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Module 15: Antineoplastic Drugs
Terms in this set (18)
A major problem with present anticancer agents is the development of resistant cells. Why does this usually happen, and what strategies can be used to try to decrease this event?
- This happens similar to the development of antibiotic-resistant bacteria. This is because when treating a patient with anticancer agents, rare cancer cells will likely be resistant, and these cells will then become dominant. This is especially true for cancer cells because the cancer genome is usually relatively unstable with a high rate of mutations.
- A major strategy to overcome this problem is to use multiple agents because it is less likely that a cancer cell will simultaneously become resistant to multiple agents if they have
different mechanisms of action and different modes of clearance/substrates for different transporters.
- Although this strategy is more effective than a single agent, most types of cancer still become resistant.
What is the mechanism of toxicity of alkylating agents? Show the chemical mechanism by which they react with DNA.
- The mechanism of toxicity is that nitrogen mustards spontaneously form a very reactive aziridinium ion that reacts with DNA, mostly with guanine, but there are other nucleophilic sites on DNA.
- The nitrogen mustards are bifunctional, and the product can again form another aziridinium ion, which can react with a second guanine base on another strand of DNA leading to cross-linking of DNA, a very difficult mutation to repair.
- Alkylating agents are bifunctional and cross-link DNA.
What is the basis for the selective toxicity of alkylating agents and many other cancer treatments, i.e. why are they more toxic to cancer cells than normal cells? How is this selective toxicity related to the most common dose-limiting toxicities associated with most traditional anticancer agents?
- Most anticancer agents are more toxic to rapidly dividing cells. This is because the DNA in dividing cells is more exposed, and damage to DNA is more likely to kill rapidly dividing cells. That is the basis for their selective toxicity.
- Thus, slowly growing tumours such as breast cancer tend to be more resistant.
- The most common dose-limiting toxicity is bone
marrow suppression. Other common targets are hair follicles and gut mucosa. These are the normal cells in the body that divide most rapidly.
- You can do without hair, but not blood cells. Neutrophils have the shortest half-life, and
therefore it is often necessary to wait until the neutrophil count recovers before the next round of chemotherapy can
What is the basis for the difference in chemical reactivity of different nitrogen mustards? For example, mechlorethamine is very reactive and must be made up fresh because it spontaneously decomposes. It must be given IV, and if it gets out of the vein it causes severe tissue necrosis. In contrast, melphalan can be given orally. While cyclophosphamide is not reactive and requires metabolism to become active.
see different nitrogen mustards image
- The basis for the differences is that the spontaneous activation of nitrogen mustards
depends on the nucleophilicity of the nitrogen with its lone pair of electrons,.
- Thus, anything that decreases the density of that lone pair of electrons makes this reaction slower, just as it makes the nitrogen less basic.
- In comparison to mechlorethamine, the nitrogen of melphalan involved in the reaction is attached to an aromatic ring, which decreases the electron density and therefore its reactivity.
- While in cyclophosphamide, the nitrogen is attached to a phosphorous, which in turn is attached to 3 electron negative
atoms that are strongly electron-withdrawing, making the nitrogen a very poor nucleophile. Thus, cyclophosphamide is not reactive at all until it is metabolized.
Show the metabolic pathway for activation of cyclophosphamide. What metabolite is thought to be responsible for the bladder toxicity associated with cyclophosphamide, what agent has been developed to prevent it, and how does it work?
- The first step of this pathway is the oxidation by CYP2B leading to an N-dealkylation. The hydrogen on the carbon next to the aldehyde group is weakly acidic and can be lost to form
acrolein and the active phosphoramide mustard. This is active where cyclophosphamide was not because the negative charge on the oxygen significantly increases the electron density on the nucleophilic nitrogen.
- In addition to the active nitrogen mustard, acrolein is also formed. Acrolein is
the simplest of the Michael acceptor reactive metabolites, and it is thought to be responsible for the bladder toxicity associated with cyclophosphamide.
- Mesna was developed to decrease this toxicity. It is highly polar and concentrated in urine where the thiol reacts with acrolein.
Cisplatin is often referred to as an alkylating agent even though that is not strictly true because there is no alkyl group. How is the mechanism of cisplatin related to that of nitrogen mustards?
see cisplatin image
- This is because cisplatin reacts with water to replace the negatively charged chloride anion with a neutral water molecule. This leaves a positive charge on the platinum and makes it electrophilic. Then it can attack DNA, mostly guanine, and
because there are two chlorides, it can react twice and crosslink DNA much like nitrogen mustards.
- However, it is not strictly an alkylating agent because there are no alkyl groups.
What is the mechanism of action of methotrexate and how is it related to the mechanism of action of the antibiotics trimethoprim and pyrimethamine? Why is methotrexate more toxic than the antibiotics?
- the mechanism of action is that the structure of methotrexate is very similar to that of folic acid, and it is a potent inhibitor of dihydrofolate reductase in all species. Therefore, methotrexate is toxic in all species. The product of dihydrofolate reductase, tetrahydrofolate, is the methylating agent required to convert uracil to thymine.
- This mechanism of action is related to that of antibiotics trimethoprim and pyrimethamine because they also inhibit the production of tetrahydrofolic acid. However, the structure of dihydrofolate reductase is different in humans and bacteria, so trimethoprim inhibits bacterial dihydrofolate reductase, but does not inhibit human and other mammalian dihydrofolate reductases significantly.
- The difference in the structure of the dihydrofolate reductase between bacteria and mammals is the basis for the selective toxicity of trimethoprim, and why methotrexate is more toxic than the antibiotics because methotrexate is a potent inhibitor of dihydrofolate reductase in all species
How is the mechanism of action of 5-fluorouracil related to the mechanism of action of methotrexate? Why is 5-fluorouracil often combined with leucovorin?
see 5-FU and related image
- Both mechanisms of action are related because methotrexate inhibits thymine synthesis by depleting tetrahydrofolate, which is the source of the methyl group
in the conversion of uracil to thymine. And 5-fluorouracil inhibits the same conversion of uracil to thymine. This is because the fluorine on 5-fluorouracil is in the same position on uracil as the methyl group of thymine; therefore, when it binds to the enzyme responsible for the conversion, thymidine synthase, it prevents the synthesis of thymine.
- The mechanism of the conversion involves a ternary complex of thymidine synthase, uracil, and tetrahydrofolate,
and an increase in tetrahydrofolate increases the binding of 5-fluorouracil to the complex. Thus 5-fluorocail is often combined with leucovorin whose pharmaceutical name is 5-formyltetrahydrofolate.
What genetically polymorphic metabolic pathway affects a patient's response to 6-mercaptopurine? What immunosuppressant is closely related to 6-mercaptopurine?
- A major metabolic pathway of 6-mercaptopurine is methylation of the thiol group leading to an inactive product. Thus, patients with a deficiency in thiopurine methyltransferase have much higher blood levels of 6-
mercaptopurine and are therefore at a higher risk of toxicity, mostly bone marrow suppression.
- The immunosuppressant closely related is azathioprine, which is
a 6-mercaptopurine prodrug, and therefore a deficiency in thiopurine methyltransferase also increases the risk of azathioprine toxicity. However, the usual indications for azathioprine such as transplant immunosuppression and rheumatoid arthritis do not require as high a dose as the treatment of cancer;
therefore, a deficiency in thiopurine methyltransferase is less likely to lead to a fatal adverse reaction with
Cancer often recurs in the brain after apparently effective chemotherapy. What is the reason for this, and what strategies have been proposed to deal with the issue?
- This is because most anticancer drugs do not reach therapeutic concentrations in the brain because of the efflux pumps in the blood-brain barrier (BBB).
- Strategies to deal with this issue include structural modification to make the drug more lipophilic, disruption of the BBB with agents such as mannitol, inhibition of specific transporters, and intrathecal injection of antibody drugs.
What strategy is used for the treatment of brain metastases with methotrexate?
- Methotrexate is a substrate for MRP1 and MRP2. Therefore, methotrexate is pumped out of the brain in the
blood brain barrier and a therapeutic level of methotrexate is not achieved in the brain with typical therapeutic
doses of methotrexate.
- Therapeutic concentrations of methotrexate can be achieved by increasing the dose, but
that would be lethal. However, if the patient is "rescued" by giving leucovorin (tetrahydrofolate), and this protects the rest of the body from the lethal effects of the methotrexate by bypassing the need to reduce dihydrofolate to tetrahydrofolate, and because, like methotrexate, leucovorin is a substrate for MRP1 and MRP2, it does not protect the cancer cells in the brain.
Why is allopurinol given to patients with certain types of cancer (e.g. non-Hodgkin's lymphoma, acute lymphocytic leukemia) in conjunction with their first cycle of chemotherapy?
- This is because when there is a very rapid death of many cancer cells, there is a significant release of purine bases that are metabolized to uric acid. This can lead to gout or renal toxicity.
Why do patients sometimes experience a hypersensitivity reaction when given paclitaxel or other taxanes? What is usually done to prevent this or to treat a patient who has had a previous reaction?
There appear to be 3 mechanisms:
- One is complement activation by the solvent used to dissolve the drugs. These drugs have very poor solubility and are sometimes dissolved in Cremophor, which is polyethoxylated castor oil.
- Another apparent mechanism is the direct activation of mast cells by the drug.
- However, it now appears that many reactions are true allergic reactions mediated by IgE antibodies against the taxane.
- To prevent this, pretreatment with steroids decreases the risk. And If a patient has had a previous reaction it is usually possible to desensitize them by starting with a very low dose and rapidly escalating to a therapeutic dose.
What is imatinib (Gleevec) and how does it work?
- Imatinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia. In the past, chronic myelogenous leukemia was a death sentence. Soon thereafter, with bone marrow transplants, many patients survived, but they required life-long immunosuppression with all of its complications.
- Imatinib works by blocking the tyrosine kinase required for the survival of these malignant cells and leads to apoptosis. However, it does not cure leukemia.
What is trastuzumab (Herceptin), and how does it work?
- Trastuzumab is an antibody that binds to and blocks the human epidermal growth factor (HER2/neu) receptor.
- It works because certain types of cancers, notably some breast cancers, over-express this receptor, and this leads to uncontrolled replication. Therefore, if the breast cancer cells in a specific individual are found to over-express this receptor these patients are a good candidate for this drug.
- This is an early example of personalized medicine in which the phenotype of the cancer is used to determine the optimal treatment
What are ipilimumab and pembrolizumab and how do they work?
- These are antibodies that bind to CTLA-4 and PD-1, respectively, and are known as checkpoint inhibitors. CTLA-4 and PD-1 are expressed on cytotoxic T cells and prevent their activation.
- Tumors usually contain
immunosuppressive cells that protect them from destruction by the immune system. If these checkpoints are blocked it allows the immune system to attack tumor cells that express molecules on their surface that are not expressed on normal cells and are therefore "foreign".
What do the suffixes tinib, mab, ximab, zumab, and mumab indicate?
- tinib indicates a tyrosine kinase inhibitor
- mab indicates a monoclonal antibody
- ximab is a chimeric antibody with the variable region being murine and the constant region being human.
- zumab is a humanized antibody with a murine component less than 10%
- mumab is a fully human monoclonal antibody cloned into a bacteriophage.
Is chaparral an effective anti-cancer agent? What is its toxicity?
- Chaparral produces toxins that smell like creosote. And this plant has been claimed to have anti-cancer properties, but there is no credible evidence that it is useful for the treatment or prevention of cancer.
- In regards to its toxicity, it contains agents such as
nordihydroguaiaretic acid (NDGA) that are toxic at higher doses, and there are several reports of chaparral-induced
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