in proteins that are involved in regulating the cell cycle
Most cancers incur a minimum of 5 different gene mutations

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4
Q

What are the genetic factors in breast/ovarian cancer?

A

BRCA 1/2 mutations

It is a normal gene is activated by ATM kinase and targets p53

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5
Q

What can cause cancer?

A

Nitrites, asbestos, benzene, hydrocarbons (soot), tobacco, alcohol, obesity, viruses (HPV, HIV), estrogen

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6
Q

What is the promoter-initiator model?

A

An initial mutation event is an initiator. It must occur first, followed by a strong promotor (lifestyle) to drive the cancer anytime after

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7
Q

What are some examples of tumor initiators (mutagens)?

A

X-rays, ultraviolet light, DNA alkylating agents

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8
Q

What are some examples of tumor promoters (proliferation inducers)?

A

Phorbol esters (croton oil), inflammation (hepatitis), alcohol, estrogens and androgens, epstein-barr virus

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9
Q

What are the phases of the cell cycle?

A

G1 (gap): the cell grows and prepares to synthesize DNA
S (synthesis): cell synthesizes DNA
G2 (2nd gap): cell prepares to divide
M (mitosis):cell division occurs
G0 (arrest): when the cells is in a resting state (can be in this or G1 depending what it wants to do)

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10
Q

What are the 3 checkpoints of the cell cycle?

A

G1/S: Cell monitors its size and DNA integrity
G2/M: Cell monitors DNA synthesis and damage
M: Cell monitors spindle formation and attachment to kinetochores

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11
Q

What are cyclins and cyclin dependent kinases (Cdks)?

A

Cyclin surges and function of CDk (stable levels) determine the drive of the cell through the cell cycle checkpoints

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12
Q

How do cyclins and Cdks work?

A

Cdks must bind the correct cyclin in order to function and add phosphate groups to proteins to “turn them on”. This causes a cascade of kinases adding phosphates to other proteins to activate them, eventually leading to the transcription of genes.

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13
Q

What are oncogenes? What happens to them in cancer?

A

Normally function in cell growth and gene transcription, in cancer they are activated due to a mutation giving it a new function or expressed at abnormally high levels
myc, ras, src, abl, bcl2, HER2/neu

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14
Q

What are tumor suppressor genes? What happens to them in cancer?

A

Normally function in DNA repair, cell cycle control and cell death, in cancer they are inactivated due to a mutation
Causes a “mutator phenotype”, which causes mutation rates to increase
p53, Rb, APC, MEN1, NF1

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15
Q

How does tumor suppressor p53 work?

A

Senses genomic damage (via ATM), halts the cell cycle and initiates DNA repair.
If the DNA is irreparable, p53 will initiate the death process.

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16
Q

How does tumor suppressor Rb work?

A

Binds to E2F1 and stops it from initiating the G1/S cell cycle transition
Rb is a crucial cell cycle checkpoint

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17
Q

How does oncogene ras work?

A

It is a growth factor that is responsive to small GTPase and transduces multiple cell signals

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18
Q

What are some DNA defects that must be repaired?

A

Base modifications, Single strand breaks, bulky lesion, cross link, double strand breaks

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19
Q

What is the philadelphia chromosome?

A

An oncogenic rearrangement that is associated with leukemias

BCR-ABL tyrosine kinase function

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20
Q

What is used to treat philadelphia chromsome CML?

A

Imantinib is an Abl-kinase targeted inhibitor

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21
Q

What is used to treat HER2/neu breast cancers?

A

Herceptin binds and inhibits the function of this receptor

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22
Q

What are the stages of tumor growth?

A

Early: High growth fraction, short doubling times
Late: Low growth fraction, long doubling times
Chemo is most effective when growth fraction is high (early stages)

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23
Q

What is the nomenclature for benign tumors?

A

-oma

Adenoma, fibroma, lipoma

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24
Q

What is the nomenclature for malignant cancer?

A

Carcinoma or sarcoma

Adenocarcinoma, fibrosarcoma

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25
What is the difference between hyperplasia and hypertrophy?
Hyperplasia is an increased number of cells | Hypertrophy is an increased size of cells
26
What is the difference between dysplasia, neoplasia and anaplasia?
Dysplasia is disorderly proliferation. Neoplasia is an abnormal new growth. Anaplasia is a lack of differentiation
27
How do benign neoplasms present?
Non-invasive, well-defined borders, well differentiated, regular nuclei and rare mitoses
28
How do malignant neoplasms present?
Invasive/metastatic, irregular borders, poorly differentiated, irregular, larger nuclei, more frequent and/or abnormal mitoses
29
What can predict the behaviour of a cancer?
Grade (how bad do the cells look, nuclei, order): 1 is well differentiated, 4 has no structure Stage (where has it spread): Tumor (size), Nodes (number of lymph), Metastatses (seeding body cavities, lymph nodes, blood)
30
How is cancer named and treated when it metastasizes?
It keeps its old name and is treated the same as where it is spread from (breast to lung is still breast cancer)
31
What are the objectives of cancer treatment?
Kill cancer cells and/or lead them to apoptosis | Contain and/or limit cell growth
32
What are some cancer factors that can affect treatment outcomes?
``` Growth fraction (number of cells undergoing cell cycle-not in G0) Doubling time affects course scheduling Type, stage, Resistance, overall health, bone marrow capacity, liver and kidney function, age and compliance (more issue with greater age) ```
33
Which cells are affected by cytotoxicity?
Cancer cells Bone marrow, GI mucosa, hair follicles, taste buds (fast replicating cells) Fetus (CI)
34
What is radiation recall reaction?
Erythema and desquamation (peeling) of the skin at sites of prior or simultaneous radiation therapy Localized reaction is worsened because of this Most commonly associated with anthracycline antibiotics
35
What types of cancers can be cured by chemo alone?
Non-Hodgkin's lymphoma, Hodgkin's disease, choriocarcinoma, other lymphomas, Wilm's tumor, rhabdomyosarcoma
36
What types of cancers can be cured by chemo, radiation and surgery together?
Bladder, breast, prostate, H and N, rectal cancer
37
What types of cancers need palliative therapy?
Lung, esophageal, pancreatic, malignant brain tumors
38
How does radiation work?
Ionization and excitiation of atoms that kills cells Nausea, vomiting, fatigue, somnolence Skin and mucosal reactions are accentuated by things like chemo Late effect (fibrosis, gliosis)
39
How can cancer be detected?
blood work, palpitation, symptomatic, coincidental, CT scan, PET/CT, SPECT/CT, MRI
40
What are the different types of radiation?
External beam radiation (gamma photons, neutron beams) Radioimmunoconjugates (antibody targeted radiation) Radioconjugates (isotope targeted to bone seeking material) Free isotopes (131I, gallium)
41
When should phase specific agents (CSS) be given?
More effective if given in divided doses at repeated intervals Use in tumors with high growth fraction (only proliferating cells killed)
42
How should phase non-specific agents (NCCS) be given?
Exert effects throughout the cell cycle, dose or concentration dependent effects and may have effect in resting phase Both proliferating and non-proliferating cells kills (both high and low growth factor tumors)
43
How are CCS and NCCS drugs used together?
Give NCCS to induce the cell cycle so CCS works
44
What are some examples of CCS drugs? What part of the cell cycle do they work on?
Plant alkaloids act on G2-M | DNA synthesis inhibitors act on S
45
What are some examples of NCCS drugs?
Crosslinking agents, alkylating agents, anthracycline antibiotics Cisplatin, carboplatin, doxorubicin, epirubicin, cyclophosphamide, ifosfamide
46
What is the fractional kill hypothesis?
Cancer chemotherapeutics are given in cycles to allow normal cells time to recover from treatment but stopping allows any remaining cancer cells to recover and develop resistance
47
How can we reduce resistance during recovery from chemo treatments?
Use high doses or dose escalation, minimize recovery intervals and employ sequential scheduling during combination therapy
48
What are the critical factors to chemotherapy?
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 that a sufficient log-kill is obtained
49
What are the mechanisms of genotoxic agents (NCCS)?
Alkylation of DNA bases Creation of inter/intra-strand DNA cross links (inhibits replication, causes double strand break) Induce mispairing of nucleotides (change how base look then induce mutogenesis)
50
What are some adverse effects of genotoxic agents?
Hematopoietic effects, GI, hair loss (less likely to occur with cyclophosphamide-prodrug) Renal toxicity/otoxicity with cisplatin Heart effects with doxorubicin Bladder effects with cyclophosphamide
51
How do antimetabolites (CCS) work?
S phase Interferes with the production of nucleic acids, RNA and DNA So no new DNA is made so cells are unable to divide
52
What are some examples of antimetabolites?
Folate antagonists (methotrexate, pemetrexed), purine antagonists (6-MP, 6-TG), pyrimidine antagonists (5-fluorouracil, cytarabine)
53
How do folate antagonists work?
Inhibit dihydrofolate reductase, an enzyme involved in the formation of purine and pyrimidine nucleotides for DNA synthesis
54
How does pemetrexed work?
Inhibits DHFR, inhibits thymidylate synthase, inhibits glycinamide ribonucleotide formyl transferase More effective
55
What is folinic acid used for?
As an adjuvant to antifolate therapy to reduce myelosuppression
56
How do purine antagonists work?
6-MP acts as adenine 6-TG acts as guanine Mimics purines, which are used to build the nucleotides of DNA and RNA
57
What is the importance of thiopurine methyltransferase (TPMT)?
It is an enzyme involved in the metabolism (S-methylation) of purine antagonists. Has different polymorphisms (high activity most common) Defects in TPMT lead to decreased in activation of the drugs, leading to enhanced side effects and bone marrow toxicity
58
How do pyrimidine antagonists work?
Block synthesis of pyrimidine containing nucleotides, thus stopping DNA/RNA synthesis
59
How does 5-fluorouracil (5-FU) work?
Acts as an antimetabolite that irreversibly inhibits thymidylate synthase which makes thymidine
60
What is 5-FU used to treat?
Colorectal cancer
61
What are some examples of cytoskeletal inhibitors?
Taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine, vinblastin)
62
How do taxanes work?
Affect anaphase and depolymerization
63
How do vinca alkaloids work?
Affect metaphase and polymerization | alpha/beta tubulins
64
What are the side effects of vinca alkaloids?
Loss of white blood cells and platelets, GI, hypertension, excessive sweating, hair loss, peripheral neuropathy, muscle cramps, hyponatremia
65
What are the side effects of taxanes?
Nausea and vomiting, loss of appetite, pain in joint, thinned or brittle hair, changes in nail colour, tingling in hands or toes, bruising, bleeding, Hand-foot syndrome, facial flushing, female infertility
66
What are some examples of topoisomerase I inhibitors?
Topotecan, Irinotecan | Stops the resealing of the DNA
67
What are some examples of topoisomerase II inhibitors?
Etoposide, teniposide | Causes DNA breaks
68
What are some examples of hormonal antagonists?
Selective estrogen receptor modulators (SERMs-tamoxifen, raloxifene, toremifene, ER positive breast cancer cells), aromatase inhibitors (AI-exemestane, anastrozole, letrozole), selective androgen receptor modulators (SARMs-flutamide, bicalutamide)
69
How do SERMs work?
Block the binding of the hormone to the receptor
70
How do aromatase inhibitors work?
Block the production of the hormone
71
What is a consideration with tamoxifen chemotherapy?
It's anti-estrogen affinity is dependent on the primary metabolite (endoxifen) which is 100x more active CYP2D6 polymorphisms
72
What are some potential drug interactions with tamoxifen?
Antidepressants (paroxetine, fluoxetine, bupropion) can reduce the activity
73
How is combination therapy useful in chemotherapy?
Synergistic effects at lower doses with decreased toxicity (cytarabine and 6-thioguanine) Decreased development of resistance Broader cell kill in cancers with a heterogeneous tumour cell population
74
How can resistance to methotrexate occur?
Increased concentrations of DHFR enzyme in cancer cells (gene amplification) which dilutes the effects of the drug
75
What is p-glycoprotein?
A transmembrane ATP-dependent efflux pump that actively transports many types of chemotherapy from cells Overexpression in cancers causes drug resistance
76
What causes increased synthesis of p-glycoprotein?
Increased MDR1 gene amplification
77
How does resistance to tamoxifen occur?
Down regulation of estrogen receptors so the tamoxifen has nowhere to bind
78
What are some examples of immunomodulators? What are they indicated for?
Interferons, interleukin-2 | Primarily for hematopoietic neoplasias
79
What are the side effects of immunomodulators?
Flu like symptoms to fever and capillary leak syndrome
80
How does rituximab work?
Binds to the CD20 antigen present on B cells, this targets the cell to complement-activated phagocytosis and antibody-dependent apoptosis Inhibits proliferation of lymphocytes and lymphoma cells Monoclonal antibody therapy
81
What are some side effects of rituximab?
Severe hypersensitivity reactions, anaphylactic shock
82
How does trastuzumab work?
Binds to epidermal growth factor receptor protein-2 (HER2)
83
What are some side effects of trastuzumab?
Allergic reactions, heart muscle damage (heart failure), pulmonary toxicity
84
How does cetuximab work?
``` A chimeric (mouse/human) monoclonal antibody against epidermal growth factor receptor protein Resistance is associated with upregulation of HER2 ```
85
What are the side effects of cetuximab?
Acne, fever, chills, hypotension, bronchospasm, wheezing, angioedema, cardiac arrest
86
What is imatinib?
A selective tyrosine kinase inhibitor that prevents the phosphorylation of specific proteins involved in cell growth and differentiation
87
What are antibody-drug conjugates?
Combine the properties of monoclonal antibodies with cytotoxic small molecule drugs which allows for discrimination between healthy and diseased tissue
88
What are some examples of antibody-drug conjugates?
``` Brentuximab vedotin Black box warning Trastuzumab emtansine (combined with an antimitotic) ```
89
What is an example of an angiogenesis inhibitor?
Bevacizumab fewer side effects, less chance of resistance Angiogenesis is important in wound healing and normal development
90
What are the benefits of gene therapy?
Can attack existing cancer at the molecular level, eliminating the need for drugs, radiation or surgery Identifying cancer susceptibility gene can help prevent the disease
91
How could gene therapy be done?
Injecting cancer cells with special genes to make the tumor more receptive to the side effects of anticancer drugs Introducing the multi-drug resistant gene into bone marrow to make stem cells more immune to the toxic side effects of anticancer drugs
92
What's wrong with naturopathic methods?
Often active compound is not known, levels vary or activities differ Extracts instead of active compound (more drug interactions and side effects)

Pharmacology 2 (23 decks)

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