Antineoplastic and Anticancer drugs Flashcards Preview

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Flashcards in Antineoplastic and Anticancer drugs Deck (49):
1

Cancer definition

Loss in the normal control mechanisms that govern cell survival, proliferation, and differentiation

2

Oncogenes

Normally tightly regulate growth and differentiation of cells
Always on = cancer
Ex: Bcl-2 is up or downregulated in cancer

3

Tumor suppressor genes

Normally suppress overgrowth of cells
Missing = cancer
Ex: p53 is downregulated or absent in many cancers

4

4 most common cancers in Canada and their 4 year survival rate

Lung (17%)
Prostate (95%)
Breast (87%)
Colorectal (64%)

5

Stages of cancer

0: early cancer, not detectable
1-3: higher number reflects increase in size and spread
4: Invasion of other tissues and metastasis

6

3 ways cancer is treated

1. Surgical removal of tumor
2. Radiation (non-specific cytotoxicity and cell death)
3. Chemotherapy

7

3 Processes chemotherapy targets

1. Targets cell cycle (kill rapidly dividing cells - traditional agents)
2. Target proliferation pathways (newer agents)
3. Target cancer specific molecules (targeted anticancer agents)

8

3 Principles of chemotherapy

1. Chosen dose must be tolerable (so that course can be completed - administer maximum tolerated dose (MTD))
2. Dose and regimen must be chosen to maximize effectiveness (cyclic therapy - multiple growth cycles of tumor)
3. Use combinations to increase efficacy

9

4 Classes of traditional antineoplastic agents

Alkylating and platinum agents (cross link DNA molecule)
Antimetabolites (nucleotide synthesis)
Topoisomerase inhibitors and antibiotics (interfere with DNA replication and transcription machinery)
Vinca alkaloids and taxanes (mitotic spindle)

10

Alkylating and Platinum Agents

Covalently (irreversibly) bind to DNA
Inhibits synthesis and function = death
Not cell cycle specific

11

Cyclophosphamide

Alkylating agent
Has a bis(chloroethyl)amine group
Needs to be activated in the liver (its a prodrug) - end up with Phosphoramide mustard
Metabolites cross link DNA (instead of H bonds holding the DNA together you get covalent bonds - cannot unwind)
Can bind to other molecules with similar functional groups - causes issues

12

Platinum containing agents

Similar to the alkylating agents, but do not necessarily contain alkyl groups
Cause inter and intra DNA strand cross links in cells, similar to mechanism of alkylating agents

13

Antimetabolites

Similar in structure to endogenous compounds (folic acid, nucleotide bases)
Prevents DNA synthesis
S phase specific

14

Purine antagonists

An antimetabolite
Ex: Mecaptopurine (structurally similar to adenine, interacts with enzymes involved in purine nucleotide synthesis)
Incorporated into RNA and DNA like adenine would be, but is unable to make correct base pair
Interferes with DNA replication and RNA translation

15

Pyrimidine antagonists

An antimetabolite
Ex: Flurouracil (Similar structure to uracil and thymine)
Binds thymidylate synthase, preventing further synthesis of thymidine nucleotides
Interferes with DNA replication and RNA translation

16

Folic acid antagonists

Folic acid is an essential co-factor in DNA and protein synthesis
Methotrexate is structurally similar to folic acid (an antimetabolite)

17

Topoisomerase 1 inhibitors

Ex: Topotecan
Bind to enzyme, produces a fixed complex that prevents further DNA replication and transcription
Halting the replication process signals cell death

18

Topoisomerase 2 inhibitors

Anthracyclin antibiotics (ex: doxorubicin)
Prevents re-ligation of DNA strands by TopoII
Strand breaks in DNA signal Cell death pathways

19

Anthracycline Antibiotics

Ex: Doxorubicin
Natural products from Strep.
Intercalate between strands, stabilize DNA-TopoII complex
Forms free radicals that can cause additional DNA damage
Side effect: cardiotoxicity

20

Vincristine
(mechanism and adverse effects)

A Vinca alkaloid
Prevents microtubule formation of mitotic spindles (inhibits cellular division)
Adverse effects: abdominal pain, bone pain, constipation
Neuropathic pain

21

Docetaxel

A taxane
Stabilizes microtubules of mitotic spindles (can't disassemble)
Inhibits cellular division

22

Adverse effects of antineoplastic drugs

Do not differentiate between cancerous and non-cancerous cells
Cells with high turnover rate are more susceptible to damage (oral cavity, GI tract, skin/hair, immune system)
Some cause immunosuppression (kill actively dividing immune cells)
Infections

23

Example of combination therapy

CAV for lung cancer
C (cyclophosphamide - alkylating agent)
A (doxorubicin - intercalates DNA, stabilizes TopoII, generates free radicals)
V (vincristine - anti-mitotic agent)

24

5 things the newer targeted anticancer drugs effects

Cellular markers
Growth and proliferation
New blood vessel growth
Survival proteins
Hormone sensitive growth

25

CD-20

Protein expressed on surface of immune B cells
Many forms of lymphoma and leukemia are CD-20 positive
Normal B cells also have CD-20 but they are replaced by progenitor stem cells after treatment

26

Rituximab

Membrane bound Ab targeted to CD-20 (flags B cells for destruction by immune system)
Given by IV
Once bound, immune cell recognizes and kills via ADCC
Results in the death of CD-20 positive B cells

27

Radioimmunoconjugates

Radiation therapy effective in treating localized solid tumors (significant damage to neighbouring tissues)
mAb conjugated radioactive isotopes (targets radioactivity to tissues expressing antigen)

28

Tositumomab

CD-20 targeted radionuclides - conjugated with I-131
Radiation kills CD-20 positive cell and adjacent cells

29

Sipuleucel-T vaccine

Provenge
Personalized medicine
Remove cells patient's tumor or blood, manipulate them and re-inject into patient

30

Angiogenesis

Growth of blood vessels
Inhibit VEGF (vascular endothelial growth factor) to decrease blood vessel growth

31

3 drug target sites in tyrosine kinases

1. Bind circulating ligand
2. Block receptor
3. Prevent receptor activation (inhibit phosphorylation)

32

Bevacizumab

mAB targeted against VEGF
Binds ciruclating VEGF so less available to bind to receptor
Results in reduced blood vessel growth in tumors

33

Sorafenib

Small molecule TK inhibitor
Binds to intracellular domain of VEGFR
Prevents initiation of signalling cascade

34

Epidermal growth factor (and its receptors)

Stimulates cellular growth and proliferation
2 receptors: EGFR and HER-2
Both tyrosine kinase receptors
HER-2 upregulated in breast cancer

35

2 main types of tyrosine kinases and their receptors

1. Receptor TKs (membrane bound) - Ex: HER-2
2. Cytosolic TKs (cytosolic) - Ex: Bcr-Abl

36

Trastuzumab

Interferes with EGF signalling (mAb against EGFR)
Specifically targets HER-2
First line therapy in HER-2 positive breast cancer
It prevents intracellular binding and flags for immune system to destroy
Also enhances the effects of chemo

37

Trastuzumab emansine

Trastuzumab and antimicrotubule agent
Drug circulates and targets HER-2 positive cells
Cytotoxic drug enters cell and inhibits microtubule assembly (like vincristine)

38

Gefitinib

Binds to intracellular domain of EGFR (small molecule TK inhibitor)
Prevents initiation of signalling cascade
Inhibits cell growth and proliferation

39

Bcl-2

Pro-survival signal on mitochondrial membrane
Elevated levels of Bcl-2 allow cells to ignore signals to undergo apoptosis

40

Imatinib

Inhibits intracellular TK receptor BCR-ABL
BCR-ABL activation results in upregulation of Bcl-2 (drug prevents this)

41

Primary resistance

Drug is ineffective on first attempt

42

Acquired resistance

Drug worked at first, then become ineffective
Related to adaptation and mutation of tumor cells

43

Altered expression of proteins in tumor cells

Increased DNA repair mechanisms
Alterations in drug targets
Removal of drug from target cells

44

P-glycoprotein pumps
(and what are particularly sensitive to them)

Increase drug efflux = decrease drug effect!
Particularly sensitive are the: antibiotics, vinca alkaloids, taxanes, small molecule inhibitors (the -nib agents)

45

Leuprolide

Synthetic analogue of GnRH
Agonist-Antagonist (antagonist long term, agonist short term)
Over time, decrease in FSH and LH production (negative feedback) = decreased estrogen (yay!)
Also decrease testosterone

46

Letrozole

Inhibits the aromatase enzyme necessary for the conversion of estrogen

47

Tamoxifen

Estrogen antagonist
Competes for estrogen receptor binding in tumor cells (binds to receptor and prevents downstream signalling and proliferation)
Slows growth of estrogen sensitive tumor cells

48

Combination therapy

More targets available
Principles of combo therapy are the same
Combos of old and new agent antineoplastics are first line chemo in most cancers

49

R-CHOP regimen

Combination therapy used in non-Hodgkin's lymphoma
R: Rituximab
C: cyclophosphamide
H: doxoribicin
O: vincristine
P: prednisone (corticosteroid, reduces some side effects)