Lecture 15 Chemotherapy targeting DNA, replication, transcription and cell division Flashcards
Explain how curative chemotherapy is used for solid tumours
Tumour is initially reduced via surgery/radiation
Then chemotherapy is used after the clinical signs are gone in order to reduce chances of relapse
Explain how curative chemotherapy is used for disseminated cancers e.g. leukemia
chemo is 1st line therapy
combination therapy used to reduce the chance of drug resistance
Explain how palliative chemotherapy is used
used to extend survival and reduce symptoms but patient will eventually die
what is meant by the phrase ‘cell cycle specific drugs’?
effective for high growth fraction malignancies i.e. rapidly cycling examples: antimetabolites bleomycin peptide antibiotics vinca alkaloids etoposide
what is meant by the phrase ‘non cell cycle specific drugs’?
effective for low growth fraction malignancies such as solid tumours as well as high growth malignancies Examples: alkylating agents antibiotics cisplatin nitrosoureas
generally how do anti-metabolites work?
inhibit/interfere with DNA/RNA synthesis
specifically S phase
Name examples of anti-metabolites
Methotrexate 6-mercaptopurine 5-flurouracil Gemcitbine Cytarabine
Explain how methotrexate works
targets cells in S phase
structurally related to folic acid
competitively inhibits dihydrofolate reductase (DHFR)
retained in cell as MTX-polyglutamate compounds
therefore inhibits production of precursor for amino acids/DNA nucleotides = no DNA
[see slide for pathway inhibited]
What is methotrexate used for?
used against acute lymphoblastic leukaemia (ALL), breast cancer, head and neck cancer
low doses used to treat rheumatoid arthritis/psoriasis
In what form is methotrexate given?
High doses given intramuscularly (IM), intravenously (IV), intrathecally (into the brain and CNS as poor CNS penetration)
What is the importance of hydration with methotrexate?
Adequate hydration must be sustained at high doses to avoid renal toxicity
Explain how 6-mercaptopurine works
Purine analogue
Drug phosphorylated by the enzyme Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to produce thio-IMP
this inhibits purine biosynthesis =
incorporated into DNA and RNA leading to non-functional molecules
Thio-IMP also inhibits the production of AMP/XMP which are precursor molecules for nucleic acid biosynthesis
What is 6-mercaptopurine used for?
used in maintenance of remission in Acute Lymphoblastic leukaemia (ALL)
Explain how resistance to 6-mercaptopurine can occur
resistance due to lack of Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
or increased drug metabolism in individual
Explain how 5-flurouracil works
Modified pyrimidine Drug is phosphorylated and competes with dUMP for thymidylate synthetase = inhibits production of dTMP (needed for DNA synthesis and cell growth)
Depletes intracellular nucleotide pools
Explain why 5-flurouracil and methotrexate are given together
The enzyme thymidylate synthetase also requires tetrahydrofolate therefore giving methotrexate will inhibit the ligand and reduce the function of the enzyme to produce nucleotides
synergistic effect
In what form is 5-flurouracil given?
IV
How does gemcitabine work?
analogue of deoxycytidine
incorporates into DNA and stops DNA synthesis via acting like a stop codon due to its structure
What can gemcitabine be used to treat?
used in treatment of advanced metastatic pancreatic cancer as a way to prolong the lifespan of the patient but not cure
In what form is gemcitabine given?
IV
How is gemcitabine excreated?
deaminated to non-toxic product (difluorodeoxyuridine)
excreted in urine
What is the main side effect of gemcitabine?
myelosuppression is a major side-effect
How does cytarabine work?
chain terminator of DNA synthesis by incorporating itself into DNA and stopping translation
AraCTP also inhibits DNA polymerases
In what form is cytarabine given?
IV
Intrathecal due to poor CNS penetration
What is the main side effect of cytarabine
myelosuppression
Generally how does antibiotic chemotherapy work?
bind to DNA, disrupt function of DNA
Name examples of antibiotic chemotherapy
Dactinomycin Anthracyclines Alkylating agents Platinum coortination complexes Topoisomerase inhibitors Telomerase inhibitors Vinca alkaloids Taxanes
How does dactinomycin/actinomycin D work?
Binds to DNA (minor groove)and interferes with transcription and DNA replication
may also cause DNA strand breaks
Resistance to dactinomycin is caused by what?
P-glycoprotein
In what form is dactinomycin given?
IV
Though poor penetration into CNS
How is dactinomycin excreted?
bile
urine
Name examples of anthracyclines
Doxorubicin Daunorubicin
How do anthracyclines work?
intercalate into DNA
generate free radicals that break DNA strands - interacts with O2 which produces superoxide ions and hydrogen peroxide = single strand breaks in DNA
can also interfere with DNA breakage repair system
target cells in S and G2 phases
What conditions are treated with anthracyclines?
Used in combination , for breast, lung, leukaemia
What is the name of the drug that is not an anthracycline but acts via a similar mechanism
Bleomycin
What form is anthracycline given as?
IV
Poor penetration into CNS
How are anthracyclines excreted
bile
urine
Name examples of alkylating agents
Mechlorethamine, cyclophosphamide, ifosphamide, carmustine, dacarbazine, temezolomide
How do the alkylating agents work?
transfer alkyl groups to DNA
Interfears with the link between G-G
are mutagens (possible problem as could cause new mutations)
target rapidly dividing cells to inhibit DNA replication
Which enzyme is involved in the activation of alkylating agents?
cytochrome P450
What conditions are treated with alkylating agents?
used in combination to treat solid and lymphatic tumours
In what form is alkylating agents given?
IV
Oral - drug crosses the BBB
How are alkylating agents excreted?
urine
What are examples of platinum coordination complexes?
Cisplatin, carboplatin, oxaliplatin
How does platinum coordination complexes work?
Mechanism of action similar to alkylating agents
Binds to double stranded DNA and forms intra- and inter-strand crosslinks
Interferes with DNA replication and transcription
Act in G1 and S phases
What conditions are treated with platinum coordination complexes?
Cisplatin used in solid tumours e.g.testicular cancer (with VBL and bleomycin) and single agent in bladder cancer
Oxaliplatin used in advanced colorectal cancer
In what form is platinum coordination complexes given?
IV
Poor penetrance into CNS
How are platinum coordination complexes excreted?
urine
Name examples of topoisomerase I inhibitors
Topotecan
irinotecan
How do topoisomerase I inhibitors work?
S phase specific
Topo I makes reversible single-stranded breaks (knicks) in the DNA duplex to allow it to unwind
Topotecan and irinotecan bind to enzyme-DNA intermediate, preventing re-ligation/reformation of DNA strand
In what form are topoisomerase I inhibitors given?
IV
What conditions are treated with topoisomerase I inhibitors?
Topotecan used against metastatic ovarian cancer and lung cancer
Irinotecan used against colon and rectal cancer along with 5-FU and leucovorin
How is topoisomerase I inhibitors excreted?
urine
What is a side effect of topoisomerase I inhibitors?
Myelosupression - specifically topotecan
Name examples of topoisomerase II inhibitors
Daunorubicin
Doxorubicin
Etoposide
teniposide
How do topisomerase II inhibitors work?
S phase specific
Daunorubicin and Doxorubicin intercalate into DNA, preventing topo II – catalysed breakage/reunion of DNA strands therefore breaks not repaired
Etoposide, teniposide bind to transient cleavable form of enzyme-DNA complex leading to double-strand breaks in DNA.
What conditions are treated with topoisomerase II inhibitors?
Etoposide used in combination with bleomycin and cisplatin for testicular cancer
Teniposide used for ALL, gliomas and neuroblastomas
In what form are topoisomerase II inhibitors given?
IV (both teniposide and etopside) or oral (etoposide)
How are topoisomerase II inhibitors excreted?
urine
What is the function of telomerase inhibitors?
replicate the end of chromosomes in order to keep the DNA functional
Binds to RNA in stem cells/cancer cells and works via reverse transcription
How do telomerase inhibitors work?
Direct enzyme inhibitors e.g. Imetelstat (Geron; Phase I trial)
Modified oligonucleotides – compete for binding with telomerase RNA
Name examples of vinca alkaloids
Vincristine (VX)
vinblastine (VBL)
How do vinca alkaloids work?
block mitosis in metaphase
Bind to tubulin and inhibit its polymerisation into microtubules
Induce spindle dysfunction
Chromosome segregation therefore blocked
What are side effects/problems associated with vinca alkaloids?
Drug resistance a problem
VX is neurotoxic inducing peripheral neuropathy
VBL is myelosuppressant
What types of tumours are vinca alkaloids used for?
Used against rapidly dividing tumours, in combination with other anticancer drugs
Name examples of taxanes
Paclitaxel
Docetaxel
How do taxanes work?
Active in the G2/M phase of the cell cycle
Taxanes bind to tubulin and promote polymerization but stabilise (“freeze”) the microtubules preventing chromosome segregation - spindles are not formed
What conditions are treated with taxanes?
advanced ovarian and breast cancers and non-small cell lung cancer
What are the side effects/problems associated with taxanes?
Dose-limiting toxicity is neutropenia
Drug resistance is a problem
What can be used to reverse the side effect of neutropenia?
Granulocyte colony –Stimulating Factor (Filgrastim)
What is drug resistance in chemotherapy drugs mediated by
mediated by P-glycoprotein
ATP-dependent membrane transport protein (ABC transporter family)
present on most cells but gene amplification can take place in cancer cells
What drug can be used to inhibit P-glycoprotein?
Verapamil - closes the channel so that the drug cannot leave the cell
How can the problem of myelosupression from chemotherapy be treated?
can remove patient’s bone marrow, treat then re-implant - must keep the patient in sterile conditions
can mitigate toxicity in certain cases e.g. leucovorin given with methotrexate
