Chemotherapy Lecture 13 Flashcards
What are the different ways chemotherapy can be given?
- Primary treatment (sole treatment, usually aims to cure)
- Neoadjuvant treatment (before surgery or radiotherapy to downsize the disease)
- Concurrent treatment (with radiotherapy to sensitize radiotherapy)
- Adjuvant treatment (after surgery to kill cancer cells or microscopic disease)
- Palliative treatment (to control disease)
Briefly describe chemotherapy
Attacks tumours at the cellular level by interfering with processes or substances needed for cellular replication
Goals- cure, prolonged survival, palliation, radiosensitive
Can be cell cycle specific- schedule dependent
Cell cycle non-specifc- dose dependent
What phases does the cell cycle consist of?
G1 Phase: Cell prepares for DNA synthesis
S Phase: Cell generates complete copy of genetic material
G2 Phase: Cell prepares for mitosis
M Phase: Replicated DNA is condensed and segregated into chromosomes
G0 Phase: Resting state
What are the different classes of chemotherapies?
- Alkylating agent
- Platinum based chemotherapies
- Antimetabolites
- Mitotic inhibitors
- Anti-tumour antibiotics
- Topoisomerase inhibitors
When in combo each drug should be active individually, different mechanisms of action, minimal cross-resistance and different toxicities Common toxicities occur because because they target cells that are fast multiplying including normal cells- neutropenia, anaemia, thrombocytopenia- collectively myelosuppression, nausea and vomiting, mucosistis and diarrhoea, alopecia, sterility and infertility
Describe alkylating agents
Attach an alkyl group to the guanine base in DNA and stops tumour growth by crosslinking guanine nucleobases in DNA so strands cannot separate and the cell cannot divide
Act non-specifically- mainly on synthesis.
Tumour cells are more sensitive because of faster cycling and less DNA repair, but also works on normal cells like those in the GIT and bone marrow
Also most are carcinogenic
What are the types of alkylating agents and how do they interact with DNA?
- SN1: react directly with biological molecule e.g. Ifosfamide
- SN2: form a reactive intermediate, which then react with biological molecules
Reaction:
-Alkylating agents react with the ring nitrogens and extracyclic oxygen atoms of DNA bases to generate a variety of covalent adducts
Toxicities of cyclophophamide and ifosfamide- nausea and vomiting, myelosuppression, alopecia, high-dose cardiotoxicity (endothelial injury–> haemorrhagic necrosis and decline left ventricular systolic failure), ifosfamide high-dose neurotoxicity (metabolite crosses BBB, encephalopathy–> cerebellar ataxia, mental confusion, complex visual hallucination), high-dose haemorrhagic cystitis (acrolein metabolite excretion into bladder) Mesna- can prevents haemorrhagic cystitis, detoxifies metabolites by reacting with sulfhydryl group
Describe platinum based chemotherapy
Cause crosslinking of DNA as a monoadduct, interstrand crosslinks, intrastrand crosslinks or DNA protein crosslinks
Mechanism:
- Consist of central metal ion surrounded by bound molecules/ions
- Form intrastrand crosslink of DNA at N-7 position of guanine
- This inhibits DNA repair/synthesis
Eg. Cisplatin, carboplatin, oxalaplatin
Toxicities- nausea and vomiting, myelosuppression, ototoxicity (irreversible high frequency hearing loss), peripheral neuropathy, nephrotoxicity (prevention with aggressive hydration and electrolyte supplements)
Describe antimetabolites
Inhibits the use of a metabolite Eg. methotrexate (folic acid analogue) and 5-fluorouracil (uracil analogue)
Similar structure to the metabolite competitive inhibition. Infere with DNA prodction and cell division.
How does 5-FU work
Is an antimetabolite i.e. 5-FU
Analogue of uracil with a fluorine atom substituted at the c5 position
Mechanism:
- Is a pro-drug subject to both catabolism and anabolism
- Cytotoxic activity depends on its anabolism to nucleotides, which exert their effects through inhibition of thymidylate synthase activity or incorporation in DNA (signalling DDR)
- 5-FU: Active metabolite, FdUMP, inhibits dTMP–> increased levels of dNTP and dUTP–> cause DNA damage
- Can activate p53 by incorporation of FUTP into RNA, FdUTP into DNA and the DNA damage Up to 80% of 5-FU is broken down by DPD in the liver- bioavailibility, variation in DPD levels and function
Pharmacokinetics:
-80% broken down by DPD in the liver
Toxicities:
- Myelosuppression
- GIT disturbance
- Cardiotoxicity
Describe mitotic inhibitors
Mitoticinhibitor inhibits mitosis or cell division.
Disrupt microtubule polymerisation. Interferes with assembly/disassembly of tubulin into microtubles polymers - interupping cell division during mitosis plhase.
Usually derived from natural sources, cannot separate chromosome
Eg. vinca alkaloids (vinblastine- lymphomas and is myelosuppression, vincristine- leukaemia and is neurotoxic, and vinorelbine- lung cancer and is neurotoxic and myelosuppressive) and taxanes (paclitaxel, docetaxel)
Describe topoisomerase inhibitors
Topoisomerase 1 inhibitors- irinotecan, topotecan Topoisomerase 2 inhibitors- etoposide May lead to secondary neoplasms
- Interfere with action of topoisomerase enzymes which regulate DNA over/underwinding
- Blocking them inhibits the ligation step of cell cycle, generating s/ds breaks causing apoptosis
i. e; Toptecan for Topo I
Describe Anti-tumour antibiotics
i.e. Mitomycin
Mechanism:
- Intercalates DNA strands resulting in complex formation inhibiting synthesis of DNA/RNA
- Also triggers DNA cleavage by Topoisomerase II, resulting in apoptosis
- Generates free radicals causing further cell death
Side effects:
- Myelosuppression
- Nausea/vomiting
Describe Mitomycin
Aziridine-containing natural products from bacteria
SE- bone marrow suppression, nausea, vomiting, stomatitis, rash, fever and malaise
Delivered in 6-week intervals because of delayed myelosuppression
Metabolised by liver enzymes and exctreted in bile- possible enzyme abnormalities caused rare- haemolytic uraemic syndrome, renal failure, haemolysis, neurological abnormalities and interstitial pneumonitis
How does chemotherapy cause vomiting?
- Through its effect on chemoreceptor trigger zone (CTZ) and vomiting centre
- The CTZ is located within the area postrema, which is part of the vomiting centre and located in the medulla oblongata
Vomiting centre = 5-HT3 receptors, dopamine receptors, NK receptors
CTZ stimulates vomiting centre
CTZ = same receptor
