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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
Q

What is the difference between hyperplasia and hypertrophy?

A

Hyperplasia is an increased number of cells

Hypertrophy is an increased size of cells

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26
Q

What is the difference between dysplasia, neoplasia and anaplasia?

A

Dysplasia is disorderly proliferation. Neoplasia is an abnormal new growth. Anaplasia is a lack of differentiation

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27
Q

How do benign neoplasms present?

A

Non-invasive, well-defined borders, well differentiated, regular nuclei and rare mitoses

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28
Q

How do malignant neoplasms present?

A

Invasive/metastatic, irregular borders, poorly differentiated, irregular, larger nuclei, more frequent and/or abnormal mitoses

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29
Q

What can predict the behaviour of a cancer?

A

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)

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30
Q

How is cancer named and treated when it metastasizes?

A

It keeps its old name and is treated the same as where it is spread from (breast to lung is still breast cancer)

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31
Q

What are the objectives of cancer treatment?

A

Kill cancer cells and/or lead them to apoptosis

Contain and/or limit cell growth

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32
Q

What are some cancer factors that can affect treatment outcomes?

A 
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)
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33
Q

Which cells are affected by cytotoxicity?

A

Cancer cells
Bone marrow, GI mucosa, hair follicles, taste buds (fast replicating cells)
Fetus (CI)

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34
Q

What is radiation recall reaction?

A

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

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35
Q

What types of cancers can be cured by chemo alone?

A

Non-Hodgkin’s lymphoma, Hodgkin’s disease, choriocarcinoma, other lymphomas, Wilm’s tumor, rhabdomyosarcoma

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36
Q

What types of cancers can be cured by chemo, radiation and surgery together?

A

Bladder, breast, prostate, H and N, rectal cancer

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37
Q

What types of cancers need palliative therapy?

A

Lung, esophageal, pancreatic, malignant brain tumors

38
Q

How does radiation work?

A

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
Q

How can cancer be detected?

A

blood work, palpitation, symptomatic, coincidental, CT scan, PET/CT, SPECT/CT, MRI

40
Q

What are the different types of radiation?

A

External beam radiation (gamma photons, neutron beams)
Radioimmunoconjugates (antibody targeted radiation)
Radioconjugates (isotope targeted to bone seeking material)
Free isotopes (131I, gallium)

41
Q

When should phase specific agents (CSS) be given?

A

More effective if given in divided doses at repeated intervals
Use in tumors with high growth fraction (only proliferating cells killed)

42
Q

How should phase non-specific agents (NCCS) be given?

A

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
Q

How are CCS and NCCS drugs used together?

A

Give NCCS to induce the cell cycle so CCS works

44
Q

What are some examples of CCS drugs? What part of the cell cycle do they work on?

A

Plant alkaloids act on G2-M

DNA synthesis inhibitors act on S

45
Q

What are some examples of NCCS drugs?

A

Crosslinking agents, alkylating agents, anthracycline antibiotics
Cisplatin, carboplatin, doxorubicin, epirubicin, cyclophosphamide, ifosfamide

46
Q

What is the fractional kill hypothesis?

A

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
Q

How can we reduce resistance during recovery from chemo treatments?

A

Use high doses or dose escalation, minimize recovery intervals and employ sequential scheduling during combination therapy

48
Q

What are the critical factors to chemotherapy?

A

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
Q

What are the mechanisms of genotoxic agents (NCCS)?

A

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
Q

What are some adverse effects of genotoxic agents?

A

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
Q

How do antimetabolites (CCS) work?

A

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
Q

What are some examples of antimetabolites?

A

Folate antagonists (methotrexate, pemetrexed), purine antagonists (6-MP, 6-TG), pyrimidine antagonists (5-fluorouracil, cytarabine)

53
Q

How do folate antagonists work?

A

Inhibit dihydrofolate reductase, an enzyme involved in the formation of purine and pyrimidine nucleotides for DNA synthesis

54
Q

How does pemetrexed work?

A

Inhibits DHFR, inhibits thymidylate synthase, inhibits glycinamide ribonucleotide formyl transferase
More effective

55
Q

What is folinic acid used for?

A

As an adjuvant to antifolate therapy to reduce myelosuppression

56
Q

How do purine antagonists work?

A

6-MP acts as adenine
6-TG acts as guanine
Mimics purines, which are used to build the nucleotides of DNA and RNA

57
Q

What is the importance of thiopurine methyltransferase (TPMT)?

A

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
Q

How do pyrimidine antagonists work?

A

Block synthesis of pyrimidine containing nucleotides, thus stopping DNA/RNA synthesis

59
Q

How does 5-fluorouracil (5-FU) work?

A

Acts as an antimetabolite that irreversibly inhibits thymidylate synthase which makes thymidine

60
Q

What is 5-FU used to treat?

A

Colorectal cancer

61
Q

What are some examples of cytoskeletal inhibitors?

A

Taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine, vinblastin)

62
Q

How do taxanes work?

A

Affect anaphase and depolymerization

63
Q

How do vinca alkaloids work?

A

Affect metaphase and polymerization

alpha/beta tubulins

64
Q

What are the side effects of vinca alkaloids?

A

Loss of white blood cells and platelets, GI, hypertension, excessive sweating, hair loss, peripheral neuropathy, muscle cramps, hyponatremia

65
Q

What are the side effects of taxanes?

A

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
Q

What are some examples of topoisomerase I inhibitors?

A

Topotecan, Irinotecan

Stops the resealing of the DNA

67
Q

What are some examples of topoisomerase II inhibitors?

A

Etoposide, teniposide

Causes DNA breaks

68
Q

What are some examples of hormonal antagonists?

A

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
Q

How do SERMs work?

A

Block the binding of the hormone to the receptor

70
Q

How do aromatase inhibitors work?

A

Block the production of the hormone

71
Q

What is a consideration with tamoxifen chemotherapy?

A

It’s anti-estrogen affinity is dependent on the primary metabolite (endoxifen) which is 100x more active
CYP2D6 polymorphisms

72
Q

What are some potential drug interactions with tamoxifen?

A

Antidepressants (paroxetine, fluoxetine, bupropion) can reduce the activity

73
Q

How is combination therapy useful in chemotherapy?

A

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
Q

How can resistance to methotrexate occur?

A

Increased concentrations of DHFR enzyme in cancer cells (gene amplification) which dilutes the effects of the drug

75
Q

What is p-glycoprotein?

A

A transmembrane ATP-dependent efflux pump that actively transports many types of chemotherapy from cells
Overexpression in cancers causes drug resistance

76
Q

What causes increased synthesis of p-glycoprotein?

A

Increased MDR1 gene amplification

77
Q

How does resistance to tamoxifen occur?

A

Down regulation of estrogen receptors so the tamoxifen has nowhere to bind

78
Q

What are some examples of immunomodulators? What are they indicated for?

A

Interferons, interleukin-2

Primarily for hematopoietic neoplasias

79
Q

What are the side effects of immunomodulators?

A

Flu like symptoms to fever and capillary leak syndrome

80
Q

How does rituximab work?

A

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
Q

What are some side effects of rituximab?

A

Severe hypersensitivity reactions, anaphylactic shock

82
Q

How does trastuzumab work?

A

Binds to epidermal growth factor receptor protein-2 (HER2)

83
Q

What are some side effects of trastuzumab?

A

Allergic reactions, heart muscle damage (heart failure), pulmonary toxicity

84
Q

How does cetuximab work?

A 
A chimeric (mouse/human) monoclonal antibody against epidermal growth factor receptor protein
Resistance is associated with upregulation of HER2
85
Q

What are the side effects of cetuximab?

A

Acne, fever, chills, hypotension, bronchospasm, wheezing, angioedema, cardiac arrest

86
Q

What is imatinib?

A

A selective tyrosine kinase inhibitor that prevents the phosphorylation of specific proteins involved in cell growth and differentiation

87
Q

What are antibody-drug conjugates?

A

Combine the properties of monoclonal antibodies with cytotoxic small molecule drugs which allows for discrimination between healthy and diseased tissue

88
Q

What are some examples of antibody-drug conjugates?

A 
Brentuximab vedotin
Black box warning
Trastuzumab emtansine (combined with an antimitotic)
89
Q

What is an example of an angiogenesis inhibitor?

A

Bevacizumab
fewer side effects, less chance of resistance
Angiogenesis is important in wound healing and normal development

90
Q

What are the benefits of gene therapy?

A

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
Q

How could gene therapy be done?

A

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
Q

What’s wrong with naturopathic methods?

A

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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