Lecture 4 - Chemotherapy Flashcards
Alkylating agents are nucleic acid targets used in cancer. Explain how they work and list a few examples.
Alkylating agents are highly electrophilic agent which form strong covalent bond with nucleophiles. There are several nucleophile on the DNA such as N1 and N3 of adenine bases, N3 of cytosine and N7 of guanine.
Alkylating agents incluse nitrogen mustard, nitrosoureas, cisplatin and analogues, decarbazine and procarbazine and mitomycin C. They are normally used to treat leukemia, non-hodgkin lymphoma, Hodgkin disease, multiple myeloma, lung, breast, testicular and ovarian cancer.
Drugs with 2 alkylating groups react with the guanine on each chain and cross links the strands preventing it to replicate or transcript.
What is Chlormethine used for?
Chlormethine is used intravenously for Hodgkin’s lymphoma.
What is melphalan used for?
It can be given orally and it is used in multiple myeloma, breast and ovarian cancer.
What is the advantage of using cyclophosphamide?
It is a non toxic prodrug which can be used in various cancers. It is orally bioavailable and it is metabolised by the cytochrome P450.
Cytotoxic antibiotics is part of intercalating agent which target the nucleic acid. Describe their mechanism of action and provide a few examples.
These drugs contain a planar aromatic or a heteroaromatic ring system which can slip into the double helix system and distorts it structure by forming ionic bond with the phosphate backbone of the DNA. When bound, it inhibits enzyme such as topoisomerase II which is involved in transcription and replication processes.
Examples are doxorubicin, epirubicin, daunorubicin, mitoxantrone and bleomycins.
They may have cardiotoxic side effects and can develop resistance.
What are the mechanism of action of anti metabolites?
They normally resemble the purine and pyrimidines structures. They are mistaken to be normal metabolites by the cells. They disrupt DNA synthesis by inhibiting key enzymes required for DNA synthesis and by becoming incorporated into DNA or RNA to produce wrong codes which cause the strand to break or terminate.
Give a brief summary of the mechanism of action of methotrexate, a folate antagonist.
Methotrexate inhibit the dihydrofolate reductase, an enzyme involved in the folate metabolism. Dihydrofolate reductase is important to maintain the levels of tetrahydrofolate which is involved in the DNA building block dTMP.
Describe the the dihydrofolate reductase role in the synthesis of dTMP.
This enzyme reduce vitamin folic acid to dihydrofolate then to tetrahydrofolate. Once FH4 is formed, it picks up a single carbon unit to form N5, N10 methylene FH4. This acts as a carbon unit source to form dUMP and dTMP.
At the end of the process FH2 is formed where the enzyme is needed for further reaction.
List the acute side effects of methotrexate.
Bone marrow suppression
Mucositis
Diarrhea
Why is folinic acid given to patient on methotrexate?
It is given to reduce the toxic effects of methotrexate. Folinic acid is a tetrahydrofolate which is going to be a alternative source for synthesis of nucleic acids
How does anti metabolite 5-flourouracil works on the cancer cell?
5- flourouracil is an effective inhibitor. It inhibits the thymidylate synthase, the enzyme involve in sythesis of dTMP from dUMP. 5-flourouracil binds irreversibly to the active site. This drug is used for treatment of breast, liver and skin cancer and it has cardiotoxic and neurotoxic side effects. Resistance can occur if cell makes too much dUMP.
Give an example of a DNA polymerase inhibitor and a brief summary of how it works.
Cytarabine.
It is phosphorylated to a triphosphate (ara-CTP) which then act as a substrate to the DNA polumerases which would lead to chain termination or prevent replication of the modified DNA.
List some examples of drug which target inhibition of tubulin polymerisation.
These drugs bind to tubulin to prevent polymerisation.
- Vincristine - leukemias, Hogdkin’s lymphoma, small cell lung carcinoma
- Vinblastine - testicular cancer, ovarian cancer
- Vindesine - leukemias, lymphomia
- Vinorelbine - breast cancer, small cell lung cancer.
Provide a summary of inhibition of tubulin depolymerisation.
The drug binds to the beta-subunit of tubulin. Their binding accelerates polymerisation and stabilises the resultant microtubules, thus inhibiting depolymerisation.. The cell division cycle is halted at the G2/M stage then apoptosis takes place.
How are sex hormones and hormone antagonists used in cancer treatment?
It a tumour requires a certain specific hormone to function then a hormone can be administered to produce the opposing effect. Hormone antagonists also can be used to block the action of the required hormone.
