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Pharmacology (Winter) > Anticancer > Flashcards

Anticancer 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 or spread to other parts of the body

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2
Q

What is the most common cancer type in MALE Canadians?

A

Prostate

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3
Q

What is the most common cancer type in FEMALE Canadians?

A

Breast

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4
Q

What is the path to cancer?

A

Serial accumulation of mutations (clonal evolution Resistance)

Pre-maligant states (Polyp, MDS, MGUS)

Expansion in steps

Starts from a single cell

Clonal Proliferation

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5
Q

Where does cancer arise from?

A

from the accumulation of genetic changes (somatic mutations)
- genetic selection at the level of single cells

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6
Q

Most cancers incur a minimum of ___ (often ____) diff gene mutations

A

5

6-7

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7
Q

Not a ______ disease

A

hereditary

we do NOT pass on cancer to offspring

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8
Q

We can ___________

A

inherit dispositions (susceptibility) to cancer

BRCA 1/2 mutations (breast & ovarian cancer)
- normal gene is activated by ATM kinase & targets p53

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9
Q

Cancer is a _______ disease

A

GENETIC

  • Many genes that are mutated in cancer code for proteins that are involved in REGULATING THE CELL CYCLE
  • Increases in mutation rate or genomic instability increase frequency of cancer.
  • Aneuploidy is a hallmark of cancer cells.
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10
Q

________ is a hallmark of cancer cells

A

ANEUPLOIDY

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11
Q

What is the etiology components of cancer?

A

Nature (genetic/developmental) component

Nurture component

Environmental factors

Lifestyle and other factors

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12
Q

Nature (genetic/developmental) component etiology component:

A

Inherited cancer syndromes
- p53, BRCA1 and 2, MMR

Immune deficiency syndromes
- Inherited/Congenital or acquired

Polymorphisms (influences risk, occurrence, progression, treatment)

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13
Q

Nurture (exposure) etiology component:

A

Radiation (cosmic, fallout, radon, sunlight)

Chemotherapy (MDS)

Viruses and bacteria
- EBV, HTLV-I/II, H. pylori

Repeated injury (Acid reflux, hepatitis)

Workplace/home exposures

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14
Q

Environmental factors (etiology component):

A

Food additives (nitrites)

Pollution (asbestos)

Occupational (benzene)

Industrial (hydrocarbons – soot)

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15
Q

Lifestyle and other factors (etiology component):

A

Tobacco (leading cause of NSCLC)

Alcohol (beer – rectal cancer)

Diet (obesity)

Viruses (HPV, HIV)

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16
Q

What are the Promoter-Initiator Models?

A

Initiator BEFORE Promoter –> cancer (can soon/long after the initiator events)

Initiator WAY BEFORE Promoter –> cancer

Promoter BEFORE Initiator –> NO CANCER

Initiator BEFORE spaced before Promoter –> NO CANCER (low freq. therefore never dev. it)

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17
Q

What is an initiator vs promoters?

A

initiators = ex: loss of tumour suppressor

promotors = ex: smoking, drinking

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18
Q

Tumor Initiators =

A

= Mutagens
- X rays
- Ultraviolet Light
- DNA alkylating agents

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19
Q

Tumor Promoters =

A

Proliferation Inducers
- Phorbol Esters (croton oil)
- Inflammation (hepatitis)
- Alcohol
- Estrogens and Androgens
- Epstein-Barr Virus

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20
Q

Cell Cycle: How cells normally reproduce to replace cells:

A

Cancer
Dysregulated cell cycle
- Cells divide when they not supposed to.
- Cells divide in a place they are not supposed to.

Need to understand how the cell is coordinating this process

Understanding can lead to cancer treatments (chemotherapy)

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21
Q

Cancer = cell division in overdrive!

A

unregulated cell division:
- malignant (if tumor invades surrounding tissue - cancerous)
- benign (if tumor has no effect on surrounding tissue - non-cancerous)
- metastatic (if individual cells break away & start a new tumor elsewhere - cancerous)

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22
Q

What are the cell cycle phases?

A

G1, or gap, phase, in which the cell grows and prepares to synthesize DNA;

S, or synthesis, phase, in which the cell synthesizes DNA;

G2, or second gap, phase, in which the cell prepares to divide;

M, or mitosis, phase, in which cell division occurs.

G0, arrest/quiescent – cell is in resting state

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23
Q

Mutations to combinations of both ________ and _____________ can lead to cancer

A

oncogenes

tumor suppressor genes

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24
Q

An __________ (activated proto-oncogene) is a gene that when mutated ___________ or is expressed at abnormally-high levels and/or high activity (often kinases, transcription factors or growth factors/receptors)

A

oncogene (mutated from a normal gene)

gains a function

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25
Q

A ____________ encodes for a protein that is involved in suppressing cell division (p53, or other __________). When mutated it is no longer functional.

A

tumor suppressor gene

checkpoint proteins

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26
Q

What is the cancer pathogenesis?

A

ONCOGENES are activated
Normal function: cell growth, gene transcription
myc, ras, src, abl, bcl2

TUMOR SUPPRESSOR genes are INactivated
Normal function: DNA repair, cell cycle control, cell death
p53, Rb, APC, MEN1, NF1

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27
Q

What are tumour suppressors?

A

“Guardian(s) of the genome” (best ex: p53)

Often involved in maintaining genomic integrity (DNA repair, chromosome segregation)‏

Mutations in tumor suppressor genes lead to the “mutator phenotype”—mutation rates increase

Often the 1st mutation in a developing cancer

(loss of tumour suppressor is typ. the start)

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28
Q

What is Oncogenes?

A

Drives cell cycle forward and bypasses checkpoints

Accumulate defects associated with improper cell division (ie. DNA content, mutations, improperly segregated chromosomes, aneuploidy)

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29
Q

What are the hallmarks of cancer?

A

Self-sufficiency in growth signals –> insensitivity to anti-growth signals –> evading apoptosis –> limitless reproductive potential (grows further in petry dish) –> sustained angiogenesis –> tissue invasion & metastases –> genomic instability

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30
Q

Cell Cycle Checkpoints:

A
  1. G1/S checkpoint - cell monitors size & DNA integrity
  2. G2/M checkpoint - cell monitors DNA synthesis & damage
  3. M checkpoint - cell monitors spindle formation & attachment to kinetochores
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31
Q

DNA damage signaling:

A

DNA damage:
- cell cycle transitions
- apoptosis
- transcription
- DNA repair

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32
Q

Distinct DNA repair pathways…

A

repair specific DNA lesions

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33
Q

Genomic instability: Chromosomal instability

A

Gross translocations, loss and gain of chromosome parts

Detectable cytogenetic abnormalities

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34
Q

Genomic instability: Dysfunctional DNA repair enhances GI

A

Repair genes/Mutator Phenotypes (many are tumour suppressors)
- Xeroderma pigmentosum (XP)
- Mismatch repair genes
- ATM (Lymphoma and sarcoma)
- BRCA1/2 (Breast, ovarian, brain tumours)

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35
Q

What are Cytogenetic abnormalities?

A

Translocations
- Balanced
- Reciprocal

Aneuploidy
- Pseudodiploid
- Hyperdiploid
- Complex
- Random loss or gain
– Loss of tumour suppressor function
– Proto-oncogenic gain of function (into oncogene)

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36
Q

What is the Philadelphia Chromosome?

A

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 Ph+ CML and other tumours

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37
Q

What is the nomenclature of benign?

A

“polyp”

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38
Q

What is the nomenclature of malignant?

A

Epithelial
- ‘Carcinoma’

Mesenchyme
- ‘Sarcoma’

Hematopoietic
- Leukemia, lymphoma, myeloma

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39
Q

Hyperplasia:

A

increased # of cancer

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40
Q

Hypertrophy:

A

increased size of cellss

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41
Q

Dysplasia:

A

disorderly proliferation

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42
Q

Neoplasia:

A

abnormal new growth

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43
Q

Anaplasia:

A

lack of differentiation

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44
Q

Tumor:

A

originally meant any swelling, but now equated w/ neoplasia

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45
Q

Metastasis:

A

growth at a distant site

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46
Q

What is the classification of benign tumor (-oma):

A

Adenoma (“adeno-” means gland-like)

Fibroma

Lipoma (“lipo-” means fat)

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47
Q

What is the classification of Malignant Cancer (carcinoma or sarcoma):

A

Adenocarcinoma

Fibrosarcoma (“sar-” means fleshy)

Liposarcoma

Leukemia and Lymphoma

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48
Q

What are some common carcinomas?

A
  • lung
  • breast (women)
  • colon
  • bladder
  • prostate (men)
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49
Q

What are the leukemias?

A

bloodstream

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50
Q

What are the lymphomas?

A

lymph nodes

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51
Q

What are some common sarcomas?

A
  • fat
  • bone
  • muscle
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52
Q

What are the stages of tumor progression?

A

Hyperplasia

Dysplasia

Carcinoma insitu (not cross the basallamina)

Cancer (Malignant tumors) - Metastasis (invasion into bloodstream or surrounding tissue)

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53
Q

What are benign neoplasms?

A
  • NON-INVASIVE
  • ~well-defined borders
  • ~well differentiated
  • ~regular nuclei
  • ~rare mitoses
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54
Q

What are malignant neoplasms?

A
  • INVASIVE/METASTATIC
  • ~irregular borders
  • ~poorly differentiated
  • ~irregular, larger nuclei
  • ~more frequent &/or abnormal mitoses
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55
Q

Benign vs Malignant Histology (tissue):

A

~irregular borders

~poorly differentiated

~irregular, larger nuclei

~more frequent and/ or abnormal mitoses

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56
Q

Predictors of Behaviour:

A

Grade (1-4) - how bad do the cells look?

Stage - where has the cancer spread?
- tumor
- nodes (lymph)
- metastases

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57
Q

What are Metastases?

A
  • Seeing body cavities
  • Lymphatic drainage to lymph nodes
  • Hematogenous via blood vessels
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58
Q

Cancer arises from…

A

single cells

1858 – Rudolf Virchow proposes that “omnis cellula e cellula”.
All cells come from cells.
Metastatic cancer cells resemble the primary.
All cells of a cancer come from a single cell.

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59
Q

If cancer spreads to other parts of the body, it…

A

keeps its old name.

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

60
Q

What is the detection methods?

A

Blood work

Palpation

Symptomatic

Coincidental

CT scan

PET/CT

SPECT/CT

MRI

61
Q

What is the Cancer Tx?

A

Type of tumor

Location and amount of disease

Health status of the patient

Treatments used in combination
Objective:
- kill cancer cells
- and/or lead them to apoptosis
- contain and/or limit cell growth

62
Q

What are the possible therapeutic routes?

A

Surgery

Radiotherapy

Chemotherapy
- Hormonal therapy
- Specific inhibitors

Immunotherapy

Biologic therapy (vaccines, gene therapy)

Can be more than one of these
- Ie. Surgery followed by chemo and radiotherapy
- Neoadjuvant – prior to definitive local therapy (surgery) – potentially organ sparing
- Adjuvant – following definitive therapy

63
Q

A Brief Look at the Numbers ?

A

Approximately 500,000 fatalities / yr are attributable to cancer (2005 US figures)

Approximately 50% of the patients diagnosed with cancer can be cured

Surgery &/or radiation - 30% cure rate

Chemotherapy alone - 10-15% cure rate

64
Q

Chemotherapy is…

A

A wide range of drugs:
- Non cell cycle dependent (Genotoxic agents)
- Cell cycle dependent
– Cytoskeletal inhibitors
– Topoisomerase inhibitors
– Antimetabolites
– Hormonal therapy
- Others

65
Q

What are the Tumour Growth Concepts?

A

Growth Fraction

Doubling time

Early stages – high growth fraction, short doubling times

Late stages – low growth fraction, long doubling times

Chemotherapy – most effective when growth fraction is high.

66
Q

What are the factors affecting CANCER outcome?

A

CANCER
- Growth fraction(% of cells not in G0)
- Doubling time
- Type
- Stage
- Resistance

growth fraction determines efficacy of CCS drugs

doubling time affects course scheduling (how often you give the drug)

type and stage can determine cure vs. palliation

resistance can limit treatment and/or force a switch in medication

67
Q

What are the PATIENT factors affecting outcome?

A
  • Overall health
    – Karnofsky Performance Scale
  • Bone marrow capacity
  • Liver function
  • Kidney function
  • Age
  • Compliance

bone marrow suppression is the major dose-limiting toxicity for many drugs, so capacity will determine both dose and duration of treatment

many antineoplastic drugs are metabolized in the liver and/or eliminated in the urine, so liver and kidney function will determine drug selection and/or dosage

effects of many cancer drugs are so severe that patients will choose to stop treatment

for example, the nausea and vomiting associated with CISPLATIN and MECHLORETHAMINE are particularly disabling

68
Q

What are the purposes of chemotherapy?

A

Primary – shrink or eliminate tumor

Neoadjuvant – make tumor more amenable to other therapies

Adjuvant – eradicate micro metastasis

Palliation – symptom control

69
Q

What is the response to chemotherapy?

A

CR – complete disappearance for at least 1 month

PR – 50% or > reduction in tumor size or markers and no new disease for 1 month

SD – no reduction or growth
Progression – 25% increase in tumor size

70
Q

What are the chemotherapy considerations?

A

Tumor cells undergo the same cellular processes (replication, division)

Tumor cells don’t always grow faster than normal cells

Non-specific agents interfere with these processes

Ideal chemotherapy is toxic to tumor cells but spares normal cells

Cell cycle specific agents – antimetabolites, Vinca alkaloids

Cell cycle non-specific agents – Doxorubicin, Cisplatin

Give the most effective therapy early in disease process

71
Q

What do most chemotherapy agents affect?

A

Most agents affect normal rapidly dividing cells (bone marrow, reproductive system and lining of the intestine)

72
Q

What do most effective chemotherapy involve?

A

Multiple agent regiments

Optimization of PK / PD

Optimization to genetics of patient and cancer

73
Q

Kinetic Basis of Chemotherapy:

A

Phase specific agents (CCS) - schedule dependent

Phase non-specific agents (NCCS)

Fractional kill hypothesis

Tumour heterogeneity (leads to resistance)

74
Q

Phase specific agents (CCS) - schedule dependent:

A

more effective when given in divided doses at repeated intervals

more effective in tumors with high growth fraction

75
Q

Phase non-specific agents (NCCS):

A

exert effects throughout the cell cycle

dose or concentration dependent effects

may have effect in resting phase

76
Q

Fractional kill hypothesis:

A

Tumor accumulates between cycles

chemotherapy follows exponential log kill (never reaches zero)

77
Q

Fractional kill hypothesis:

A

Cancer chemotherapeutics are typically given in CYCLES — to allow normal cells time to recover from the treatment. Unfortunately, stopping the drug therapy also allows any remaining cancer cells to recover — and develop resistance

78
Q

In order to reduce the impact of the recovery/resistance problem, the key principles to antineoplastic drug therapy are:

A

use high doses (including increasing doses during treatment; called DOSE ESCALATION)

minimize recovery intervals (cell kill hypothesis)

employ sequential scheduling during combination therapy

79
Q

What is the fractional kill hypothesis?

A

RED LINE: Tumour burden in an untreated patient

DARK BLUE LINE: Infrequent scheduling of treatment courses with low (1 log kill) dosing and a late start prolongs survival but does not cure the patient (i.e., kill rate < growth rate)

LIGHT BLUE LINE: More intensive and frequent treatment, with adequate (2 log kill) dosing and an earlier start is successful (i.e., kill rate > growth rate)

GREEN LINE: Early surgical removal of the primary tumour decreases the tumour burden. Chemotherapy will remove persistent secondary tumours, and the total duration of therapy does not have to be as long as when chemotherapy alone is used.

80
Q

What are the critical factors to tx for fractional kill hypothesis?

A

early start to the treatment
(healthcare delays/capacity)

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 are also crucial factors that enable success

81
Q

What is the Chemotherapy MOA?

A

Genotoxic agents (Non cell-cycle specific)

Anti-metabolites (S phase)

Cytoskeletal inhibitors (Mitosis)

Topoisomerase inhibitors (G2 phase)

Steroid hormones (G1 phase)

82
Q

What is the Genotoxic Agents (NCCS)?

A

Affect the function of nucleic acids

Bind directly to DNA

Inhibit DNA replication enzymes

DNA damage leads to apoptosis

Genotoxic agents include:
- Alkylating and intercalating agents

83
Q

What are ex’s of the Genotoxic Agents (NCCS)?

A

Busulfan
Cisplatin
Carboplatin
Oxaliplatin
Carmustine
Lomustine
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Chlorambucil
Cyclophosphamide
Ifosfamide
Mechlorethamine
Melphalan
Mitomycin C
Mitoxantrone
Dacarbazine
Procarbazine
Temozolamide

84
Q

What are the most commonly used genotoxic agents?

A

Platinum based chemotherapeutic agents
-cisplatin
-carboplatin
-oxaliplatin
Doxorubicin analogs

Cyclophosphamide-prodrug, orally active, less side effects in normal cells

85
Q

What do Platinums treat?

A

Platinums treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas, bladder cancer, cervical cancer,[3] and germ cell tumors. It is used in combinations with bleomycin and vinblastine in testicular cancer.
effective against testicular cancer; the cure rate was improved from 10% to 85%

86
Q

What are the multiple actions of genotoxic chemotherapeutic agents?

A
  • Alkylation of DNA bases
  • Creation of inter/intra-strand DNA cross-links
  • Induce mispairing of nucleotides
87
Q

What are the AE’s of commonly used genotoxic agents?

A

Hematopoietic effects; GI; hair loss
- Less likely to occur with cyclophosphamide

Associated with increased risk of developing cancer

Renal toxicity / ototoxicity w/ cisplatin

Heart effects with doxorubicin based cpds
- Cardiomyopathy / CHF

bladder effects w/ cyclophosphamide cpds
hemorrhagic cystitis

88
Q

What are Antimetabolites (S Phase- CCS)?

A

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 nucleicacids, RNA and DNA

If new DNA cannot be made, cells are unable to divide!!

89
Q

What are the Antimetabolites (S Phase)?

A
  • Folate Antagonists
  • Purine Antagonists
  • Pyrimidine Antagonists
90
Q

What are the Folate Antagonists (Antifolates)?

A

Methotrexate (MTX) –> inhibit dihydrofolate reductase, an enzyme involved in the formation of purine & pyrimidine nucleotides for DNA synthesis –> w/out DNA replication, cell growth is blocked!

F → FH2 → FH4 → CH2=FH4 → 1-carbon chemistry –> DNA synthesis

91
Q

Methotrexate MOA

A

?

92
Q

What are the indications of Methotrexate?

A
  • Acute lymphocytic leukemia
  • Large cell lymphoma
  • High grade lymphoma
  • Head and neck cancers
  • Breast cancer
  • Bladder cancer
  • Rheumatoid arthritis
93
Q

What are Pyrimidine Antagonists?

A

Block synthesis of pyrimidine containing nucleotides (dCTP & dTTP in DNA; CTP & UTP in RNA)
–> Stop DNA/RNA synthesis & inhibit cell division –> Pyrimidine antagonists used for cancer therapy are:
- 5-Fluorouracil (5-FU)
- Cytarabine (cytosine arabinoside, ARA-C)

94
Q

What are the ex’s of the Pyrimidine Antagonists?

A

Uracil –> RNA synthesis –> Protein synthesis

Thymine –> DNA synthesis

5-Fluorouracil

95
Q

What is the MOA of 5-Fluorouracil (5-FU)?

A

5-Fluorouracil (5-FU), acts as an antimetabolite that irreversibly inhibits Thymidylate (TS) by competitive binding

96
Q

What are the indications of 5-Fluorouracil (5-FU)?

A

Colorectal cancer

Breast cancer

Pancreatic cancer

Stomach cancer

Genito-urinary tract cancers (anus, bladder, cervix, endometrium, ovaries, penis, prostate, and vulva)

Esophageal cancer

Liver cancer

Skin cancer

97
Q

What are the Purine Antagonists?

A
  • Adenine (A)
  • 6-MP
  • Guanine (G)
  • 6-TG
98
Q

What are the indications of Purine Antagonists?

A

Acute lymphocytic or myelocytic leukemia

Lymphoblastic leukemia (especially in childhood cases)

Acute myelogenous and myelomonocytic leukemias

Inflammatory bowel disease

Organ transplant

99
Q

What is Thiopurine methyltransferase?

A

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 myelosuppression, anemia, bleeding tendency, leukopenia & infection

100
Q

What is the importance of TPMT?

A

?

101
Q

What are the TPMT polymorphisms?

A

WT/WT normal allele found in 90% population-phenotype extensive metabolizer (EM)

WT/MUT allele found in 10% population-phenotype intermediate metabolizer (IM)

MUT/MUT allele found in 1/300 people-phenotype poor metabolizer (PM)

102
Q

Summary of TPMT polymorphisms:

A

Mutations in gene cause IM & PM to occur

Active substance (thiopurines) INHIBIT TPMT –> too much active substance –> too great an effect; undesirable effect

103
Q

What is the MOA of Chemotherapy?

A

Genotoxic agents (Non cell-cycle specific )

Anti-metabolites (S phase)

Cytoskeletal inhibitors (Mitosis)!

Topoisomerase inhibitors (G2 phase)

Steroid hormones (G1 phase)

104
Q

What is Chromosomal Separation - Mitosis?

A

Mitotic spindle – attaches to kinetochores, helps align chromosomes and then separates them.

MAD and BUB – part of the spindle checkpoint that halt the cell cycle until all chromosomes are aligned at the middle of the cell.

105
Q

What is Cytoskeletal Inhibitors (Mitosis)?

A

Affect the mechanics of cell division

Without proper microtubule formation, cell division is not possible!

106
Q

What is Cytoskeletal Inhibitors (Mitosis)?

A

Taxanes
- Paclitaxel
- Docetaxel
(affect anaphase); affects depolymerization

Vinca alkaloids
- Vincristine
- Vimblastin
- Vindesine
(affect metaphase); affects polymerization

107
Q

What are the Cytoskeletal Chemotherapeutics?

A

Breast cancer (taxol, vincristine)

Testicular cancer (vincristine)

Hodgkin’s disease and other lymphomas (MOPP regimen)
(vincristine)

Childhood leukemias

Rhabdomyosarcoma

Neuroblastoma

108
Q

What are the Vinca SE’s (cytoskeletal chemotherapeutics)?

A

loss of white blood cells and blood platelets, gastrointestinal problems, high blood pressure, excessive sweating, depression, muscle cramps, vertigo and headaches, peripheral neuropathy, hyponatremia, constipation, and hair loss

109
Q

What are the Taxane SE’s (cytoskeletal chemotherapeutics)?

A

nausea and vomiting, loss of appetite, thinned or brittle hair, pain in the joints of the arms or legs lasting two to three days, changes in the color of the nails, and tingling in the hands or toes

bruising or bleeding, Hand-foot syndrome, fever, chills, cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe exhaustion, skin rash, facial flushing, female infertility by ovarian damage

110
Q

What is the MOA of Topoisomerase inhibitors (G2 Phase)?

A

Topoisomerase (Top1) inhibitors interfere with the action of topoisomerase enzymes (Top I and II), 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.

(control change of DNA structure)

111
Q

What are the names of Topoisomerase inhibitors (G2 Phase)?

A
  • Topotecan, Irinotecan
  • Etoposide
  • Teniposide
112
Q

What is Hormonal Therapy (G1 Phase)?

A

Objective:
Starve cancer cells from hormonal signals necessary for growth

Approach:
- Hormone blocking drugs at target cell
- Prevent hormone production

Indications:
- Breast cancer
- Ovarian cancer
- Prostate cancer
- Endometrial cancer

113
Q

What are the types of hormonal antagonists?

A

Selective estrogen receptor modulators (SERMs)

Aromatase inhibitors (AI)

Selective androgen receptor modulators (SARMs)

114
Q

What are the Selective Estrogen Receptor Modulators (SERM)?

A

ER - positive breast cancer cells

Changes in geneexpression, preventing cell division

Drugs:
- Tamoxifen
- Raloxifene
- Toremifene

115
Q

What are the SERM Indications?

A

Advanced or metastatic breast cancer

High risk population for invasive breast cancer (e.g. ductal carcinoma in situ)

Recent use in lung tumor and GBM

116
Q

What do SERMs do?

A

inhibition of estrogen’s growth stimulating effects (compete w/ estrogen)

117
Q

What is Tamoxifen Chemotherapy?

A

Anti-estrogen affinity is dependent on primary metabolite, endoxifen (100x more active).

CYP2D6 enzyme responsible for metabolism of tamoxifen

CYP2D6 polymorphisms – lower activity can reduce endoxifen formation and drug effectiveness

Be careful of potential drug-drug interactions with antidepressants (Paroxetine, fluoxetine, bupropion) which can reduce endoxifen levels even with functional CYP2D6 allele

118
Q

What are Aromatase Inhibitors (AI)?

A
  • Exemestane
  • Anastrozole
  • Letrozole

(prevents hormone formation)

119
Q

What are SERM & AI Indications?

A

Advanced or metastatic breast cancer

High risk population for invasive breast cancer (e.g. ductal carcinoma in situ)

120
Q

What is Specific Androgen Receptor Modulators (SARM)?

A

(Flutamide,
Bicalutamide)
Competitively binds AR

121
Q

What are the adverse side effects of chemotherapy drugs?

A

Bone marrow depression
- Anemia
- Bleeding
- Infections
- Secondary cancers (Procarbazine)

Teratogenesis

Carcinogenesis

Resistance

122
Q

What is the Combination therapy?

Principles of drug selection for CT:

A
  • active when used alone
  • different mechanisms of action (including different mechanisms for the development of resistance) and/or different chemical classes
    – NCCS vs. CCS (NCCS to draw cells into particular stage for CCS kill)
    – active in different stages of cell cycle
  • different toxicities
123
Q

What is the Combination therapy?

Enables use of more specific strategies (recruitment and synchrony)
Can result in:

A
  • synergistic effects (effect greater than the sum of the actions of the individual drugs) at lower doses with decreased toxicity
    – e.g., Daunorubicin (Genotoxic Agent) + Cytarabine (Pyrimidine Antagonist)
  • decreased development of resistance
  • broader cell kill in cancers that consist of a heterogeneous tumour cell population
124
Q

What is the summary?

A
  • Chemotherapy drugs can be classified based on the mode they inhibit stages of cell cycle
  • Drugs are cell cycle specific and block cell replication
    – 5-FU (S-phase), Tamoxifen (G1-phase)
  • Other drugs are non-cell cycle specific, blocking key enzymatic events important for cell replication
    – Daunorubicin or cisplatin (cytotoxic)
  • Chemotherapy drugs also act on normal cells
  • Combination therapy can boost therapeutic success and reduce non-specific effects

Daunorubicin (Genotoxic Agent) + Cytarabine (Pyrimidine Antagonist)

  • Invariably, chemotherapy can fail…
125
Q

What is the Resistance Mechanisms to Chemotherapy?

A

Increased expression of target proteins

Failure of the drugs to enter target cell or increased
intracellular drug ejection rate

Drugs fail to reach target cells

The target molecule is no longer present

The target molecule is altered
- Mutation/deletion

Often more than one of these!

126
Q

What is DHFR (CANCER)?

A

Increased concentrations of DHFR enzyme in cancer cells (gene amplification)

127
Q

What is the P-glycoprotein?

A

Failure of drugs to enter cancer cells
- in plasma mem.
- drives efflux of drug (actively pumping out the drug from the cell)

128
Q

P-glycoprotein?

A

First multidrug resistance mechanism to be characterized (Vic Ling, OCI, 1975)

P-glycoprotein is transmembrane ATP-dependent efflux pump

Actively transports many types of chemotherapy from cells
(anthracyclines, vinca alkaloids, taxanes)

Overexpression in cancers causes drug resistance

P-glycoprotein inhibitors tested in clinical trials

129
Q

What is resistance to Tamoxifen?

A

The target molecule is no longer present

Triple Negative Breast Cancer= ER-,PR-, HER2-
- v. aggresive b/c doesn’t express
- therefore, how would target it to treat it

130
Q

What is resistance to EGFR inhibitors?

A

inhibition of EGFR by Gefitinib/erlotinib

T790M mutation reduces ATP affinity of gefitinib/erlotinib

131
Q

What is targeting cell survival pathways?

A

Recent evidence that failure of DNA damaged cells to undergo apoptosis is major cause of multidrug resistance (ABT-199, BH3 memetic)

Suppression of apoptosis often occurs due to oncogenic mutations – i.e. common feature of cancers

Potential to reverse this mechanism by molecular therapies – e.g. p53 gene therapy or small molecule inhibitors of PI3-kinase pathway

132
Q

Where is Chemotherapy Going?

A

Incremental improvements in patient outcome continue, using newer drugs and combinations

Unlikely that this will result in major improvements in cure rates for common forms of cancer

Over past 2-3 years drug development programs refocused on molecular targeted therapeutics

Potential for major advances based on new biology

Molecular oncology revolution will need close interactions between clinical oncology, pathology, pharmacology, and basic science

133
Q

What is New Generation Chemotherapeutics?

A

Target specific enzymes (kinases)

Imatinib (Gleevec) selective tyrosine kinase inhibitor (TKi)- Bcr-Abl, Kit and PDGF-prevents the phosphorylation of specific proteins involved in cell growth and differentiation

Also used as last line of defense to treat cancers with other overactive TKi

134
Q

What is the Philadelphia Chromosome?

A

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 Ph+ CML and other tumours

135
Q

What is Monoclonal Antibody Therapy

Rituximab (Rituxan, Mabthera)

A

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

Side effects include severe hypersensitivity reactions, anaphylactic shock

136
Q

What is Monoclonal Antibody Therapy - Trastuzumab (Herceptin)?

A

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

HER2 overexpressed in some cancers (25% breast cancers); associated with faster growth and higher relapse

Currently indicated for HER2+ metastatic breast cancer and early stage HER2+ breast cancer

Side effects include-allergic rxs; heart muscle damage (heart failure); pulmonary toxicity

137
Q

What is Monoclonal Antibody Therapy - Cetuximab (Erbitux)?

A

Chimeric (mouse/human) monoclonal antibody against epidermal growth factor receptor protein (EGFR)

EGFR overexpressed in some cancers, signals KRAS downstream.

metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer

Side effects include: acne, fevers, chills, hypotension, bronchospasm, dyspnea, wheezing, angioedema, anaphylaxis, and cardiac arrest

Resistance associated with upregulation of HER2

138
Q

What are the Antibody-drug conjugates?

A

Antibody-drug conjugates (ADCs)

combines the properties of monoclonal antibodies (mAbs) with cytotoxic small molecule drugs.

monoclonal antibody, a stable linker and a cytotoxic (anticancer) agent

Monoclonal antibodies are attached to biologically active drugs by chemical linkers with labile bonds

Combining mAbs targeting with cytotoxic drugs, allows discrimination between healthy and diseased tissue.

139
Q

What are Antibody-drug conjugates?

Brentuximab vedotin (Adcetris)

A
  • Used in Hodgkin’s and anaplastic large cell lymphomas
  • Anti-CD30 mAb combined with the anti-mitotic monomethyl auristatin E (MMAE, blocks microtubule formation)
  • MMAE is a synthetic peptide derived from molluscs
    – 200x more potent than vinca, cannot be given alone
  • Side effects: peripheral neuropathy, neutropenia, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, fever, rash, thrombocytopenia, cough and vomiting
  • Black box warning: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
140
Q

What are Antibody-drug conjugates?

Trastuzumab emtansine

A

Used in HER+ breast cancer patients who used Herceptin

Anti-HER2 mAb combined with the anti-mitotic MERTANSINE (DM1) – inhibits microtubule polymerization

Common side effects: fatigue, nausea, musculoskeletal pain, thrombocytopenia (low platelet counts), headache, increased liver enzyme levels, and constipation,

Rare SE: hepatotoxicity (liver damage), liver failure, hepatic encephalopathy, and nodular regenerative hyperplasia; heart damage interstitial lung disease, thrombocytopenia; and peripheral neuropathy

141
Q

What is the New Gen Chemotherapeutics?

A

Angiogenesis inhibitors (VEGF)
- Bevacizumab (Avastin)-approved in 2004 for metastatic colorectal cancer and NSCL cancer, 2009 RCC, 2011, GBM

  • Targets new endothelial cell growth into the tumor
  • Advantages are fewer side effects, less chance of resistance
  • Disadvantages- angiogenesis is important in wound healing and normal development, long term effects of treatment yet unknown
142
Q

What are the other targeted therapies?

A

Cyclin Dependent Kinase inhibitors – Flavoperidol

Farnesyl transferase inhibitors – R115777

Matrix Metalloproteinase inhibitors – NSC683551

Proteosome inhibitor – Bortezomib (Velcade)

DNA demethylating agent – 5-Azacytidine (Vidaza)

Parp inhibitors (PARPi) – synthetic lethality

143
Q

What are the DNA strand break repair pathways?

A

Inhibit:
- Homologous recombination
- Non-homologous end-joining
- Base excision repair (BER)

144
Q

What is the mechanism of cell death from synthetic lethality?

A

as Induced by Inhibition of Poly(Adenosine Diphosphate [ADP]–Ribose) Polymerase 1 (PARP1)

force the cell into the drug

145
Q

What is Gene therapy?

A

The potential benefits of gene therapy are two-fold:
- Gene-based treatments can attack existing cancer at the molecular level, eliminating the need for drugs, radiation or surgery (CRISPR/Cas9)
- Identifying cancer susceptibility genes in individuals or families can have a major role in preventing the disease before it occurs
- All experimental!

146
Q

What is CAR-T cell-based therapies?

A
  • Using patients own T-Cells
  • T-cells engineered to recognize specific tumour marker
  • Cells expander in vitro
  • CAR-T cells used to replace patients T-Cells
  • T-Cells attack and kill cancer cell

Issues
- Tumour Lysis Syndrome
- Antigen that T-Cells recognize becomes downregulated or no-longer expressed

Pharmacology (Winter) (23 decks)

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