Chemotherapy Flashcards
What is metastasis?
abnormal cell growth with potential to spread to other parts of the body
What causes cancer?
- environmental factors (e.g. tobacco, radiation, pollution)
- viral infections (e.g. HIV)
- genetics (e.g. BRCA1 in breast cancer)
What is cancer defined as, in terms of disease? Based on this definition, how does cancer arise?
cancer = disease of cell growth REGULATION
cancer arises when GENES that regulate cell growth are MUTATED
What occurs to a cancer cell when there is unfixable DNA damage?
a) apoptosis
b) cell continues dividing
b) cell continues dividing
What occurs to a normal cell when there is unfixable DNA damage?
a) apoptosis
b) cell continues dividing
a) apoptosis
What are all the phases of the cell cycle?
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) M phase: mitotic phase (cell divides into 2 daughter cells)
5) G0 phase: quiescent state
What are the 2 groups of genes important for regulation of the cell cycle?
1) tumor suppressor genes (and the proteins they encode)
2) oncogenes
What is the overall goal/function of tumor suppressor genes? What are some mechanisms to achieve this goal?
function: repress cell cycle/promote apoptosis
mechanisms:
1) inhibit cell division
2) initiate apoptosis following DNA damage
3) DNA repair proteins
What is p53?
tumor suppressor protein that regulates the cell cycle
p53 is mutated in __ % of all tumors
50%
What is the difference between proto-oncogenes and oncogenes?
proto-oncogenes = normal genes involved in cell growth and proliferation or inhibition of apoptosis (i.e. opposite of tumor suppressor genes)
oncogenes = cancer genes due to mutations that can increase expression
what are the 2 types of mutations that can cause oncogenes to form? define them.
1) point mutations = small-scale deletions or insertions which affect its expression
2) chromosomal translocation = 2 separate chromosomal regions become abnormally fused
What is the Philadelphia chromosome? what kind of cancer cells is this chromosome found in? This chromosome leads to unregulated expression of which protein?
- an oncogene
- abnormal chromosome 22 (translocation of chromo 9 and 22)
- found in LEUKEMIA cancer cells
- fusion –> new gene –> BCR-ABL (BCR gene from 22 and ABL from 9)
- unregulated expression of TYROSINE KINASE ACTIVITY
TRUE or FALSE: Usually, MULTIPLE oncogenes and tumor suppressor genes will act in concert to cause cancer.
TRUE
1/3 of cancers can be cures with local treatment (surgery and radiotherapy); however, anti-cancer drugs are required in other cases. Why are anti-cancer drugs used instead of local treatment?
anti-cancer drugs address metastasis
When diagnosed at an advanced stage, anti-cancer drugs alone cure less than ___% of cancer patients.
10%
TRUE or FALSE: Normal tissues that proliferate rapidly (bone marrow, hair follicles, intestinal epithelium) are susceptible to damage from cytotoxic anti-cancer drugs.
TRUE
e.g. hair loss from chemotherapy
Which 2 phases of the cell cycle do MOST anti-cancer drugs interfere with?
S phase and M phase
What are 4 types of DNA Synthesis Inhibitors used to treat cancer?
1) pyrimidine analogues
2) purine analogues
3) alkylating agents
4) anti-folates
What are pyrimidine analogues? What are the nucleoside bases used? What is the mechanism? Provide an example drug and its mechanism.
- DNA synthesis inhibitor
- DNA bases = T and C; RNA bases = U and C
- mechanism: compete with normal pyrimidine precursors for the enzyme THYMIDYLATE SYNTHASE (changes dUMP to dTMP)
- drug: 5-FLUOROURACIL (5-FU)
- 5-FU mechanism: must be activated to FdUMP to act as a pyrimidine analogue
What are purine analogues? What are the nucleoside bases used? What is the mechanism? Provide an example drug and its mechanism.
- DNA synthesis inhibitor
- DNA and RNA bases = A and G
- mechanism: rate-limiting facto for purine synthesis (alter synthesis and function of RNA and DNA)
- drug: 6-MERCAPTOPURINE
- drug mechanism: inhibit enzyme PHOSPHORIBOSYL PYROPHOSPHATE AMIDOTRANSFERASE (PRPP amidotransferase) –> inhibit purine nucleotide biosynthesis and metabolism
What is an alkylating agent? What is the mechanism? Provide an example drug and its mechanism.
- DNA synthesis inhibitor
- mechanism:
highly reactive compounds –> covalently link to chemical groups found in nucleic acids –> these modified nucleic acids cross-link between DNA strands –> lead to strand breakage - drug: CISPLATIN
- drug mechanism: platinum analogue –> lead to cross links –> strand breakage
What atom of guanine is most susceptible to formation of covalent bond with alkylating agents?
N7
Which 2 phases of the cell cycle are most susceptible to alkylating agents?
(hint: alkylating agents are DNA synthesis inhibitors)
G1 and S
What is an anti-folate? What is folic acid and how is it relevant for DNA synthesis? What is its mechanism? Provide an example drug and its mechanism.
(hint: the drug name rhymes with anti-folate)
- DNA synthesis inhibitor
- folic acid = essential dietary factor converted/reduced to FH4 cofactors, which provide methyl groups for synthesis of or T or U bases (for DNA or RNA)
- mechanism:
- anti-folate = folic acid analogue
- interfere with FH4 metabolism, which inhibits DNA synthesis
- drug: METHOTREXATE
- drug mechanism: bind with high affinity to DIHYDROFOLATE REDUCTASE
Which phase of the cell cycle is methotrexate most effective?
(hint: methotrexate is an anti-folate)
S phase ( when cells are rapidly proliferating during DNA synthesis)
What are 4 natural products that can be used to treat cancer?
1) vinca alkaloids
2) taxanes
3) camptothecins
4) antibiotics
What are vinca alkaloids?
a) DNA synthesis inhibitors
b) natural product
c) tyrosine kinase inhibitors
d) hormonal anticancer agents
b) natural product
What plant are vinca alkaloids derived from?
periwinkle plant (vinca rosea)
What is the mechanism/function of vinca alkaloids?
inhibit tubulin polymerization –> disrupts assembly of microtubules involved in mitotic spindle apparatus
What phase of the cell cycle do vinca alkaloids interfere with?
(hint: consider the function/mechanism of vinca alkaloids)
M phase
What are taxanes?
a) DNA synthesis inhibitors
b) natural product
c) anti-biotics
d) anti-folates
b) natural product
What plant are taxanes derived from?
Pacific yew tree (Taxus brevifolia)
What is the function/mechanism of taxanes?
promote microtubule assembly through high affinity binding –> inhibit mitosis and cell division
What phase of the cell cycle do taxanes interfere with?
hint: consider its function/mechanism
M phase
What is an example of a taxane drug?
hint: “tax” is in its name
PACLITAXEL
What are camptothecins?
a) DNA synthesis inhibitors
b) anti-folates
c) tyrosine kinase inhibitors
d) natural product
d) natural product
What plant are camptothecins derived from?
Camptotheca acuminata tree
What is the mechanism/function of camptothecins? (hint: name the enzyme involved)
DNA topoisomerase = nuclear enzyme that reduce torsional stress in supercoiled DNA (through strand breakage and re-ligation)
camptothecin function:
bind and stabilize the DNA topoisomerase –> re-ligation step inhibited –> accumulation of single-stranded breaks in DNA (cytotoxicity)
(i.e. camptothecin stops DNA topoisomerase from re-ligating the broken DNA)
What phase of the cell cycle do camptothecins interfere with? (hint: consider its function)
S phase (ongoing DNA synthesis is necessary for cytotoxicity/accumulation of DNA strands)
What are antibiotics?
a) natural product
b) DNA synthesis inhibitors
c) camptothecins
d) taxanes
a) natural product
What are antibiotics derived from?
soil microbe Streptomyces
What is the mechanism of antibiotics in treating cancer?
bind DNA through intercalation –> block DNA synthesis and cell replication
What is an example of an antibiotic drug used to treat cancer? what are the 4 mechanisms of action?
drug: ANTHRACYCLINES (DOXORUBICIN)
mechanisms:
1) inhibit topoisomerases
2) generate free radicals (DNA mutagenesis)
3) high affinity binding to DNA
4) bind cellular membrane to alter fluidity and ion transport
What is the most widely used anticancer drug? Classify this drug fully.
drug: ANTHRACYCLINES (DOXORUBICIN)
class: antibiotic, natural product
What are 3 miscellaneous anti-cancer drugs? (i.e. not natural product or DNA synthesis inhibitor)
1) tyrosine kinase inhibitors
2) epidermal growth factor receptor (EGFR) inhibitors
3) hormonal anticancer agents
What is IMATINIB?
a) tyrosine kinase inhibitor
b) hormonal anticancer agent
c) epidermal growth factor receptor (EGFR) inhibitor
d) antibiotic
e) DNA synthesis inhibitor
a) tyrosine kinase inhibitor
What is the mechanism of IMATINIB? (hint: consider what type of anticancer drug it is)
inhibit tyrosine kinase domain of the Bcr-Abl oncoprotein (Philadelphia chromo?)
What kind of cancer does IMATINIB treat?
leukemia cancer
How do epidermal growth factor receptor (EGFR) inhibitors work? (hint: solid tumors)
- solid tumors are caused by OVEREXPRESSION of EGFR
- i.e. activation of EGFR promotes cell proliferation, angiogenesis, metastasis, etc.
- EGFR inhibitors stop excessive proliferation of cell growth
What is CETUXIMAB?
a) tyrosine kinase inhibitor
b) hormonal anticancer agent
c) epidermal growth factor receptor (EGFR) inhibitor
d) antibiotic
e) DNA synthesis inhibitor
c) epidermal growth factor receptor (EGFR) inhibitor
What is the mechanism of CETUXIMAB?
monoclonal antibody directed against extracellular domain of EGFR
What is TAMOXIFEN?
a) tyrosine kinase inhibitor
b) hormonal anticancer agent
c) epidermal growth factor receptor (EGFR) inhibitor
d) antibiotic
e) DNA synthesis inhibitor
b) hormonal anticancer agent
What is the mechanism of TAMOXIFEN?
- selective estrogen receptor antagonist
- blocks binding of estrogen to estrogen-sensitive cancer cells in breast tissue
What kind of cancer does TAMOXIFEN treat? (hint: remember its mechanism)
breast cancer
Primary drug resistance:
a) develops spontaneously in the absence of prior exposure to anti-cancer drugs
b) develops in response to a given anticancer agent
a) develops spontaneously in the absence of prior exposure to anti-cancer drugs
Acquired drug resistance:
a) develops spontaneously in the absence of prior exposure to anti-cancer drugs
b) develops in response to a given anticancer agent
b) develops in response to a given anticancer agent
hint: ACQUIRED drug resistance develops after you ACQUIRE the drug
TRUE or FALSE: Many anticancer drugs are carcinogenic in nature; therefore, there is an increased risk of second malignancies.
TRUE
What are 5 symptoms of anticancer treatment?
1) impaired immune system
2) hair loss
3) nausea
4) diarrhea
5) vomiting
Adverse effects of anticancer treatments occur primarily in ________ _________ tissues, such as bone marrow, intestinal mucosa, and the reproductive system.
rapidly growing
