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Pharmacology quiz 4 > Anticancer Therapy part 2: anticancer drugs > Flashcards

Anticancer Therapy part 2: anticancer drugs Flashcards

1
Q

List 3 key areas in the cell cycle that chemotherapy works

A
  1. Inhibition of cell growth (growth factor proteins; hormones)
  2. Inhibitors of DNA replication
  3. Inhibitors of cell division
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2
Q

Describe the range of chemo drugs

A

Wide range of drugs:

  • non-cell cycle dependent (genotoxic agents)
  • cell cycle dependent: cytoskeletal inhibitors, topoisomerase inhibitors, antimetabolites, hormonal therapy
  • Other treatments
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3
Q

Cancer drugs can be divided into what 2 general classes? Describe

A

1) Cell cycle specific drugs (CCS): especially plant alkaloids and anti-metabolites
2) Non cell cycle specific drugs (NCCS): especially alkylating agents and some natural products

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4
Q

Where do antineoplastic agents fit into the two general classes of cancer drugs?

A

They are organized according to their chemical class, MOA, therapeutic use, or their toxicities

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5
Q

T/F: all cells progress through the cell cycle

A

True! all normal and neoplastic cells do

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6
Q

CCS drugs will be least effective in low growth or high growth fraction tumors? Explain

A
  • least effective in low growth fraction cells.
  • For low growth fraction cells, they spend most of the time in G0
  • CCS drugs target cells in a specific portion of the cell cycle (either growth or division)
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7
Q

Why might we follow up chemo with a NCCS drug with a CCS drug?

A
  • NCCS drugs may recruit cells into the cell cycle

- CCS drug can then be more effective

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8
Q

Briefly compare CCS and NCCS drugs

A

CCS:

  • primary action only during a SPECIFIC phase of the cell cycle
  • only proliferating cells are killed ; high growth factor tumors are preferentially eliminated
  • schedule dependent ; based on DOA and timing rather than dose of drug

NCCS:

  • works in any phase, including G0, although final toxicity may be manifested during a specific phase
  • both proliferating and non-proliferating cells killed; attacks both high and low growth factor tumors
  • is dose dependent rather than schedule
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9
Q

MOA of genotoxic agents (NCCS)

A
  • affect the function of nucleic acids
  • bind directly to DNA
  • inhibit DNA replication enzymes
  • DNA damage leads to apoptosis
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10
Q

Genotoxic agents include what types of drugs?

A

Alkylating and intercalating agents

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11
Q

Genotoxic agents bind to DNA in a few different ways to damage it. List them

A
  • alkylation of DNA bases
  • Creation of inter/intra-strand DNA cross-links
  • Induce mispairing of nucleotides
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12
Q

What are the most commonly used genotoxic agents?

A
  • Platinum based chemo agents
  • doxorubicin analogs
  • cyclophosphamide-prodrug
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13
Q

List a few Pt-based chemo drugs

A
  • cisplatin
  • carboplatin
  • oxaliplatin
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14
Q

What is an advantage of cycllophosphamide genotoxic agents?

A
  • given as a pro-drug
  • orally active
  • less side effects in normal cells
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15
Q

List adverse effects of commonly used genotoxic agents

A
  • Hematopoietic effects; GI effects; hair loss [less likely to occur with cyclophosphamide]
  • associated with increased risk of developing cancer
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16
Q

Cisplatin, doxorubin, and cyclophosphamides all have specific adverse effects that they cause. Describe

A
  • Cisplatin: renal toxicity, ototoxicity
  • Doxorubin-based compounds: heart effects (cardiomyopathy, CHF)
  • Cyclophosphamide compounds: bladder effects, hemorrhagic cystitis
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17
Q

Anti-metabolites target what phase of the cell cycle?

A

S-phase (synthesis, DNA replication phase)

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18
Q

describe the MOA of anti-metabolites

A
  • structurally similar to natural metabolites
  • prevents cell from carrying out vital functions and they are unable to grow and survive
  • interfere with the production of nucleic acids, RNA, DNA (why it’s S-phase specific)
  • Logic: if new DNA can’t be made, cells are unable to divide
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19
Q

List 3 types of anti-metabolite drugs

A
  • Folate antagonists
  • purine antagonists
  • pyrimidine antagonists
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20
Q

Describe folate antagonist’s MOA and list one drug example

A
  • Ex: Methotrexate (MTX)
  • MOA: inhibit dihydrofolate reductase, an enzyme involved in the formation of purine and pyrimidine nucleotides for DNA synthesis
  • without DNA replication, cell growth is blocked!
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21
Q

Methotrexate indications

A
  • acute lymphocytic leukemia
  • large cell lymphoma
  • high grade lymphoma
  • head and neck cancers
  • breast cancer
  • bladder cancer
  • RA
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22
Q

Name a next-generation anti-folate (folate antagonist) and describe its MOA

A

Pemetrexed

  • inhibits DNFR
  • inhibits thymidylate synthase
  • inhibits glycinamide ribonucleotide formyl transferase
  • overall more effectively inhibits DNA and RNA synthesis than Methotrexate
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23
Q

Describe the use of folinic acid as an adjuvant in antifolate therapy

A
  • Folinic acid is aka leucovorin
  • used with methotrexate and antifolates to reduce myelosuppression (rescue therapy, as this is often the most significant dose-limiting adverse rxn)
  • some DNA and RNA synthesis is allowed to be carried out in normal cells (blood, GI tract)
  • overall, in patients who qualify this type of adjunct therapy helps to minimize adverse rxns of folate antagonists
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24
Q

What are purines?

A

compounds used to build the nucleotides of DNA and RNA

- adenine and guanine are purines

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25
Q

How do purine antagonists work?

A

Prevent continued replication of DNA, and therefore cell division

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26
Q

List two purine antagonists and name the nucleotide it mimics

A
  • 6-Mercaptopurine (6MP): adenine

- 6-Thioguanine (6TG): guanine

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27
Q

Purine antagonist indications

A
  • acute lymphocytic or myelocytic leukemia
  • lymphoblastic leukemia (esp. in children)
  • acute myelogenous leukemias
  • infl. bowel disease
  • organ transplant
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28
Q

Why is the thiopurine methyltransferase enzyme important?

A
  • Helps metabolize thiopurine drugs like 6MP and 6TG (purine antaonists)
  • It catalyzes the S-methylation of thiopurine drugs
  • defects in the gene that codes for this enzyme leads to decreased metabolism of thiopurine drugs and hence decreased inactivation. This leads to enhanced side effects like bone marrow toxicity.
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29
Q

Describe thiopurine methyltransferase (TPMT) polymorphisms

A
  • normal allele found in 90% of the population
  • WT/MUT allele found in 10% of the population; phenotype is intermediate metabolizer of thiopurines
  • MUT/MUT allele of the TPMT gene found in 1/300 people. These people are poor metabolizers
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30
Q

Why is knowing a patient’s TPMT phenotype important prior to Tx with thiopurines?

A
  • TPMT is a deactivation pathway enzyme, so if the patient is a poor metabolizer the result is more active drug and increased toxicity (overdose situation)
  • knowing TPMT phenotype is important especially in leukemia and RA
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31
Q

Pyrimidine antagonists MOA

A
  • block synthesis of pyrimidine containing nucleotides (cytosine, thymine)
  • Stop DNA/RNA synthesis and inhibit cell division
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32
Q

Name two pyrimidine antagonists used for cancer therapy and name which nucleotide they resemble

A
  • 5-Fluorouracil (thymine, uracil [RNA])

- Cytarabine (cytosine)

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33
Q

5-fluorouracil MOA

A

acts as an anti-metabolite that irreversibly inhibits Thymidylate synthase by competitive binding

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34
Q

Main indication for 5-Fluorouracil? Other indications?

A

Main: Colorectal cancer
Other: breast, pancreatic, stomach, GI tract, esophageal, liver, skin

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35
Q

Role of the mitotic spindle

A

Attaches to kinetochores and helps align chromosomes and then separate them in anaphase of mitosis

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36
Q

What are MAD and BUB?

A

Part of the mitotic spindle checkpoint that halt the cell cycle until all chromosomes are aligned at the middle of the cell.
It is made of microtubule polymers

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37
Q

MOA of cytoskeletal inhibitors (mitosis)

A
  • affect the mechanics of cell division in the mitosis phase

- without proper microtubule formation, cell division is not possible

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38
Q

Name two types of cytoskeletal inhibitos and how they affect the microtubule

A

1) Taxanes: affects depolymerization of the microtubule in anaphase
2) Vinca alkaloids: affects polymerization of the tubule in metaphase

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39
Q

List 2 examples of Taxanes

A

Paclitaxel

Docetaxel

40
Q

List two examples of Vinca alkaloids

A

Vincristine
Vimblastin
Vindesine

41
Q

Vinca side effects

A
  • loss of WBC’s and platelets
  • GI problems
  • High BP
  • sweating
  • depression
  • muscle cramps
  • vertigo and headaches
  • peripheral neuropathy
  • constipation
  • hair loss
42
Q

Taxane side effects

A

Basically everything

  • N&V, appetite loss, thin/brittle hair, pain in joints of arms or legs, change in nail colour, tingling in hands and toes
  • bruising or bleeding, hand-foot syndrome, fever, chills, cough, sore throat, dysphagia, dizziness, SOB, exhaustion, rash, flushing, female infertility by ovarian damage
43
Q

What phase of the cell cycle do Topoisomerase I and II inhibitors work?

A

G2

44
Q

MOA of Topoisomerase inhibitors

A
  • Topoisomerase (Top) 1 inhibitors inferfere 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, leading to apoptosis
45
Q

Name two Top I inhibitors that prevent the re-sealing of DNA strands

A

Topotecan, Irinotecan

[-tecans]

46
Q

What does Tyrosyl-DNA phosphodiesterase 1 (TDP1) do?

A

Reverses the toxicity of Top1 inhibitors; can re-seal DNA

47
Q

Name two Top II inhibitos

A

Etoposide, Teniposide

[-posides]

48
Q

TDP2 does what?

A

Reverses the toxicity of Top II inhibitors

49
Q

Steroid hormones act on what phase of the cell cycle?

A

G1 phase

50
Q

Describe steroid hormone action in the cell

A
  1. Steroid hormone enters target cell
  2. hormone binds to receptor (in cytosol or nucleus), induces conformational change
  3. Hormone-receptor complex binds to DNA, induces start of transcription
  4. Many mRNA transcripts are produced, amplifying the signal
  5. Each transcript is translated many times, further amplifying the signal
51
Q

What is the goal of hormonal therapy in the G1 phase?

A

Starve cancer cells from hormonal signals necessary for growth

52
Q

Approach to hormonal therapy

A
  • hormone blocking drugs at target cell

- prevent hormone production

53
Q

Indications for hormone Tx

A

breast, ovarian, prostate, endometrial cancers

54
Q

List the types of hormonal antagonists

A
  • Selective estrogen receptor modulators (SERMs)
  • Aromatase inhibitors
  • Selective androgen receptor modulators (SARMs)
55
Q

MOA of SERMs

A
  • target estrogen receptors in positive breast cancer cells
  • inhibits estrogen’s growth stimulating effects in G1 phase
  • changes gene expression, preventing cell division
56
Q

List drug examples of SERMs

A
  • Tamoxifen
  • Raloxifene
  • Toremifene
57
Q

Describe how Tamoxifen chemotherapy utilizes an active metabolite

A

Anti-estrogen therapy of Tamoxifen is dependent on its primary metabolite, endoxifen (100x more active)
- CYP 2D6 is responsible for Tamoxifen metabolism

58
Q

How do CYP 2D6 polymorphisms affect Tamoxifen chemotherapy?

A

lower activity of CYP 2D6 can reduce endoxifen formation and hence drug effectiveness

59
Q

What kind of Drug-drug interactions may occur with Tamoxifen treatment?

A

Potential DDIs with antidepressants (Paroxetine, fluoxetine, bupropion) which can reduce endoxifen levels even with functional CYP 2D6 allele

60
Q

SERM indications

A
  • advanced or metastatic breast cancer
  • high risk population for invasive breast cancer
  • recent use in lung tumor and glioblastoma
61
Q

List 3 aromatase inhibitors. How do they work?

A
  • Exemestane
  • Anastrozole
  • Letrozole

Prevents hormone formation

62
Q

AI indications

A
  • similar to SERM

- used in high risk populations for invasive breast cancer, and in advanced or metastatic breast cancer

63
Q

List 2 SARMs. Briefly describe their MOA

A
  • Flutamide
  • Bicalutamide

Competitively binds the androgen receptor

64
Q

Describe the principles of drug selection for combination chemotherapy

A
  • active when drug is used alone
  • select drugs with different MOA (including different mechanisms of resistance devl.) and/or different chemical classes
  • NCCS vs. CCS or select drugs that are active in different stages of the cell cycle
  • Try to select drugs with different toxicities
65
Q

Describe the benefits of Combination therapy (combo. chemotherapy)

A

Enables use of more specific strategies (recruitment and synchrony)
Can result in:
- synergistic effects at lower doses with decreased toxicity
- decreased devl. of resistance
- broader cell kill in cancers that consist of a heterogeneous tumor cell population

66
Q

Define synergistic effects

A

The effect of two drugs in combination is greater than the sum of the actions of the individual drugs used alone

67
Q

What is a good synergistic drug combination?

A

Cytarabine (pyrimidine antagonist) + 6-thioguanine (purine antagonist)

68
Q

Brief summary of chemo drugs

A
  • Chemo drugs can be classified based on where/if they inhibit the cell cycle
  • CCS drugs block cell replication in a specific phase
  • NCCS drugs block key enzymatic events important for cell replication
  • Chemo drugs also act on normal cells
  • Combo. therapy can boost therapeutic success and reduce non-specific events
  • Invariably, chemo can fail
69
Q

Adverse effects of chemo drugs

A
  • Bone marrow depression (leads to anemia, bleeding, infections, secondary cancers)
  • teratogenesis (abnormal physiological devl.)
  • Carcinogenesis (initiation of cancer formation)
  • Resistance
70
Q

List and briefly describe 3 Cellular mechanisms of chemo drug resistance

A

1) Drug target alterations: up-regulation of enzyme target (ex: thymidylate synthase) ; or enhanced drug metabolism
2) Multi-drug resistance: drug efflux via P-glycoprotein transporters; drug conjugation by glutathione to render it inactive
3) Enhanced survival: suppression of apoptosis; enhanced DNA repair systems to overcome mutations by chemo drugs

71
Q

List and briefly describe 2 non-cellular mechanisms of chemo drug resistance

A

1) Pharmacological sanctuaries: Poor penetration of BBB; poor penetration of drugs into some solid tumors
2) Altered in-vivo growth kinetics: non-cycling cells in hypoxic regions distant from blood vessels (drug can’t access location of tumor); tumor re-population between chemo treatments

72
Q

How can resistance to Methotrexate occur?

A

By increased concentrations (up-regulation) of Dihydroflorate reductase (DHFR) enzyme in cancer cells

73
Q

Describe resistance to chemo drugs due to P-glycoprotein

A
  • P-glycoprotein is a transmembrane ATP-dependent efflux pump
  • it acively transports many types of chemo drugs from cells (anthracyclines, vinca alkaloids, taxanes)
  • Overexpression of P-gly in cancers causes drug resistance
74
Q

amplification of what gene leads to increased synthesis of P-glycoprotein?

A

MDR1

75
Q

What is the resistance mechanism that often leads to resistance to Tamoxifen and 5-Fluorouracil?

A

Their respective target molecule (estrogen receptor for tamoxifen, Thymidylate syntase for 5-Flu) is no longer present

76
Q

Summarize resistance mechanisms to chemotherapy. Why are they hard to overcome?

A

1) increased expression of target proteins
2) failure of drugs to enter target cell or increased intracellular drug ejection rate
3) drugs fail to reach target cells
4) target molecule is no longer present
5) Target molecule is altered (mutation/deletion)

Hard to overcome due to the multi-factoral nature of resistance (ie resistance often involves more than one mechanism)

77
Q

List 2 epidermal growth factor receptor inhibitors. How can resistance to these drugs be achieved?

A

Gefitinib, Erlotinib

Resistance due to a mutation that reduces ATP affinity of the drugs

78
Q

What is a major cause of multi chemotherapy drug resistance?

A

the failure of DNA-damaged cells to undergo apoptosis, often due to suppression of apoptosis due to oncogenic mutations

79
Q

How may we be able to reverse drug resistance due to suppression of apoptosis?

A

Potential to reverse it by molecular therapies, eg: p53 gene therapy or small molecule inhibitors of P13-kinase pathway

80
Q

What are new targets in cancer therapy, ie other targets than the cancer cells themselves?

A
  • Immuno-modulators; interferons and interleukin-2
  • other immune cells

New target is to modify the immune system response to cancer

81
Q

List 3 Monoclonal antibody therapy drugs

A

Rituximab, Trastuzumab, Cetuximab

-mab’s

82
Q

Describe rituximab and it’s MOA

A

Monoclonal Ab therapy

  • binds to CD20 present on B-lymphocytes
  • binding targets the cell to complement-protein-activated phagocytosis of cancer cells and antibody-dependent apoptosis
  • inhibits proliferation of lymphocytes and lymphoma cells
  • SE: severe hypersensitivity reactions and anaphylaxis
83
Q

Describe Trastuzumab and its MOA

A

Monoclonal Ab Tx

  • binds to human epidermal growth factor receptor protein 2 (HER2)
  • HER2 is overexpressed in some cancers and is associated with faster growth and higher relapse
84
Q

Trastuzumab indications and side effects

A

Indications: for HER2+ metastatic breast cancer and early stage HER2+ breast cancer
SE’s: allergic rxn, heart failure, pulmonary toxicity

85
Q

Describe Cetuximab and its MOA

A

It is a Chimeric mouse/human monoclonal antibody against EGFR protein
- EGFR is overexpressed in some cancers, signals KRAS downstream

86
Q

Cetuximab indications and SE’s

A

Indications: metastatic colorectal cancer, lung cancer, head and neck cancer
SE: acne, fever, chills, hypotension, bronchospasm, wheezing, angioedema, anaphylaxis, cardiac arrest

87
Q

Resistance to Cetuximab is associated with what?

A

Up-regulation of HER2, the epidermal growth factor receptor protein-2

88
Q

New generation chemotherapeutics target what?

A

Target specific enzymes (kinases)

89
Q

Imatinib

A
  • selective Tyr-kinase inhibitor
  • prevents phosphorylation of specific proteins involved in cell growth and differentiation
  • Also used as last line of defense to treat canceers with other overactive Tyr kinase
90
Q

Gefitinib and Erlotinib

A

Gefitinib:

  • interrupts mutated or overactive EGFR receptor signaling
  • used in breast and lung cancer
  • can be used in combination with methotrexate

Erlotinib:
- reversible EGFR Tyr-kinase inhibitor (similar MOA to Gefitinib)

These 2 drugs have fewer SE’s as the target is much more selective for tumor cells

91
Q

Describe antibody-drug conjugates (ADCs) and the benefits

A
  • combines the properties of monoclonal antibodies with cytotoxic small molecule drugs
  • consists of a mAb, a stable linker, and a cytotoxic agent
  • mAbs are attached to biologically active drugs by chemical linkers with labile bonds
  • Combining mAbs with cyotoxic drugs allows for discrimination between healthy and diseased tissue
92
Q

List two drug examples of ADCs

A
  • Brentuximab vedotin

- Trastuzumab emtansine

93
Q

How are Angiogenesis inhibitors useful as New Generation Chemotherapeutics? Give a drug example

A

Drug ex: Bevacizumab

  • angiogenesis inhibitors target new endothelial cell growth into the tumor
  • advantages: fewer SE’s, less chance of resistance
  • disadvantages: angiogenesis is imp in wound healing and normal development, long term effects of this drug is still unknown
94
Q

List other targeted anti-cancer therapies and give a drug example

A
  • Cyclin dependent kinase inhibitors: Flavoperidol
  • Farnesyl transferase inhibitors - R115777
  • Matrix Metalloproteinase inhibitors: NSC683551
  • Proteosome inhibitors: Bortezomib
  • DNDA demethylating agent: 5-Azacytidine
95
Q

Describe the 2 important potential benefits of gene therapy for canceer

A
  • gene-based Tx can attack existing cancer at the molecular level, eliminating the need for drugs, radiation or surgery
  • identifying cancer susceptibility genes in individuals or families can have a major role in preventing the disease before it occurs

Unfortunately it is still experimental!

96
Q

Describe two likely approaches to gene therapy

A
  • injecting cancer cells w/ special genes that make the tumor more receptive to the effects of anti-cancer drugs
  • introducing the MDR gene into bone marrow to make stem cells mroe immune to the toxic SE’s of anti-cancer drugs. Stem cells are responsible for the production of blood cells
97
Q

Describe osteopathic and naturopathic therapies

A
  • varying accounts and studies showing benefits and adverse drug reactions to these
  • often, active compound is not known, levels vary, or activities differ
  • If using extracts instead of active compound => can lead to more DDI and ADR
  • not used in clinic

Pharmacology quiz 4 (9 decks)

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