26 Chemotherapy Flashcards
What characterizes cancer?
Cancer is characterized by abnormal cell growth with potential to spread to other parts of the body (Metastasis)
Cancer is caused by ______ and ______ factors
Cancer is caused by environmental and genetic factors
the spread of cancer cells is called ______
the spread of cancer cells is called metastasis
Cancer is fundamentally a disease of ______
Cancer is fundamentally a disease of cell growth regulation
- cancer arises when genes that regulate cell growth are mutated
What are the five phases of the cell cycle?
- G1 phase
- checkpoint to ensure cell is ready for DNA synthesis
- S-Phase
- DNA synthesis
- G2 phase
- Checkpoint to ensure cell is ready for mitosis
- M phase
- Mitotis
- G0 phase
- quiescent state
Genes important in the regulation of cell cycle are divided into which two groups?
- Tumor suppressor genes
- Oncogenes
What role do tumor suppressor genes play in cell cycle regulation?
(3)
Tumor suppressor genes (and the proteins they encode) repress cell cycle or promote apoptosis
- Inhibit cell division
- Initiate apoptosis following irreversible DNA damage
- DNA repair proteins (BRCA)
What is p53?
p53 is a tumor suppressor protein that regulates the cell cycle. It is mutated in 50% of all tumors
What are proto-oncogenes?
Normal genes involved in cell growth and proliferation or inhibition of apoptosis
What is an oncogene?
Mutated proto-oncogene that leads to increased expression
What mutations can create an oncogene?
- Point mutations
- Small scale deletions or insertions which affect its expression
- Chromosomal translocation
- when two separate chromosomal regions become abnormally fused
What is Philadelphia chromosome?
A specific genetic abnormality in chromosome 22 found in leukemia cancer cells (abnormal translocation of chromosome 9 and 22)
- The broken end of chromosome 22 contains the BCR gene which fuses with a fragment of chromosome 9 that contains the ABL1 gene
- fusion creates a new gene BCR-ABL
- Leads to unregulated expression of protein tyrosine kinase activity leading to unregulated cell cycle and cell division
What does the oncogene BCR-ABL lead to?
Unregulated expression of protein tyrosine kinase activity = unregulated cell cycle and cell division
What is the ABL gene?
Codes for a tyrosine kinase protein
Important in regulating cell growth
What is the “multiple hit” theory for cancer?
That there is sequential mutation in proto-oncogenes (to oncogenes) and tumor suppressor genes that will all act in concert to cause cancer
What fraction of cancers are cured with local tx strategies (eg surgery/radiotherapy)?
1/3
In the majority of cancer cases, what is the tx approach?
Systemic approach with anti-cancer drugs is required (because metastasis)
Anti-cancer drugs alone cure _______ of all cancer patients when tumor is diagnosed at advanced stage. Better outcomes result from:
Anti-cancer drugs alone cure less than 10% of all cancer patients when tumor is diagnosed at advanced stage. Better outcomes result from: anti-cancer drugs given in combination with surgery or radiation
What do anti-cancer drugs target?
Anti-cancer drugs interfere with the cell cycle
- Some act at specific phases in the cell cycle (mainly at the S and M phase)
- Others are cytotoxic at any point in the cell cycle (eg estrogen receptor antagonist tamoxifen)
Tumor cells are more susceptible to S and M phase anti-cancer drugs. Why?
They generally have a higher percentage of proliferating cells than normal cells
What other types of body tissues might be susceptible to damage from cytotoxic drugs?
Normal tissues that proliferate rapidly such as bone marrow, hair follicles, and intestinal epithelium
What phase of the cell cycle do Vinca Alkaloids and taxanes primarily target?
M phase
What phase of the cell cycle does Bleomycin target?
G2
What phase of the cell cycle do Antimetabolites target?
S phase
What is an example of a DNA synthesis inhibitor?
Pyrimidine Analogues
What is the action of pyrimidine analogues to inhibit DNA synthesis?
Provide an example of a pyrimidine analogue
Pyrimidine analogues compete with normal pyrimidine precursors for the enzyme thymidylate synthase (TS)
- TS required for the conversion of dUMP to dTMP (ie thymine+deoxyribose sugar)
- eg of a pyrimidine analogue: 5-fluorouracil (5-FU)
What enzyme is required for the conversion of dUMP to dTMP
Thymidylate synthase
5-FU is a _______ that requires activation to the active metabolite: _______
5-FU is a prodrug that requires activation to the active metabolite: FdUMP
What is FdUMP?
the active metabolite of 5-FU that inhibits thymidylate synthase to prevent conversion of dUMP to dTMP
What are Purine analogs?
Drugs that look like purines (A and G)
DNA synthesis inhibitors
- inhibits purine nucleotide biosynthesis and metabolism by inhibiting an enzyme called phosphoribosyl pyrophosphate amidotransferase (PRPP amidotranferase)
What is the action of Purine analogs?
inhibits purine nucleotide biosynthesis and metabolism by inhibiting an enzyme called phosphoribosyl pyrophosphate amidotransferase (PRPP amidotransferase)
What enzyme is the rate limiting factor for purine synthesis?
PRPP amidotransferase (phosphoribosyl pyrophosphate amidotransferase)
- alters the synthesis and function of RNA and DNA
What are alkylating agents and how do they interfere with DNA synthesis?
- Alkylating agents are highly reactive compounds that covalently link to chemical groups (phosphates, amines, sulfhydryl, and hydroxyl groups) commonly found in nucleic acids
- Lead to cross-linking between strands of DNA and strand breakage
- halts replication process
Which base is particularly susceptible to the formation of covalent bonds with alkylating agents?
N7 of Guanine
In what phase are cancer cells the most susceptible to Alkylating agents?
Late G1 and S phases
Cisplatin is an example of what kind of drug?
Alkylating Agent
What are anti-folates?
DNA synthesis inhibitors
- Folic acid is essential - converted by enzymatic reduction into FH4 cofactors
- Provide methyl groups for the synthesis of precursors of DNA and RNA (thymine and uracil)
- Folic Acid Analogs interfere with FH4 metabolism thereby inhibiting DNA replication
Methotrexate is an example of what kind of anti-cancer drug?
Anti-folates
How does Methotrexate work?
- Methotrexate is a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase - interferes with FH4 metabolism
- Effective during S Phase and are most effective when cells are proliferating rapidly
What are Vinca alkaloids?
Anti-cancer drug derived from the periwinkle plant that inhibits tubulin polymerization
- disrupts the assembly of MT involved in mitotic spindle apparatus (M-Phase)
What are taxanes?
Provide an example
Naturally derived anti-cancer drug
- promotes microtubule assembly through high affinity binding
- inhibits the depolymerization of MT into tubulin dimers
- Inhibits mitosis and cell division
- Example: Paclitaxel
Taxanes inhibit microtubule ____________ while Vinca Alkaloids inhibit microtubule ________
Taxanes inhibit microtubule de-polymerization while Vinca Alkaloids inhibit microtubule polymerization
What class of anti-cancer drug is derived from the pacific yew tree?
Taxanes
eg Paclitaxel
What class of anti-cancer drug is derived from the periwinkle plant?
Vinca alkaloids
What class of anti-cancer drug is derived from the Camptitheca acuminata tree?
Camptothecins
How do Camptothecins work?
- Target DNA topoisomerases (enzymes that reduce the torsional stress in supercoiled DNA through strand breakage and resealing)
- Bind and stabilize the normally transient DNA-topoisomerase I complex
- Topisomerases cleave and unwind to release tension and then reseal - cutting is not affected
- re-ligation step is inhibited, leading to the accumulation of single-stranded breaks in DNA which eventually interferes with DNA synthesis
- S-phase specific
Which phase of the cell cycle do Camptothecins target?
S-phase specific - cell has to be actively undergoing DNA synthesis for these drugs to work as they act on DNA-Topoisomerase during DNA synthesis
What class of anti-cancer drugs are the products of the soil microbe streptomyces?
Antibiotics
How do antibiotics from streptomyces interfere with DNA synthesis?
Bind DNA through intercalation, block DNA synthesis and cell replication
Target at multiple points
What is an example of an anti-cancer antibiotic?
Anthracyclines (doxorubicin)
What are anthracyclines?
What are the 4 mechanisms of action?
Anti-cancer antibiotics
- most widely used anti-cancer drug
- 4 mechanisms of action
- inhibit topoisomerases (increase single strand breaks)
- Generate free radicals (DNA mutagenesis)
- High affinity binding to DNA (similar to the platinum analog)
- Bind cellular membrane to alter fluidity and ion transport (reduce bioavailability of the cell)
What are tyrosine kinase inhibitors? Provide an example?
Inhibits the tyrosine-kinase domain of the Bcr-Abl oncoprotein (Philadelphia chromosome)
- help control the unregulated cell division
- Treat leukemia
Eg:
Imantinib
What are epidermal growth factor receptor inhibitors? Provide an example.
- EGFR is over-expressed in a number of solid tumors
- Activation of EGFR promotes cell growth and proliferation, invasion and metastasis, and angiogenesis
- Eg Cetuximab
What is Cetuximab?
A monoclonal antibody directed against the extracellular domain of EGFR (Epidermal growth factor receptor)
- EGFR inhibito
Provide an example of a hormonal anti-cancer agent
Tamoxifen
- Selective estrogen receptor antagonist
- blocks binding of estrogen to estrogen-sensitive cancer cells in breast tissue
Tamoxifen inhibits _______ signalling that can promote cell division
Tamoxifen inhibits estrogen signalling that can promote cell division
What are two types of resistance that can arise from cancer treatment?
- Primary Resistance
- Tumour spontaneously resistant to anti-cancer drug
- ie p53 mutations
- collection of mutations that drive the cancer are not affected by drugs that impact the cell cycle
- Acquired Resistance:
- develops in response to a given anti-cancer agent
- cells are rapidly dividing and acquiring more mutations = increase chance of acquiring a mutation that infers some sort of resistance to the drug
- develops in response to a given anti-cancer agent
What are the adverse effects of anti-cancer drugs?
Recall: Anticancer drugs have a very narrow therapeutic window
- adverse effects are 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
- vomiting
- cancer (mutagenesis) = increased risk of secondary malignancies
- symptoms include:
