Chemotherapy

Question 1

cancer

Answer 1

abnormal cell growth with potential to spread to other parts of the body (metastasis)

leading cause of death in Canada (1 in 4)
over 100 types

Question 2

causes of cancer

Answer 2

tobacco, ionizing radiation, environmental pollution (asbestos, radon)
viral infections (HIV - Hodgkins and non-Hodgkins lymphoma; HPV - cervical cancer)
genetics - BRCA1 in breast cancer

Question 3

cancer and the cell cycle

Answer 3

cancer is a disease of cell growth regulation
arises when genes that regulate cell growth are mutated

Question 4

cell cycle

Answer 4

events leading to duplication of DNA and division of cytoplasm to produce to daughter cells
1. G1 phase - checkpoint to ensure cell is ready for DNA synthesis
2. S phase - DNA synthesis
3. G2 phase - checkpoint to ensure cell is ready for mitosis
4. Mitotic phase - cell divides
5. G0 phase - not actively dividing or preparing to divide

regulation of cell cycle → tumor suppressor genes and protooncogenes

Question 5

tumor suppressor genes

Answer 5

repress cell cycle or promote apoptosis
1. inhibit cell division
2. initiate apoptosis following irreversible DNA damage
3. DNA repair proteins (BRCA)

ex. p53 - tumor suppressor protein that regulates cell cycle → mutated in 50% of tumors
→ either cell cycle arrest or apoptosis

Question 6

protooncogenes

Answer 6

normal genes involved in cell growth and proliferation or inhibition of apoptosis

Question 7

oncogene

Answer 7

mutated protooncogene → increased expression and proliferation

mutations: point mutations or chromosomal translocation

Question 8

BCR gene

Answer 8

strong promoter - drives expression of genes
on chromosome 22

Question 9

ABL1 gene

Answer 9

tyrosine kinase - involved in cell division
on chromosome 9

Question 10

philadelphia chromosome

Answer 10

genetic abnormality in chromosome 22 in leukemia cancer cells
abnormal translocation of chromosome 9 and 22
broken end of chromosome 22 - BCR gene → fuses with fragment of chromosome 9 - ABL1 gene
= BCR-ABL gene

→ unregulated expression of protein tyrosine kinase activity = unregulated cell cycle and cell division

Question 11

cancer genes

Answer 11

usually multiple oncogenes and mutated suppressor genes will all act together to cause cancer

pressure to divide, acquire additional mutations → collapse of regulation of cell cycle

Question 12

cancer therapy

Answer 12

1/3 cured with local treatment strategies - surgery, radiation
systemic approach with anti-cancer drugs is used when metastasized
anti-cancer drugs are not effective alone

Question 13

anti-cancer drugs

Answer 13

interfere with cell cycle
some act at specific stages (S and M), others are cytotoxic at any point

tumor cells are more proliferating → more susceptible to S and M phase anti-cancer drugs
tissues like bone marrow, hair follicles also proliferate rapidly = susceptible to damage from cytotoxic drugs

lots of side effects - own cells become disrupted = impossible to target only cancerous cells

Question 14

pyrimidine analogues

Answer 14

compete with normal pyrimidine precursors for enzyme thymidylate synthase → required for conversion of dUMP to dTMP

inhibitor of thymine synthesis

Question 15

5-fluorouracil

Answer 15

pyrimidine analog
inactive in its parent form → requires activation to active metabolite FdUMP by TS = enzyme isn’t available to convert dUMP to dTMP

Question 16

purine analogues

Answer 16

de novo synthesis: pentose sugar is converted to an immature nuclotide (inosine monophate) by phosphoribosyl pyrophosphate amidotransferase
IMP can then be converted to either guanine or adenine monophosphate which are then made into their respective purines → integrated into DNA

production of IMP by PRPP is the rate limiting factor for purine synthesis

Question 17

6-mercaptopurine

Answer 17

purine analogue
inhibits purine nucleotide biosynthesis and metabolism by inhibiting phophoribosyl pyrophosphate amidotransferase (attaches pentose sugar to immature nucleotide)

Question 18

alkylating agents

Answer 18

highly reactive compounds which covalently link to chemical groups in nucleic acid
lead to cross-linking between strands of DNA and strand breakage

N7 atom of guanine is especially susceptible to formation of covalent bonds - bind two guanines close together

cancer cells are the most susceptible to alkylating agents in late G1 and S phases of cell cycle

Question 19

cisplatin

Answer 19

alkylating agent
platinum analogue
lead to inter-strand crosslinks leading to inhibition of DNA synthesis and function

Question 20

folic acid

Answer 20

essential dietary factor
converted to FH4 cofactors by enzymatic reduction
FH4 metabolites provide methyl groups for the synthesis of precursors of DNA and RNA

Question 21

anti-folates

Answer 21

folic acid analogues interfere with FH4 metabolism = inhibit DNA replication

Question 22

methotrexate

Answer 22

folic acid analogue
binds with high affinity to active catalytic site of dihydrofolate reductase → can’t convert intermediate to FH4
effective during S phase and when cells are proliferating rapidly

Question 23

natural treatments of cancer

Answer 23

vinca alkaloids
taxanes
epipodophyllotoxins
camptothecins

Question 24

vinca alkaloids

Answer 24

periwinkle plant
inhibit tubulin polymerization → disrupts the assembly of microtubules involved in mitotic spindle apparatus (M phase)

Question 25

taxanes

Answer 25

Pacific yew tree promote microtubule assembly through high affinity binding → inhibit depolymerization of microtubules inhibits mitosis and cell division (M phase) ex. paclitaxel

Question 26

camptothecins

Answer 26

bind and stabilize DNA-topoisomerase I complex → can't move down DNA strand to reduce torsional stress inhibit re-ligation of topoisomerase → accumulation of single stranded breaks in DNA → damage → apoptosis S-phase specific drugs because ongoing DNA synthesis is necessary for cytotoxicity

Question 27

antibiotics

Answer 27

bind DNA through intercalation, block DNA synthesis and cell replication

Question 28

anthracyclines

Answer 28

most widely used anti-cancer drug 1. inhibit topoisomerase 2. generate free radicals → DNA mutagenesis 3. high affinity binding to DNA 4. bind cellular membrane to alter fluidity and ion transport

Question 29

tyrosine kinase inhibitors

Answer 29

ex. imantinib inhibits tyrosine kinae domain of BCR-ABL oncoprotein treat leukemia

Question 30

epidermal growth factor receptor

Answer 30

EGFR (signal that drives cell division) is over-expressed in many solid tumors activation of EGFR promotes cell growth and proliferation, invasion, metastasis, and angiogenesis

Question 31

cetuximab

Answer 31

epidermal growth factor receptor inhibitor monoclonal antibody directed against the extracellular domain of EGFR inhibits signalling pathway that is over-expressed in cancer

Question 32

tamoxifen

Answer 32

hormonal anti-cancer agent → selective estrogen receptor antagonist blocks binding of estrogen to estrogen-sensitive cancer cells in breast tissue estrogen fuels the growth and division of breast cancer cells → molecule binding to the receptor tells cell to keep dividing

Question 33

drug resistance

Answer 33

1. primary resistance: develops spontaneously in the absence of prior exposure to anti-cancer drugs ex. p53 mutations 2. acquired resistance: develops in response to a given anticancer agent

Question 34

adverse effects

Answer 34

dose related occur primarily in rapidly growing tissues, such as bone marrow, intestinal mucosa, and reproductive system symptoms include impaired immune system, diarrhea, hair loss, nausea, and vomiting many anti-cancer drugs are carcinogenic in nature → increased risk of secondary malignancies (mutagenesis)