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 such as hematologic cancer 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-fluorouracil Gemcitabine Cytarabine
Explain how methotrexate works
targets cells in S phase
structurally related to folic acid
competitively inhibits dihydrofolate reductase (DHFR)
retained in the cell as MTX-polyglutamate compounds
therefore inhibits the production of precursor for amino acids/DNA nucleotides = no DNA
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 are given IM, 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.
Explain how 5-fluorouracil works
Pyrimidine analog
The drug is phosphorylated and competes with dUMP for thymidylate synthetase = inhibits the production of dTMP (needed for DNA synthesis and cell growth)
Depletes intracellular nucleotide pools
Explain why 5-fluorouracil 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-fluorouracil given?
IV
How does gemcitabine work?
analog of deoxycytidine
incorporates into DNA and stops DNA synthesis via acting as a stop codon due to its structure
What can gemcitabine be used to treat?
used in the 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
