Cancer Chemotherapy Flashcards
Give examples of alkylating agents and how they work
Damages components that make DNA in cell cycle (G1)
Cyclophosphamide: acts as a pro drug and metabolised in liver to active agent, oral route has no damage to gut wall
Chlorambucil
Melphalan: given orally to mimic phenylalanine for treatment of multiple myeloma, ovarian and breast cancers
Lomustine
Carmustine
Thiotepa
Mitobronitol
Chlormethine: only given IV (too reactive for oral admin) for treatment of Hodgkin’s Lymphoma via multi drug regime
Give example of cytotoxic antibiotics (intercalating agents)
Doxorubicin- treats solid tumours
Mitoantrone
Bleomycin
Mitomycin
Give examples of antimetabolites and how they work
Incorporated into new nuclear material or combine irreversibly with vital enzymes to prevent normal cell division
Methotrexate
5-Fluorouracil
Mercaptopurine
Cladribine
Give examples of vinca alkaloids
Vinblastine
Vincristine
Give examples of sex hormones and hormone antagonists used
Oestrogen, progestogens
Hormone antagonists:
Tamoxifen
Anastrazole
Give a detailed explanation on how alkylating agents work
Highly electrophilic that react with nucleophiles to form strong covalent bonds
They react with nucleophilic groups in DNA which cross link and then cannot seperate
Example: Combining two strands of guanine deforms structure and polymerase cannot find DNA to replicate
What are the different nucleophilic groups in DNA
N-1: cytosine, thymine, adenine, guanine
N-3: adenine or cytosine
N-7: Guanine (most reactive, reacts with electrophilic substances)
Which cancer types do alkylating groups normally target
Blood bourne cancers:
Leukaemia and non hodgkin lymphoma
Solid tumour:
Lung, breast, testicular, ovarian
Which anticancer agent originated from mustard gas
Alkylating agents
Explain how intercalating agents work (detailed response)
- Drugs contain a planar aromatic or heteroaromatic ring which can slip into the double helix of DNA and distort its structure: many van der waals interaction with DNA, charged amino acid group is important to form ionic bond with negatively charged phosphate
- Once bound, the drug can inhibit enzymes needed for replication and transcription processes
- Intercalation prevents normal action of topoisomerase II enzyme- crucial for effective DNA replication
What form do anthracyclins have to be used
Anthracyclins are orally inactive and have to be administered via intravenous injection
What is the second mechanism of intercalating agents
- Harmful to DNA by involving hydroxyquinone moiety which can chelate iron to form a doxorubicin DNA iron complex
- Reactive O2 species then forms a single strand break on DNA
Explain antimetabolites mechanism of action
- Drugs structurally resemble naturally occurring purines and pyrimidines involved in nucleic acid synthesis
- They then disrupt DNA synthesis by inhibiting key enzymes needed (purine and pyrimidine production halted)
- Become incorporated into the DNA and RNA to produce incorrect codes and cause strand breaks or premature termination
What are dihydrofolate reductase inhibitors and their mechanism of action
- Folate antagonists like methotrexate
- Inhibits dihydrofolate reductase (DHFR) which is essential in folate synthesis
- DHFR is crucial to maintain enzyme co-factor tetrahydrofolate FH4
- No tetradihydrofolate FH4: synthesis of DNA building block dTMP is aborted which slows down DNA synthesis and cell division
How do you overcome the metabolic block effects caused by methotrexate
FOLINIC ACID:
Acts as an alternative source for nucleic acids- acts as a rescue treatment
What cancer types are methotrexate effective in
- Treats neoplastic cancers like lymphoblastic leukaemias
2. Widely distributed in body fluids so good for systemic cancers like leukaemia
What is the role of thymidylate synthase and how do you inhibit it
Role: adds methyl group onto FH4 to continue the cycle
5-Fluorouracil is an effective inhibitor that works as a suicide substrate: activated by enzyme catalysed reaction
What can you use 5-Fluouracil for to target which cancer types
Treatment of breast, liver, skin cancers and causes neurotoxic and cardiotoxic effects
How do inhibitors of DNA polymerases work and give an example
- Catalyse the synthesis of DNA using the four deoxyribonucleotide building blocks: dATP, dGTP, dCTP, dTTP
- Example: Cytarbine: analogue of 2’-doxycytidine that is phosphorylated to corresponding triphosphate which acts as competitive inhibitor: used intravenously
How does ara-CTP work as a inhibitor of DNA polymerases
- Acts as a substrate for DNA polymerase and becomes incorporated into the growing DNA chain
- Lead to chain termination or prevents replication of modified DNA
Give examples of drugs that inhibit tubulin polymerisation
Vincristine, Vinblastine, Vindesine: Vinca alkaloids
What is Vincristine used to treat (cancer wise)
Acute leukaemia
Hodgkin’s lymphoma
Small cell lung carcinoma
What is Vinblastine used to treat (cancer wise)
Lymphomas
Testicular
Ovarian cancer
What is the mechanism of action for vinca alkaloids
Prevents formation of microtubule which is necessary in the formation of a spindle
