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Pharmacology 3001 > Anineoplastic and Anticancer Agents - Farrell > Flashcards

Anineoplastic and Anticancer Agents - Farrell Flashcards

1
Q

What is cancer?

A

Loss in normal mechanisms that govern cell survival, proliferation, and differentiation
They keep growing, even where there is no space, when most cells stop

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2
Q

Causes of cancer (2)

A
  1. Oncogenes

2. Tumor suppressor genes

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3
Q

Oncogenes

A

Normally tightly regulated growth and differentiation of cells
ie. Bcl-2: unregulated or deregulated in cancer

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4
Q

Tumor suppressor genes

A

Normally suppress overgrowth of cells

ie. p53: down regulated or absent in many cancers

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5
Q

Causes of cancer

A

Genetics

Environmental

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6
Q

Most common forms of cancer

A

Lung, prostate, breast, colorectal

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7
Q

Cancer pathophysiology (3)

A
  1. Initiation
  2. Promotion
  3. Progression
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8
Q

Initiation

A

Chemical or physical carcinogen causes mutation

Not identified as foreign by immune system

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9
Q

Promotion

A

Growth factors and promoters of cell proliferation

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10
Q

Progression

A

Transformation to malignant from benign

Further mutation and variation with tumor

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11
Q

Stages of cancer

A

Stage 0-IV
0: early, not detectable
I-III: higher number reflects size and spread
IV: invasion of other tissues and metastasis

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12
Q

How is cancer treated? (3)

A
  1. Surgical removal of tutor
  2. Radiation
  3. Chemotherapy
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13
Q

Targets of chemotherapy (3)

A
  1. Target cell cycle
  2. Target proliferation pathways
  3. Target cancer specific molecules
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14
Q

Traditional antineoplastic agents

A 
Target cell cycle
Kill rapidly dividing cells
1. Alkylating and platinum agents
2. Antimetabolites
3. Topoisomerase inhibitors and antibiotics
4. Vinca alkaloids
5. Taxanes
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15
Q

Newer anticancer drugs

A

Target proliferation pathways

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16
Q

Target anticancer agents

A

Target cancer specific molecules

  1. Cellular markers
  2. Growth and proliferation
  3. Angiogenesis
  4. Hormone sensitive growth
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17
Q

Principles of chemotherapy (3)

A
  1. Chosen agent must be tolerable
  2. Dose and regiment must be chosen to maximize effectiveness
  3. Use combinations to increase efficacy
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18
Q

MTD

A

Maximum tolerated dose

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19
Q

Cyclic therapy

A

Multiple cycles of therapy to combat multiple growth cycles of tumor

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20
Q

Alkylating agents

A

Crosslink DNA causing damage and death
Groups of agents based on their structures
1. Bis(chloroethyl)amine group
2. Platinum containing agents

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21
Q

Bis(chloroethyl)amine

A

Alkylating agent

ie. Cyclophosphamide

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22
Q

Cyclophosphamide

A

Needs to be activated in liver
Metabolites cross-link DNA by binding
Can bind other molecules with similar functional groups (SH, OH, NH) like lipids and proteins

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23
Q

Platinum containing agents

A

Similar to alkylating agents but do not necessarily contain alkyl groups
Cause inter and intra DNA strand cross-links in cells

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24
Q

Antimetabolites

A

Similar in structure to endogenous compounds like Folic acid and nucleotide bases
Interfere with nucleotide synthesis
Prevent DNA synthesis
ie. Mercaptopurine, fluorocuracil, folic acid antagonists

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25
Q

Mercaptopurine

A

Structurally similar to adenine
Interacts with enzymes involved in purine nucleotide synthesis
Incorporated into RNA and DNA but unable to correctly basepair
Interferes with DNA replication and RNA translation

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26
Q

Fluorouracil

A

5-FU
Similar in structure to uracil and thymine
Binds to thymidylate synthase
Prevents further synthesis of thymide nucleotides

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27
Q

Folic acid antagonists

A

Folate, folic acid, vit B9
Essential cofactor in DNA and protein synthesis
Includes methotrexate

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28
Q

Methotrexate

A

Structurally similar to folic acid

Prevents nucleotide synthesis by eliminating cofactor

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29
Q

Topoimerase I inhibitors

A

ie. Topotecan
Bind to topoimerase I
Produces complex that prevents further DNA replication and transcription
Halting replication process signals cell death

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30
Q

Topotecan

A

Topoimerase I inhibitor, fixed enzyme to DNA

Replication cannot procede

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31
Q

Topoimerase II inhibitors

A

Includes Anthracycline antibiotics
Prevents relegation of DNA by TopoII
Strand breaks in DNA signals cell death pathways

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32
Q

Anthracycline antibiotics

A

ie. Doxorubicin
Natural products isolated from Strep species
Intercalate between strands and stabilize DNA-TopoII complex
Forms free radicals that can cause DNA damage
Cause cause cardiotoxicity

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33
Q

Doxorubicin

A

Topoimerase II inhibitor

Anthracycline antibiotic

34
Q

Vinca alkaloids

A

Natural products from Rosy periwinkle
ie. Vincristine
Prevent microtubule formation of mitotic spindles
Inhibit cellular division
Neurotoxicity: abdominal, bone pain and constipation

35
Q

Vincristine

A

Vinca alkaloid

Interferes with microtubule formation of mitotic spindle

36
Q

Taxanes

A

Include taxol, natural produce isolated from Pacific Yew
Now can be man made from other yew species
Stabilize microtubules of mitotic spindle so it cannot dissemble
Inhibits cellular division
Works the opposite as vinca alkaloids

37
Q

Docetaxel

A

Taxane

Stabilizes microtubules so mitotic spindle cannot dissemble

38
Q

Adverse effects of antineoplastic drugs

A
  1. Cannot differentiate between cancerous and noncancerous cells
  2. Cells with high turnover rate are more susceptible to damage (oral cavity, GI tract, skin and hair, immune system)
  3. Infections are common complications (antibiotics, antifungals may be used for prophylaxis)
39
Q

Combination therapy

A

Use drugs with different MOA
Maximim tutor cell killing with lower toxicity to host cells
Reduced drug resistance to tumor
Combinations of old and new antineoplastics are first line chemotherapy in most cncers

40
Q

How to choose a combination therapy (4)

A
  1. Efficacy (each drug must be effective alone)
  2. Toxicity (drugs must have different adverse effects, may need lower doses)
  3. Scheduling (chose drugs with similar recovery intervals and shortest interval)
  4. MOA (different MOA to increase efficacy, decreases possibility of resistance)
41
Q

CAV combination regimen

A

C: cyclophosphamide
A: adriamycin (doxorubicin)
V: vincristine

42
Q

Anticancer drugs targeting cellular markers

A

Therapeutics that identify unique characteristics of cancer cells
ie. CD20 protein

43
Q

CD20

A

Protein expressed on cell surface of immune B cells

Many forms of lymphoma and leukaemia are CD20 positive

44
Q

Rituximab

A

mAb targeted to CD20
Flags B cells for destruction by immune system
Death of all CD20 positive immune cells

45
Q

Radioimmunoconjugates

A

Radiation therapy effective in treating localized solid tumors
Cause significant damage to neighbouring tissues

46
Q

mAb conjugated radioactive isotopes

A

Targets radioactivity to tissues expressing antigen

47
Q

Tostiumomab

A

CD20 targeted by mAB conducted with 131-Iodine

Radiation kills CD20 positive and adjacent cells

48
Q

Cancer vaccines

A

Administed to initiate host immune response against tutor

Immune system does not typically recognize cancer cells as threats

49
Q

Personalized medicine

A

Move cells from patients tumor or blood
Manipulate and reinfect into patient
ie. provenge vaccine
ie. CRISPR gene editing

50
Q

Anticancer drugs targeting new blood vessel growth

A

Blood vessel growth feeds timor

Inhibit VEGF: vascular endothelial growth factor

51
Q

VEGF

A

Vascular endothelial growth factor
Secreted from cells to promote new blood vessel formation
In cancer growth, tumor growth requires greater blood vessel supply to continue proliferation and invasion

52
Q

Drugs that interfere with VEGF signaling

A
  1. mAb targeted against VEGF

2. Small molecule TK inhibitors

53
Q

mAb targeted against VEGF

A

Bevacizumab
Binds circulating VEGF
Less VEGF available to bind to receptor
Results in reduced blood vessel growth in tumors

54
Q

Small molecule TK inhibitors to VEGFR

A

ie. Sorafenib

Binds to intracellular domain of VEGFR prevents initiation of signal cascade

55
Q

Epidermal growth factor

A

EGF
Stimulates cellular growth and proliferation
Pathway gets amplified causing increased cell growth

56
Q

EGFR and HER-2

A

Tyrosine kinase receptors
Dimerize upon ligand binding
Phosphorylation of Tyrosine residues to initiate intracellular signal cascades
HER-2: human epidermal growth factor receptor 2, commonly unregulated in breast cancer

57
Q

Tyrosine kinases

A 
Receptor TKs (ie HER-2)
Cytosolic TKs (ie BCR-ABL)
58
Q

Drugs that interfere with TK signaling (3)

A
  1. Monoclonal antibodies against TK ligand)
  2. mAbs against TK signaling
  3. Small molecule TK receptor inhibitors
59
Q

mAbs against EGFR

A

ie. Trastuxumab

60
Q

Trastuxumab

A

mAb against HER-2

Now first tine therapy against HER-2 positive breast cancer

61
Q

Trastuzumab emtansine

A

T-DM1
Tastuzumab and antimicrotubule agent
Targets HER-2 positive cells
Cytotoxic drug enters cell and inhibits microtubule assembly
Prolongs survival in patients with HER-2 positive breast cancer compared to either drug alone

62
Q

Small molecule TK receptor inhibitors for EGFR

A

ie. Gefitnib
Binds to intracellular domain of EGFR
Prevents initiation of signaling cascade
Inhibits cell growth and proliferation

63
Q

Gefitnib

A

Small molecule TK receptor inhibitors for EGFR

Binds to intracellular domain of EGFR

64
Q

Bcl-2

A

Pro-survival hormone

Very complex signaling

65
Q

BCR-ABL

A

TK cytosol receptor involved in Bcl-2 expression

Allows for survival

66
Q

Imatinib

A

Interferes with BCR-ABL signaling

Prevents upregulation of Bcl-2

67
Q

Hormone sensitive cancers

A

Tumor cells grow and proliferate in response to hormone receptor activation
ie. Ovarian, breast and prostate cancers
Tumor cells removed and tested for hormone receptor status

68
Q

Drugs that target estrogen production

A

Leuprolide
Letrozole
Tamozifen

69
Q

Leuprolide

A

Synthetic analogue of GnRH (acts on anterior pituitary)
Agonist-antagonist
Over time, decreases RSH and LH production (negative feedback) decreases estrogen
Also decreases testosterone, so can be used in prostate cancer

70
Q

Letrozole

A

Inhibits aromatase enzyme necessary for conversion of estrogen

71
Q

Tamoxifen

A

Estrogen antagonist
Competes for estrogen receptor binding in tumor cells
Slows growth of estrogen sensitive tumor cells

72
Q

Drug resistance

A
  1. Primary
  2. Acquired
  3. Altered expression of proteins
73
Q

Primary resistance

A

Drugs ineffective on first attempt
Most commonly related to impaired responses to cell death signals in tumor cells
(ie. p53 inactivation)

74
Q

Acquired resistance

A

Drugs worked first and then became ineffective

Related to adaptation and mutation of tumor cells

75
Q

Altered expression of protein in tumor cells

A
  1. Increased DNA repair mechanisms
  2. Alterations in drug targets
  3. Removal of drug from target cells (ie. upregulation of p-glycoprotein pumps)
76
Q

P-glycoprotein pumps

A

Increase drug efflux

Particularly sensitive to: antibiotics, vinca alkaloids, taxans and small molecule inhibitors

77
Q

R-CHOP regimen

A 
Non-Hodkin's Lymphoma
R: rituximab
C: cyclophosphamide
H: hydroxydaunorubucin (doxorubicin)
O: oncovin (vincristine)
P: prednisone (corticosteroid, reduces some side effects)
78
Q

Cisplatin

A

Platinum containing agent

79
Q

Bevacizumab

A

mAb targeted to VEGF

80
Q

Sorafenib

A

Small molecule TK inhibitor

Binds intracellular domain of VEGFR

Pharmacology 3001 (19 decks)

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