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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
Mercaptopurine
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
26
Fluorouracil
5-FU Similar in structure to uracil and thymine Binds to thymidylate synthase Prevents further synthesis of thymide nucleotides
27
Folic acid antagonists
Folate, folic acid, vit B9 Essential cofactor in DNA and protein synthesis Includes methotrexate
28
Methotrexate
Structurally similar to folic acid | Prevents nucleotide synthesis by eliminating cofactor
29
Topoimerase I inhibitors
ie. Topotecan Bind to topoimerase I Produces complex that prevents further DNA replication and transcription Halting replication process signals cell death
30
Topotecan
Topoimerase I inhibitor, fixed enzyme to DNA | Replication cannot procede
31
Topoimerase II inhibitors
Includes Anthracycline antibiotics Prevents relegation of DNA by TopoII Strand breaks in DNA signals cell death pathways
32
Anthracycline antibiotics
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
33
Doxorubicin
Topoimerase II inhibitor | Anthracycline antibiotic
34
Vinca alkaloids
Natural products from Rosy periwinkle ie. Vincristine Prevent microtubule formation of mitotic spindles Inhibit cellular division Neurotoxicity: abdominal, bone pain and constipation
35
Vincristine
Vinca alkaloid | Interferes with microtubule formation of mitotic spindle
36
Taxanes
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
Docetaxel
Taxane | Stabilizes microtubules so mitotic spindle cannot dissemble
38
Adverse effects of antineoplastic drugs
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
Combination therapy
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
How to choose a combination therapy (4)
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
CAV combination regimen
C: cyclophosphamide A: adriamycin (doxorubicin) V: vincristine
42
Anticancer drugs targeting cellular markers
Therapeutics that identify unique characteristics of cancer cells ie. CD20 protein
43
CD20
Protein expressed on cell surface of immune B cells | Many forms of lymphoma and leukaemia are CD20 positive
44
Rituximab
mAb targeted to CD20 Flags B cells for destruction by immune system Death of all CD20 positive immune cells
45
Radioimmunoconjugates
Radiation therapy effective in treating localized solid tumors Cause significant damage to neighbouring tissues
46
mAb conjugated radioactive isotopes
Targets radioactivity to tissues expressing antigen
47
Tostiumomab
CD20 targeted by mAB conducted with 131-Iodine | Radiation kills CD20 positive and adjacent cells
48
Cancer vaccines
Administed to initiate host immune response against tutor | Immune system does not typically recognize cancer cells as threats
49
Personalized medicine
Move cells from patients tumor or blood Manipulate and reinfect into patient ie. provenge vaccine ie. CRISPR gene editing
50
Anticancer drugs targeting new blood vessel growth
Blood vessel growth feeds timor | Inhibit VEGF: vascular endothelial growth factor
51
VEGF
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
Drugs that interfere with VEGF signaling
1. mAb targeted against VEGF | 2. Small molecule TK inhibitors
53
mAb targeted against VEGF
Bevacizumab Binds circulating VEGF Less VEGF available to bind to receptor Results in reduced blood vessel growth in tumors
54
Small molecule TK inhibitors to VEGFR
ie. Sorafenib | Binds to intracellular domain of VEGFR prevents initiation of signal cascade
55
Epidermal growth factor
EGF Stimulates cellular growth and proliferation Pathway gets amplified causing increased cell growth
56
EGFR and HER-2
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
Tyrosine kinases
``` Receptor TKs (ie HER-2) Cytosolic TKs (ie BCR-ABL) ```
58
Drugs that interfere with TK signaling (3)
1. Monoclonal antibodies against TK ligand) 2. mAbs against TK signaling 3. Small molecule TK receptor inhibitors
59
mAbs against EGFR
ie. Trastuxumab
60
Trastuxumab
mAb against HER-2 | Now first tine therapy against HER-2 positive breast cancer
61
Trastuzumab emtansine
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
Small molecule TK receptor inhibitors for EGFR
ie. Gefitnib Binds to intracellular domain of EGFR Prevents initiation of signaling cascade Inhibits cell growth and proliferation
63
Gefitnib
Small molecule TK receptor inhibitors for EGFR | Binds to intracellular domain of EGFR
64
Bcl-2
Pro-survival hormone | Very complex signaling
65
BCR-ABL
TK cytosol receptor involved in Bcl-2 expression | Allows for survival
66
Imatinib
Interferes with BCR-ABL signaling | Prevents upregulation of Bcl-2
67
Hormone sensitive cancers
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
Drugs that target estrogen production
Leuprolide Letrozole Tamozifen
69
Leuprolide
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
Letrozole
Inhibits aromatase enzyme necessary for conversion of estrogen
71
Tamoxifen
Estrogen antagonist Competes for estrogen receptor binding in tumor cells Slows growth of estrogen sensitive tumor cells
72
Drug resistance
1. Primary 2. Acquired 3. Altered expression of proteins
73
Primary resistance
Drugs ineffective on first attempt Most commonly related to impaired responses to cell death signals in tumor cells (ie. p53 inactivation)
74
Acquired resistance
Drugs worked first and then became ineffective | Related to adaptation and mutation of tumor cells
75
Altered expression of protein in tumor cells
1. Increased DNA repair mechanisms 2. Alterations in drug targets 3. Removal of drug from target cells (ie. upregulation of p-glycoprotein pumps)
76
P-glycoprotein pumps
Increase drug efflux | Particularly sensitive to: antibiotics, vinca alkaloids, taxans and small molecule inhibitors
77
R-CHOP regimen
``` Non-Hodkin's Lymphoma R: rituximab C: cyclophosphamide H: hydroxydaunorubucin (doxorubicin) O: oncovin (vincristine) P: prednisone (corticosteroid, reduces some side effects) ```
78
Cisplatin
Platinum containing agent
79
Bevacizumab
mAb targeted to VEGF
80
Sorafenib
Small molecule TK inhibitor | Binds intracellular domain of VEGFR

Pharmacology 3001 (19 decks)

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