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Pharmacology quiz 4 > Anticancer Therapy part 1: Cancer biology > Flashcards

Anticancer Therapy part 1: Cancer biology Flashcards

1
Q

Briefly describe cancer

A

Also known as a malignant tumor or malignant neoplasm, cancer is a grooup of diseases involving abnormal cell growth with the potential to invade or to spread to other parts of the body

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2
Q

Compare cancer to other causes of death in Canada

A

Cancer is responsible for 29.9% of deaths, more than heart disease (19.7) and “other” causes (25.0%)

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3
Q

Describe the lifetime probability of getting and dying of cancer in Canada (in women, men)

A
  • Probability of devl. cancer: Women 41% ; Men 45%

- Probability of dying of cancer: Women 24% ; Men 29% (1 in 3.5)

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4
Q

What types of cancer are most prevalent among men and women, respectively?

A

Men: prostate, colorectal, lung
Women: breast, lung, colorectal

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5
Q

What population is more likely to get cancer?

A

Elderly

- cancer is primarily a disease of old age

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6
Q

What critical decisions that the cell makes can possibly lead to cancer?

A
  • Stem cell renewal
  • differentiation
  • growth/quiescence
  • death
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7
Q

When is a tumor considered to be malignant? Benign?

Metastatic?

A

Benign: tumor has no effect on surrounding tissues
Malignant: if tumor invades surrounding tissue (cancerous)
Metastatic: if individual cells break off the tumor and start a new tumor elsewhere

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8
Q

Briefly 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)
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9
Q

List the 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
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10
Q

Briefly describe how cancers develop

A

Cancer arises fromt he accumulation of genetic changes (somatic mutations)
- genetic selection at the level of single cells

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11
Q

How many mutations does a cell usually incur to become cancerous?

A

minimum of 5 (often 6-9) different gene mutations

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12
Q

Cancer is genetic but is it hereditary? Explain

A
  • Not a hereditary disease; don’t pass cancer to offspring
  • Children can inherit genetic dispositions (susceptibility) to cancer. For ex: BRCA 1/2 mutations make one more susceptible to breast and ovarian cancer.
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13
Q

What genes are most involved in cancer?

A

Many genes involved in cancer are the ones that code for proteins involved in regulating the cell cycle. Increases in mutation rate or genomic instability increases frequency of cancer

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14
Q

Aneuploidy

A

Hallmark of cancer cells. It is when a cell possesses an abnormal # of chromosomes (47 instead of 46, for example)

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15
Q

What 2 components are involved in cancer etiology?

A

Nature (genetic/devl) and nurture (environment)

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16
Q

Describe the role of ‘nature’ in cancer etiology

A
  • Inherited cancer syndromes: p53,, BRCA 1/2, MMR
  • Immune deficiency syndromes
  • Polymorphisms (influences risk, occurrence, progression, and Tx of cancer)
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17
Q

List possible environmental (nurture) causes of cancer

A
  • radiation (cosmic, fallout, radon, sunlight UV rays)
  • chemotherapy (MDS)
  • viruses and bacs
  • repeated injury (acid reflux, hepatitis)
  • workplace/home exposures
  • other envr or lifestyle factors
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18
Q

List some envr factors that can cause cancer

A
  • food additives (nitrates)
  • pollution
  • occupational factors (benzene, asbestoss)
  • industrial (hydrocarbons, soot)
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19
Q

Lifestyle causes of cancer

A
  • tobacco
  • alcohol
  • diet
  • viruses
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20
Q

What are some common mutagens of the initiator region?

A
  • X-rays
  • UV light
  • DNA alkylating agents
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21
Q

What are some common proliferation inducers that affect the tumor promoter region?

A
  • phorbol esters
  • inflammation (ex: hepatitis)
  • alcohol
  • estrogens and androgens
  • EBV
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22
Q

Describe the dysregulated cell cycle of a cancer cell

A
  • cells divide when they are not supposed to

- cells divide in a place they’re not supposed to

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23
Q

normal cell cycle phases

A
  • G1: gap phase in which the cell grows and prepares to synthesize DNA
  • S: synthesis phase which the cell synthesize DNA
  • G2: second gap phase in which the cell prepares to divide
  • Mitosis: cell division occurs
  • G0: arrest phase where the cell is in a resting state
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24
Q

List and describe the 3 checkpoints during a cell cycle

A
  • G1/S checkpoint (CP): cell monitors size and DNA integrity
  • G2/M CP: cell monitors DNA synthesis and damage
  • M CP: cell monitors spindle formation and attachment to kinetochores
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25
Q

List 2 important proteins involved in the cell cycle

A

Cyclins: Cyclin A, B, D, E

Cyclin Depedent kinases (Cdks)

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26
Q

How do Cdks and cyclins interact in the cell cycle? What is their role?

A
  • Cdk levels are pretty stable, but cyclin levels change throughout the cell cycle. Ability to drive through the checkpoint are reliant on cyclins and Cdks (oncogenes)
  • Cdks must bind the correct cyclin in order to function : act as kinases
  • cause cascade of kinases adding P’s to other proteins to activate them, that eventually leads to transcription of genes (transcription factors)
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27
Q

Oncogene

A
  • activated proto-oncogene
  • is a gene that when mutated, gains a function or is expressed at abnormally-high levels and/or activity (often are kinases, transcription factors or growth factors/receptors)
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28
Q

Tumor suppressor GENE role

A

encodes for a protein that is involved in suppressing cell division. When the gene is mutated, it will no longer translate to a functional protein

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29
Q

Give an example of a protein involved in suppressing cell division

A

p53 and other checkpoint proteins

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30
Q

In cancer, what happens with oncogenes and tumor suppressor genes?

A
  • Oncogenes are activated: their normal function is in cell growht and gene transcription
  • Tumor suppressor genes are inactivated: their normal function is DNA repair, cell cycle control and apoptosis
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31
Q

List examples of oncogenes

A

myc, ras, src, abl, bcl2

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32
Q

List examples of tumor suppressor genes

A

p53, Rb, APC, MEN1, NF1

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33
Q

“guardian(s) of the genome”

A

Tumor suppressors!

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34
Q

Describe tumor suppressors (the proteins) and their role

A
  • Often involved in maintaining genomic integrity (DNA repair, chromosome segregation)
  • mutations in tumor suppressor genes lead to the “mutator phenotype”, aka mutation rates increase
  • Often the 1st mutation in a developing cancer will involve tumor suppressors
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35
Q

T/F: 50% of all cancers incur p53/pathway mutations

A

True! The tumor suppressor pathway plays an important role in cancer

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36
Q

Function of tumor suppressors

A
  • Senses genomic damage (via ATM)
  • halts the cell cycle and initiates DNA repair
  • if the DNA is irreparable, p53 will initiate the cell death process
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37
Q

Describe the Rb protein and its tole

A
  • it is a classic tumor suppressor
  • Rb binds to a protein called E2F1, which initiates the G1/S cell cycle transition
  • When Rb is bound to E2F1, E2F1 can’t function
  • thus, Rb is a crucial cell cycle checkpoint helper
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38
Q

Briefly describe the function of oncogenes

A

Drives cell cycle forward and bypasses checkpoints

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39
Q

What is a problem with the way oncogenes function that can lead to cancer?

A

Because it drives the cell cycle forward, the DNA can accumulate defects associated with improper cell division (ex: DNA content, mutations, improperlly segregated chromosomes, aneuploidy)

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40
Q

List common functions of oncogenes

A
  • growth factors
  • growth factor receptors
  • signal transducers
  • nuclear receptors
  • transcription factors
  • anti-apoptotic factors
41
Q

What is HER2/neu? Why is it important

A
  • an amplified oncogene
  • it is a growth factor receptor
  • 23-30% of breast cancers over-express HER2/neu
42
Q

What is used as a treatment for HER2/neu overexpression

A

Herceptin

43
Q

Name a frequently mutated oncogene

A

ras

44
Q

Describe ras and its role

A
  • ras is the gene that codes for Ras protein

- Ras protein is a growth factor receptor responsive GTPase; it transduces multiple cell signals

45
Q

Describe ras mutation

A
  • most common oncogenic mutation (25% of all cancers)

- mutation results in signal-independent hyperactivation of expression, cell proliferation and anti-apoptotic signalling

46
Q

What % of all cancers have 1 or more DNA REPAIR defects?

A

95%

47
Q

describe Genetic instability

A
  • Chromosomes can be unstable: gross translocations, loss and gain of chromosome parts, detectable cytogenic abnormalities
  • Dysfunctional repair of DNA can enhance genomic instability
48
Q

How can aneuploidy lead to cancer?

A

Due to the random loss or gain of certain functions.

  • Ex: loss of tumor suppressor function if less than 46 chromosomes
  • Ex: proto-oncogenic gain of function with ore than 46
49
Q

Describe Philadelphia Chromosome

A
  • classic oncogenic rearrangement associated with a variety of leukemias (chromosomes will break and rearrange)
  • BCR-ABL tyrosine kinase fusion
  • Imatinib is an Abl-kinase targeted Tyr kinase inhibitor used in the treatment of philedelphia chromosome and other tumors
50
Q

Define growth fraction and doubling time in relation to tumors

A

Growth fraction: describes the ratio of the amount of cells in the G0 (non-growing) phase vs the amount of cells actively growing
Doubling time: the time it takes for a cell to double in size

51
Q

Describe the early and late tumor stages in relation to growth fraction and doubling time

A

Early stages: high growth fraction, short doubling times [aka, more cells are actively growing, meaning the time it takes for them to double in size will be short]

Late stages: low growth fraction, long doubling times

52
Q

When in tumor growth is chemotherapy most effective?

A

When the growth fraction is high, meaning chemo targets fast growing cells

53
Q

Benign

A

“polyp”

54
Q

hyperplasia

A

increased # of cells

55
Q

Hypertrophy

A

increased size of cells

56
Q

dysplasia

A

disorderly proliferation

57
Q

neoplasia

A

abnormal new growth

58
Q

anaplasia

A

lack of cell differentiation

59
Q

tumor

A

originally meant any swelling, but now equated with neoplasia (abnormal growth)

60
Q

metastasis

A

growth at a distant site

61
Q

Describe classifications of neoplasms

A
  • Benign tumor (-oma) [ex: lipoma]

- Malignant cancer (carcinoma or sarcoma) [ex: liposarcoma]

62
Q

List some common carcinomas

A
  • Lung
  • breast
  • bladder
  • prostate
63
Q

Leukemia and lymphomas are cancers of what?

A

leukemia: bloodstream
lymphoma: lymph nodes

64
Q

List some common sarcomas

A

fat, bone, muscle

65
Q

List the stages of tumor progression

A
  • Hyperplasia
  • Dysplasia
  • Carcinoma in situ (does not cross the basal lamina)
  • Cancer (malignant tumors) : metastasis
66
Q

Differentiate between benign and malignant neoplasms

A
  • Benign: NON-INVASIVE, well-defined borders, well differentiated, regular nuclei, rare mitoses
  • Malignant: INVASIVE / METASTATIC, irregular borders, poorly differentiated, irregular and larger nuclei, more frequent and/or abnormal mitosis
67
Q

Describe cancer grading

A

Graded based on how bad the cells look

  • grade 1: well differentiated
  • G2: moderately differentiated
  • G3: poorly differentiated
  • G4: anaplastic
68
Q

briefly describe the stage of cancer

A

based on where the cancer spread - Tumor, Nodes (lymph), Metastases

69
Q

What are predictors of cancer behaviour?

A

Grade and stage of the cancer cells

70
Q

If a cancer spreads to other parts of the body, it keeps its old name: T/F? Explain

A

True. For ex, if kidney cancer spreads to the lungs, it is called kidney cancer which has metastasized to the lung

71
Q

Describe the detection of cancers and what this allows us to do

A

Detection:

  • blood work
  • palpation
  • symptomatic
  • coincidental
  • CT scan
  • PET/CT
  • SPECT/CT
  • MRI

allows us to stage the cancer and determine an appropriate response

72
Q

What % of patients diagnosed with cancer can be cured?

A

50%

73
Q

What is the cure rate of surgery and/or radiation? Chemotherapy alone?

A
  • surgery +/- radiation: 30% cure rate

- Chemo alone: 10-15%

74
Q

List possible therapeutic routes for cancer

A
  • surgery
  • radiotherapy
  • Chemotherapy (hormonal therapy or specific inhibitors)
  • Immunotherapy
  • Biologic therapy (vaccines, gene therapy)
  • A combination of the above options
75
Q

Choice of cancer treatment is based on what

A
  • type of tumor
  • location and amnt of disease
  • health status of patient
  • Tx’s used in combination
76
Q

Objective of cancer Tx

A
  • kill cancer cells
  • lead cells to apoptosis
  • contain and/or limit cell growth
77
Q

What are cancer-specific factors that affect the outcome of cancer Tx? List and describe them (5)

A

1) Growth fraction (% of cells not in G0): growth fraction determins the efficacy of Cell Cycle Specific (CCS) drugs
2) Doubling time: affects course scheduling
3) Type: type and stage can determine whether we Tx to cure or palliative care
4) Stage: see above^
5) Resistance: can limit Tx and/or force a switch in medication

78
Q

What are patient-specific factors that can affect the outcome of cancer Tx? List and describe (6)

A

1) Overall health
2) Bone marrow capacity: bone marrow suppression is the major dose-limiting toxicity for many drugs, so capacity will determine both dose and duration of Tx
3) Liver function: many cancer drugs are metabolized in the liver and/or eliminated through the kidney, so the function of these organs determine drug selection and dosage
4) Kidney function: see above ^
5) Age
6) Compliance: effects of drugs may be severe and patients may choose to stop Tx

79
Q

List cells affected by cytotoxicity

A
  • cancer cells
  • bone marow
  • GI mucosa
  • hair follicles
  • taste buds
  • fetus
80
Q

What is “radiation recall reaction”

A

erythemia and desquamation of the skin at sites of prior radiation therapy (aka rash and skin peeling)

81
Q

Radiation recall reaction occurs with what?

A

Mostly associated with anthracycline antibiotics, but can occur with any cytotoxic drug

82
Q

What is palliative therapy?

A

Palliative treatment is designed to relieve symptoms, and improve your quality of life. It can be used at any stage of an illness if there are troubling symptoms, such as pain or sickness. Palliative treatment can also mean using medicines to reduce or control the side effects of cancer treatments

83
Q

What types of cancers respond best to a combination of chemo, radiation and surgery?

A

bladder, breast, prostate, H&N, rectal cancer

84
Q

In what types of cancers is chemo mostly palliative (Sx control)?

A

lung, esophageal, pancreatic, most brain tumors

85
Q

Describe radiation therapy

A
  • ionization and excitation of atoms that kills cells.

- It can be used as single therapy, or as an adjuvant to other Tx or as palliative therapy

86
Q

What are some effects of radiation?

A
  • cell killing, N&V, fatigue, somnolence
  • late effect: fibrosis and gliosis (hypertrophy of glial cells in the CNS)
  • skin and mucosal reactions are accentuated by other modalities like chemotherapy
87
Q

Name and describe different types of radiation

A

1) External beam radiation: gamma photons and neutron beams
2) radioimmunoconjugates: antibody targeted radiation
3) Radioconjugates: isotope tagged to bone-seeking material
4) Free isotopes: (131)^I, Gallium

88
Q

Purposes of chemotherapy

A
  • primary: shrink or eliminate a tumor
  • neoadjuvant: make tumor more amenable to other therapies
  • adjuvant: eradicate micro metastasis
  • Palliation: symptom control
89
Q

How do we evaluate the response to chemo?

A

CR: complete response and disappearance for at least 1 month
PR: 50% or more reduction in tumor size or markers and no new disease for 1 month
SD: no reduction or growth
PD: progressive disease and 25% increase in tumor size

90
Q

What are some things to consider about chemo?

A
  • tumor cells undergo the same cellular processes (replication, division) as normal cells
  • tumor cells don’t always grow faster than normal cells
  • non-specific agents interfere with these processes
  • ideal chemo is toxic to tumor cells but spares normal cells
  • we want to always give the most effective therapy early in disease process
91
Q

List a few cell cycle specific agents

A

antimetabolites, Vinca alkaloids

92
Q

List two cell cycle non-specific agents

A

Doxorubicin, Cisplatin

93
Q

List other rapid growing cells that chemo agents often affect

A

Bone marrow, reproductive system, lining of the intestine

94
Q

Most effective chemo involves what?

A
  • multiple agent regimens
  • optimization of PK/PD
  • optimization to genetics of patient and cancer
95
Q

Describe kinetic considerations of phase specific agents (cell cycle specific aka CCS)

A
  • schedule dependent
  • more effective when given in divided doses at repeated intervals
  • more effective in tumors with high growth fraction
96
Q

Describe kinetic considerations of non-specific agents (non-CCS)

A
  • exert effects throughout the cell cycle
  • dose or concentration dependent effects
  • may have effect in cell resting phase
97
Q

Describe the fractional kill hypothesis

A
  • chemo drugs are typically given in cycles to allow normal cells time to recover from the Tx
  • unfortunately, stopping the drug therapy also allows any remaining cancer cells to recover – and develop resistance
  • idea is that chemo follows an exponential log kill (never reaches zero)
98
Q

How can we reduce the impact of the recovery/resistance problem of the fractional kill hypothesis?

A
  • use high doses (including increasing doses during Tx) called dose escalation
  • minimize recovery intervals (cell kill hypothesis)
  • employ sequential scheduling during combination therapy
99
Q

What are critical factors to chemo treatment to overcome the fractional kill hypothesis

A
  • start treatment early
  • treatment 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 are also crucial factors that enable success

Pharmacology quiz 4 (9 decks)

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