Cancer chemotherapy Flashcards
Combined vs Single agent
Originally single chemotherapeutic agents used to treat cancer until the early 1960’s.
Combination therapy coupled with more aggressive treatment regimen became popular in 1960’s.
Combination therapy led to increased remission, in terms of both patient numbers and length of remission time
More aggressive regimen results in increased side effects
How do alkylating agents work? What do they target in DNA?
Alkylating agents are highly electrophilic compounds that react with nucleophiles to form strong covalent bonds. There are several nucleophilic groups in DNA such as N-1 and N-3 of adenine bases, N-3 of cytosine and in particular N-7 of guanine.
React/bind to guanine for example and cross link the chains = disrupt replication or transcription
What type of cancers are treated using alkylating agents?
used to treat a wide range of cancers including leukaemia, non-hodgkin lymphoma, Hodgkin disease, multiple myeloma, lung, breast, testicular and ovarian cancers
Why can’t chlormethine (alkylating agent) be given orally?
Too reactive to survive oral administration - so given via IV
Treatment of Hodgkin’s lymphoma via multidrug regime
How is Melphalan (alkylating agent) be given? What is it usually used for/
Less reactive so can be given orally. Mimics phenyl alanine.
Used for treatment of multiple myeloma, ovarian and breast cancers
Cyclophosphamide (alkylating agent) is given as a prodrug, what happens to it when taken?
It is a prodrug but not toxic itself but it is metabolised in the liver by cytochrome P450 to the active agent.
It can be taken orally without any damage to the gut wall.
Describe the mechanism of action of cytotoxic antibiotics
contain a planar aromatic or heteroaromatic ring system which can slip into the double helix of DNA and distort its structure. Once bound, the drug can inhibit the enzymes involved in the replication and transcription process. Examples include doxorubicin, epirubicin, daunorubicin, mitoxantrone and the bleomycins
Why can’t anthracyclines (cytotoxic antibody) be given orally?
Orally inactive need to be given as IV
Can have cardio-toxic side effects and multi-drug resistance can develop
Explain how Doxorubicin (Intercalating agent) works and where did it come from?
Was isolated from Streptomyces Peucetius & used to treat a wide range of solid tumours.
It approaches DNA via the major groove of the double helix and intercalates using the planar tricyclic system.
The charged amino group attached to the sugar is also important, as it forms an ionic bond with the -vely charged phospahte groups on the DNA backbone.
What does the Intercalating action result in?
Intercalation prevents the normal action of an enzyme called topoisomerase II. An enzyme essential to effective replication of DNA and to the mitosis process.
What is the second likely mechanism Doxorubicin proves harmful to DNA ?
A second mechanism by which doxorubicin can prove harmful to DNA involves the hydroxyquinone moiety which can chelate iron to form a doxorubicin-DNA-iron complex. Reactive oxygen species are then formed leading to single strand breaks in the DNA.
Explain how anti-metabolites (enzyme targets) work?
These drugs a similarly structured as the naturally occurring purines and pyrimidines involved in nucleic acid synthesis.
Since they are mistaken by the cell for normal metabolites they have two modes of action:
Disrupt DNA synthesis by inhibiting key enzymes required for DNA synthesis (they inhibit purine and/or pyrimidine production) AND by becoming incorporated into the DNA and RNA to produce incorrect codes and cause strand breaks or premature chain terminations
Give an example of an anti-metabolite and how it works?
Dihydrofolate reductase (DHFR) inhibitors
e.g. methotrexate
inhibit DHFR which is an essential enzyme in folate metabolism
DHFR is crucial in maintaining levels of the enzyme cofactor tetrahydrofolate FH4 - without this cofactor the synthesis of the DNA building block dTMP is aborted which in turn slows down DNA synthesis and cell division.
What are some of the side effects of methotrexate?
bone marrow suppression, mucositis and diarrhoea
How can we overcome the metabolic block caused methotrexate?
Give folinic acid
This is a tetrahydrofolate and therefore provides an alternative source for the synthesis of nucleic acids. This is important when high doses of methotrexate are used, as folinic acid can be administered to patients as a rescue from the toxic effect of the treatment
Another example of an anti-metabolite is an inhibitor of thymidylate synthase. How does this work? give an example
Stop thymidylate synthesis which stops DNA synthesis
Example: 5-Fluorouracil - works as a suicide substrate so binds irreversibly to the enzyme.
How can resistance occur with using thymidylate synthase inhibitors/5-fluorouracil?
Resistance can occur if the cell produces excess quantities of dUMP to compete with the drug for the active site of the enzyme
How do DNA polymerase inhibitors work? Give an example
DNA polymerases catalyse the synthesis of DNA using the four deoxyribonucleotide building blocks, dATP, dGTP, dCTP and dTTP.
For example cytarabine is an analogue of 2’-deoxycytidine. It is phosphorylated in the cell to the corresponding triphosphate (ara-CTP) which acts as a competitive inhibitor. In addition, ara-CTP can act as a substrate for DNA polymerases and become incorporated into the growing DNA chain. This can lead to chain termination or prevent replication of the modified DNA. All of these effects result in the inhibition of DNA synthesis and repair.
What is cytarabine (DNA polymerase inhibitor) used for and how is it administered?
used intravenously for the treatment of a wide variety of leukaemias
Give an example of a group that inhibit tubulin polymerisation (protein targets)
Vinca Alkaloids:
Vincristine
vinblastine
vindesine
vinorelbine
What is Vincristine used for?
Vincristine is used in combination therapy to treat acute leukaemias, Hodgkin’s lymphoma, small-cell lung carcinoma and a variety of other tumours
What is vinblastine used for?
Vinblastine has been used in combination therapies for the treatment of lymphomas, testicular cancer and ovarian cancer.
What is vindesine used for?
Vindesine has been used in the treatment of various leukaemias and lymphomas.
What is Vinorelbine used for?
Vinorelbine is widely used for the treatment of breast cancer and non-small-cell lung carcinomas
