Anti Cancer Drugs

Question 1

Oncogenes

Answer 1

-Normally: tightly regulated growth and differentiation of cells (ex. Bcl-2)

Question 2

Tumour Suppressor Genes

Answer 2

Normally: suppress overgrowth of cells

ex. p53

Question 3

Explain the 3 stages of cancer pathophysiology with a diagram.

Answer 3

-antineoplastics lecture

Question 4

Describe the stages of cancer

Answer 4

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

Question 5

Explain traditional and newer anti cancer drugs

Answer 5

traditional-target the cell cycle and kill rapidly dividing cells
newer-target specific proteins/processes unregulated in tumors

Question 6

What are 3 principles of chemotherapy

Answer 6

1. chosen agent must be tolerable, administer MTD
2. use combinations to increase likelihood of killing tumour cells
3. Dose and regimen must be chosen to max effectiveness –>cyclic therapy

Question 7

What are the 4 classes of traditional antineoplastic agents?

Answer 7

• alkylating and platinum agents
• topoisomerase inhibitors and antibiotics
• antimetabolites
• vinca alkaloids and taxanes

Question 8

Cyclophosphamide

Answer 8

• alkylating agent
• prodrug-activated by cyto P450 in the liver
• cross links 2 guanines, disrupts DNA structure and causes strand breaks
• can also bind to similar functional groups (SH, OH, NH-lipids, proteins, etc)

Question 9

Cisplatin

Answer 9

• platinum containing agents

- cause inter and intra DNA strand cross linking in cells (similar to alkylating agents

Question 10

Topotecan

Answer 10

• binds to topoI- makes ss breaks, untangles and ligates back together)
• prevents religation of strand breaks
• prevents movement of rep complex
• halting these processes signals cell death

Question 11

Doxorubicin

Answer 11

• topoII inhibitor, prevents religation of ds breaks–>cell death pathways
• natural product isolated from strep
• intercalates b/w strands
• form free radicals causing additional cytotoxicity
• cardiotoxicity

Question 12

Mercaptopurine

Answer 12

• purine antagonists
• structurally similar to adenine
• interacts with enzymes involved in purine nucleotide synthesis
• incorporated into DNA like adenine, unable to make correct base pair

Question 13

Fluorouracil (5-FU)

Answer 13

• pyrimidine antagonist
• similar structure to uracil and thymine
• binds to thymidylate synthase preventing further synthesis of thymidine nucleotides

Question 14

Methotrexate

Answer 14

• inhibits dihydrofolate reductase

- prevents purine nucleotide synthesis

Question 15

Antimetabolites

Answer 15

• similar in structure to endogenous compounds (folic acid, nucleotide bases)
• prevent DNA synthesis
• cells deficient in building blocks undergo cell death

Question 16

Vinca alkaloids-vincristine

Answer 16

• from rosy periwrinkle
• prevent microtubule formation of mitotic spindles
• inhibit cell division
• neurotoxicity and neuropathy is a common adverse effect

Question 17

Docetaxel

Answer 17

• taxanes
• made semi synthetically from natural products derived from a different yew species
• stabilizes microtubules so they can’t disassemble

Question 18

What are the adverse effects of traditional antineoplastic drugs?

Answer 18

• do not differentiate b/w cancerous and non cancerous cells
• cells with a high turnover rate are more susceptible to damage

Question 19

4 considerations when choosing a combo therapy

Answer 19

1. efficacy-each drug must be effective alone
2. toxicity-choose drugs with different side effects to avoid additive adverse effects
   - sometimes lower doses can be given when using combos
3. scheduling-use shortest recovery interval possible to increase killing efficacy
4. choose drugs with different MOA- to increase tumour killing efficacy, decrease resistance

Question 20

CAV combination regimen

Answer 20

• used in lung cancer
• cyclophasphamide
• adriamycin (doxorubicin)
• vincristine

Question 21

What is the problem with traditional antineoplastics?

Answer 21

-the cell targets are common to ALL cells in the body

Question 22

Rituximab

Answer 22

• mAb targeted to CD20
• flags B cells for destruction by immune system
• results in death of CD20 positive B cells
• normal B cells are regenerated from stem cells

Question 23

Tositumomab

Answer 23

• mAb conjugated radioactive isotopes

- targets radioactivity to tissues expressing antigen

Question 24

Sipuleucel-T

Answer 24

• virus expressing tumour antigen
• vaccines administered to initiate a host immune response against the tumour
• remove cells from patients tumour or blood, manipulate and re-inject into patients

Question 25

Bevacizumab

Answer 25

- mAb targeted against VEGF | - binds circulating VEGF

Question 26

Sorafenib

Answer 26

- small molecule TK inhibitors - bind to intracellular domain of VEGFR - prevent initiation of signalling cascade by inhibiting phosphorylation

Question 27

What are 2 drug targets that interfere with growth and proliferation?

Answer 27

- Epidermal growth factor (EGF)-stimulates cell growth and proliferation - HER2-TK R, upregulated in breast cancer

Question 28

Trastuzumab

Answer 28

- specifically targets HER2 - binds to the TK R and blocks ligand bind - flags for the immune system

Question 29

Gefitinib

Answer 29

- small molecule TK inhibitor - bind to intracell domain of EGFR - prevent R activation

Question 30

Imatinib

Answer 30

- small molecule TK inhibitor - inhibit the intracellular TK R, BCR-ABL - prevents the up regulation of Bcl-2 - competitively binds to active site

Question 31

What are the 2 types of drug resistance?

Answer 31

Primary-drug is ineffective on first attempt -most commonly related to impaired responses to cell death signals in tumour cells (p53 inactivation) Acquired-drug worked at first then became ineffective -related to adaptation and mutation of tumour cells

Question 32

How might cells alter expression of proteins in tumour cells to promote drug resistance?

Answer 32

- increase DNA repair mechanisms (i.e. resistant to alkylating agents, radiation) - alterations in drug targets (i.e. upreg of enzyme targeted by methotrexate - removal of drug from target cells (up regulation of p glycoprotein pumps)

Question 33

Leuroprolide

Answer 33

- synthetic analogue of GnRH - overtime decreases FSH, LH production=decreased estrogen - also decreases testosterone

Question 34

Letrozole

Answer 34

-inhibits the aromatase enzyme necessary for the conversion of androgens to estrogen

Question 35

Tamoxifen

Answer 35

- estrogen antagonist | - competes for estrogen R binding in tumour cells