Antimetabolites

What are antimetabolites?

Anticancer agents based on chemical structures that closely resemble essential metabolites

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How do antimetabolites work?

They work either by blocking biochemical pathways essential for cell growth/division (enzyme inhibitors) or by incorporating themselves into nucleic acids (DNA/RNA) and act as false substrates to block down-stream processes (replication/transcription

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What is the selectivity of antimetabolites based on?

The concept that tumour cells grow at a faster rate than healthy cells (e.g. bone marrow/suppression, hair follicles/hair loss, GI/toxicity). This is why antimetabolites are also known as antiproliferative agents

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Why is the clinical response to antimetabolites limited?

The growth differential between malignant and normal cells can be significant in leukaemia but solid tumours only have a small fraction of cells in active growth phase

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Give examples of antimetabolites

Dihydrofolate reductive, thymidylate synthase, adenosine deaminase and ribonucleotide reductase inhibitors, and the purine and pyrimidine antimetabolites (work by interfering with DNA/RNA synthesis, false substrates in S-phase to prevent division)

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How is tetrahydrofolic acid produced?

By the action of the enzyme dihydrofolate reductase - tetrahydrofolic acid is required for the synthesis of the nucleotide thymine which is incorporated into DNA

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What were the names of the compounds which were based on the small modification of the folic acid structure?

Aminopterin (rodenticide). Amethopterin (the analogue methotrexate)

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What were the benefits of using methotrexate in the treatment of cancers?

Superior therapeutic index. Clinical benefit in metastatic solid cancers and complete remission in choriocarcinoma and chorioadenoma

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What are the routes of administration of methotrexate?

Oral, IV, IM, thecal injections

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Describe the chemistry of methotrexate (1)

High affinity towards DHFR active site (>100 times fold) compared to substrate due to presence of amino acid rather than 4-OH (increases basic strength of pyrimidine ring)

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Describe the chemistry of methotrexate (2)

Pteridine ring of MTX occupies reverse position at active site of enzyme. Loose interaction between DHF and enzyme

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What are the indications of methotrexate in cancer therapy?

Acute lymphoblastic leukaemia, choriocarcinoma, non-Hodgkin's lymphoma, solid tumours (breast, head, neck, lung), intrathecal MTX is used for CNS prophylaxis of childhood AL

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What are the main side effects of methotrexate?

Myelosuppression, mucositis, and more rarely pneumonitis

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What are the cautions and contraindications for methotrexate?

Contra-indicated in patients with significant renal impairment (renal excretion, reduce dose). Caution - MTX can lead to nephrotoxicity at high doses

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What is used when there is nephrotoxicity at high methotrexate levels?

Glucarpidase (PO/IV) - recombinant bacterial enzyme that rapidly lowers the levels of methotrexate in the blood by converting it to inactive 2,4-diamino-N10-methylpteroic acid (DAMPA) and glutamic acid - hepatic metabolism

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What are the side effects of Glucarpidase?

Hypotension, headache, nausea, vomiting, flushing and paraesthesia.

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Methotrexate is contraindicated in the presence of what?

Pleural effusion or ascites (MTX accumulating in fluids, returns to circulation - myelosuppression). Systemic toxicity occurs with intrathecal administration (monitor blood count). MTX can cause GI ulceration

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Is methotrexate teratogenic?

Yes - MTS should be avoided during pregnancy (need adequate contraception)

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Is resistance a problem for methotrexate?

Yes - tumour cells can up-regulate production of DHFR or increase ATP-driven methotrexate efflux

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What are the adverse effects of methotrexate in high dose intermittent schedules?

Adverse effects of bone marrow and the lining of the mouth (chemotherapy-induced myelosuppression and mucositis)

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What can be used to relieve the adverse effects of methotrexate at high doses?

Periodic administration of the calcium salt of folinic acid or Leucovorin (PO/IV) - counteracts folate-antagonist effect of MTX

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Describe how the folinic acid rescue therapy works

Enables blockade of tetrahydrofolic acid production to be by-passed and speeds recovery. Folinic acid used in management of MTX overdose (with maintenance of fluid/electrolyte balance) and to manage renal failure

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What are the side effects of folinic acid?

Folinic acid itself is relatively free of side effects, pyrexia rarely occurs with parenteral use. Insomnia, agitation, depression can result from higher doses of folinic acid

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Does folinic acid interact with antibiotics?

Folinic acid doesn't counteract antibacterial activity of folate antagonists (e.g. trimethoprim). Folinic acid is also used in combination with fluorouracil as a treatment for advanced colorectal cancer

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What is the name of the methotrexate analogue?

Pralatrexate

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What was pralatrexate approved for?

Relapsed or refractory peripheral T-cell lymphoma (PTCL) - demonstrated tumour shrinkage but not increases survival

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Describe the significant of folinic acid in tumour cells (1)

Tumour cells take in folinic acid via the Reduced Folate Carrier Type 1/RFC-1). When normal cells evolve into malignant cells, they overproduce RFC-1 to ensure they get enough folate

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Describe the significant of folinic acid in tumour cells (2)

Pralatrexate designed to increase selective cellular transport via RFC-1

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State features of pralatrexate

Higher potency than MTX, can reduce the size of solid tumours but no evidence that it prolongs patient survival. S/E similar to MTX - mucositis and thrombocytopenia

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State features of precision medicine and pralatrexate

Polymorphism of SLC19 A1 gene can affect uptake of folate analogues (and efficacy of chemotherapy), test SNPs/profiling to predict potential efficacy of pralatrexate chemotherapy to improve outcome/reduce S/E

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Describe features of thymidylate synthase inhibitors (1)

Potent, selective, less prone to lead to resistance. Raltitrexed, pemetrexed. Highly water soluble folic acid analogues. Nolatrexed. Plevitrexed (clinical trials for gastric cancer but had dose-limiting haematological toxicities)

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Describe features of thymidylate synthase inhibitors (2)

Pyrimidine analogues e.g. 5-FU (5-fluorouracil) work through similar mechanism

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Describe features of raltitrexed (1)

IV, for palliation of advanced colorectal cancer (where 5-FU and folinic cid cannot be used). One of the most potent antimetabolites

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Describe features of raltitrexed (2)

Transported into cells by RFC then metabolised by Folyl Polygutamate Synthase (FPGS) into glutamate forms - polyglutamation (cells use this mechanism to conserve and concentrate folates)

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Describe features of raltitrexed (3)

Polyglutamated forms have a higher affinity for thymidylate synthase but effectiveness depends on expression of gamma-Glutamyl Hydrolase (conjugates glutamine residues)

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Why is raltitrexed unaffected by resistance?

It is not a substrate for FPGS and is not polyglutamated so it is not affected by resistance due to down regulation of the enzyme

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How is raltitrexed taken up into cells?

Taken up by the alpha form of the folate receptor. Folate receptors are high affinity folate binding membrane glycoproteins which are over-expressed in cells such as ovarian tumour cells

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Describe the clinical features of raltitrexed (1)

Generally well tolerated but can cause myelosuppression and GI toxicity (co-administration of Leucovorin). Caution in mild-moderate hepatic impairment (CrCl), dose reduced/longer intervals. Avoid in severe hepatic impairment

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Describe the clinical features of raltitrexed (2)

Teratogenic (adequate contraception required during treatment and for six months afterwards)

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Describe features of ONX-0801

Based on mechanism for raltitrexed. Significantly reduced tumour size. Pharmacogenomic analysis - molecular target for drug (Precision Medicine approach)

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Describe features of pemetrexed (1)

Predominantly inhibits thymidylate synthase (also inhibits DHFR and GARFT to a lesser extent). Used in combination with cisplatin in the UK for unresectable malignant pleural mesothelioma

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Describe features of pemetrexed (2)

1st/2nd line/maintenance therapy of locally advanced or metastatic non-small cell lung cancer

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Describe features of pemetrexed (3)

S/E - GI disturbances, oedema, neuropathy, dehydration, conjunctivitis, increased lacrimation, skin disorders. Potentially teratogenic (adequate contraception during treatment and six months after)

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Describe features of pemetrexed (4)

Caution in renal impairment, CVD, diabetes. Prophylatic folic acid, vitamin B12 supplementation are sometimes given

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Describe features of nolatrexed (1)

Non-classical TS inhibitor. Should not be affected by resistance mechanisms involving cellular membrane transport and/or down regulation of polyglutamation

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Describe features of nolatrexed (2)

It is uncharged at physiological pH, hence doesn't require specific transport mechanism such as RFC system to gain entry into cells. It is not a substrate for folyl polyglutamate synthetase, resistance cannot develop (clinical trials)

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Describe features of purine antimetabolites (1)

Inhibit several enzymes at various points in the purine biosynthesis pathway. Efficacious in a number of different cancer types but lacks selectivity (purines involves in other cellular processes e.g. DNA, RNA synthesis, protein production)

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Describe features of purine antimetabolites (2)

Agents in this class include 6-mercaptopurine and 6-thioguanine, followed by fludarabine and cladribine (sugar moiety in structure(

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What are the indications for mercaptopurine?

Oral treatment. Maintenance therapy for acute leukaemias and chronic myeloid leukaemia and in management of IBD (UC/CD)

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Describe the mechanism of action of mercaptopurine (1)

The free-base form of mercaptopurine is converted by Hypoxanthine-guanine 5-phosphoribosyl transferase (HGPRT) in sensitive tumour cells to 6-thio-inosine monophosphate (T-IMP) also called ribonucleotide 6-mercaptopurin-9-yl (MPRP)

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Describe the mechanism of action of mercaptopurine (2)

Although 6MP inhibits several enzymatic pathways in the biosynthesis of purine nucleotides, including ribonucleotide reductase mediated conversion of inosine-5′- phosphate to adenosine/guanosine-5′-phosphate

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Describe the mechanism of action of mercaptopurine (3)

The main inhibitory action appears to occur at an earlier stage in de novo purine synthesis, when conversion of 5′- phosphoribosylpyrophosphate to phosphoribosylamine by phosphoribosylpyrophosphate amidotransferase is inhibited by T-IMP.

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Describe the mechanism of action of mercaptopurine (4)

6MP is also metabolized by ribonucleotide reductase to 6-thio-2'–deoxyguanosine-5'-triphosphate which is incorporated into DNA and recognized by repair enzymes, thus leading to apoptosis

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How does resistance to mercaptopurine occur?

Partial or complete down-regulation of 5-phosphoribosyl transferase (HGPRT) within tumour cells.

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What is the prodrug of 6-mercaptopurine? (1)

The immunosuppressant agent azathioprine (metabolised into active form). Azathioprine has been used experimentally in the treatment of cancers such as childhood leukaemia and lymphomas in adults, but is now used mainly for autoimmune conditions

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What is the prodrug of 6-mercaptopurine? (2)

E.g. UC, CD, RA, SLE, connective tissue disorders, polymyositis severe refractory eczema and generalized myasthenia gravis. Used when corticosteroid therapy alone fails to provide adequate control and suppression of organ transplant rejection

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What are the cautions for mercaptopurine? (1)

Hepatotoxicity and renal toxicity can occur with mercaptopurine, and rarely intestinal ulceration and pancreatitis can result. Caution in renal/hepatic impairment (dose reduction)

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What are the cautions for mercaptopurine? (2)

Teratogenic (should not be taken during pregnancy, or by men who may father children)

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Describe features of allopurinol (1)

Used for the prophylaxis of hyperuricaemia in cancer chemotherapy, gout and calcium oxalate renal stones. Can interfere with the metabolism of both mercaptopurine and azathioprine

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Describe features of allopurinol (2)

It inhibits xanthine oxidase-mediated degradation of 6-MP to 6-thiouric acid, which can lead to renal damage. Dose of mercaptopurine should be reduced if a patient is receiving allopurinol, since dangerously high blood levels may result

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What is the pharmacogenomic test prior to treatment with 6-mercaptopurine? (1)

Pharmacogenomic tests relating to an anticancer therapy was for thiopurine S-methyltransferase (TPMT) which metabolizes 6-mercaptopurine, tioguanine and azathioprine by adding a methyl group to the C6-SH group

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What is the pharmacogenomic test prior to treatment with 6-mercaptopurine? (2)

After initial metabolism for tioguanine and azathioprine to free the C6-SH group. Patients with deficiency in TMPMT activity, thiopurine metabolism proceeds via other pathways

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What is the pharmacogenomic test prior to treatment with 6-mercaptopurine? (3)

Leading to active thiopurine metabolite being toxic to bone marrow at high concentrations (metabolism to 6-thioguanine nucleotides by HPRT)

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What is the pharmacogenomic test prior to treatment with 6-mercaptopurine? (4)

Deficiency of TMPT can affect a small proportion of individuals (patients only require 6-10% of standard dose). If full dose was used - risk of myelosuppression and death

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What is the pharmacogenomic test prior to treatment with 6-mercaptopurine? (5)

Testing for TMPT deficiency is recommended in the prescribing information for 6-mercaptopurine and azathioprine as well as measuring TMPT activity prior to starting mercaptopurine, tioguanine or azathiopurine therapy

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What is the pharmacogenomic test prior to treatment with 6-mercaptopurine? (6)

Patients with absent TMPT activity should not receive thiopurine drugs (those with reduced TPMT activity can be treated under specialist supervision)

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Describe features of tioguanine (1)

6-thioguanine. Purine antimetabolite (PO). Treat chronic myeloid leukaemia and IV given at various stages of treatment in short-term cycles. Metabolized to the 9-(1′- ribosyl-5′-phosphate) in cells

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Describe features of tioguanine (2)

Intermediate does not inhibit an enzyme but is further phosphorylated to the triphosphate and then incorporated into DNA as a “false” nucleic acid substrate

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Describe features of tioguanine (3)

Mainly used to treat acute leukaemia and chronic myeloid leukaemia (like mercaptopurine). Advisable to measure TMPT activity prior to treatment to determine appropriate dose

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What is the main side effect of tioguanine?

Bone marrow suppression - caused by assimilation of 6-thioguanine into the genome of bone marrow cells. Lower GI side effects compared to merceptopurine

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What are the cautions for tioguanine?

Caution in hepatic/renal impairment (reduce dose). Teratogenic (adequate contraception)

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What are the long term effects of tioguanine?

Risk of liver toxicity, stomatitis (rarely - intestinal necrosis and perforation)

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Describe how fludarabine phosphate works (1)

Inhibits DNA synthesis via inhibition of DNA polymerase and ribonucleotide reductase. Initial treatment for CLL or for use after first line treatment in patients with sufficient bone marrow reserves. Administered PO, IV or infusion

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Describe how fludarabine phosphate works (2)

Generally well tolerated. The only purine antimetabolite analogue in clinic use to incorporate a phosphate group in its structure - enhances water solubility

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What are the side effects of fludarabine phosphate?

Diarrhoea, anorexia, oedema, pneumonia, cough, peripheral neuropathy, visual disturbances, chills, fever, malaise, weakness and rash. Immune-mediated haemolytic anaemia, thrombocytopenia and neutropenia, and myelosuppression may be cumulative

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What is used if immunosuppression occurs?

Co-trimoxazole is co-administered to prevent pneumocystis infection. Patients must also be monitored for signs of haemolysis, neurological toxicity and worsening of existing (or increased susceptibility to) skin cancer

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What are the cautions and contraindications for fludarabine phosphate?

Contraindicated in haemolytic anaemia. Caution in renal impairment (reduce dose). Teratogenic (six-month contraceptive policy for both males and females recommended)

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Describe how cladribine works (1)

Analogue is phosphorylated by deoxycytidine kinase to its nucleotide form which then accumulates and becomes incorporated into DNA, ultimately causing strand breaks that lead to cell death

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Describe how cladribine works (2)

SC or IV to treat hairy cell leukaemia and B-cell chronic lymphocytic leukaemia. In non-cancer indications, used to treat highly active relapsing-remitting multiple sclerosis (PO, tablet)

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What are the adverse effects of cladribine? (1)

Severe myelosuppression with neutropenia, anaemia and thrombocytopenia, haemolytic anaemia. High doses - renal failure, hepatotoxicity, severe neurotoxicity (monitor hepatic/renal function)

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What are the side effects of cladribine?

GI (constipation, diarrhoea, abdominal pain and flatulence), skin disturbance (rash, pruritis and purpura), oedema, tachycardia, dyspnoea, asthenia, myalgia and arthralgia

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Is cladribine teratogenic?

Yes - contraception for both men and women is recommended during, and for six months after, treatment

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Why is anti-infective therapy used for patients on cladribine and fludarabine? (1)

Cladribine and fludarabine have the potential for a prolonged immunosuppressive effect, and so patients treated with either drug are more prone to serious bacterial, opportunistic fungal and viral infections

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Why is anti-infective therapy used for patients on cladribine and fludarabine? (2)

Therefore, prophylactic anti- infective therapy is recommended for those patients at risk. To prevent potentially fatal transfusion-related graft versus host reactions, only irradiated blood products should be administered

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Describe how clofarabine works (1)

Second generation synthetic nucleoside analogue, designed to be resistant to deamination by adenosine deaminase

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Describe how clofarabine works (2)

Analog inhibits both DNA polymerase and ribonucleotide reductase. Approved for use in relapsed or refractory acute lymphoblastic leukaemia (ALL) in patients who have received at least two previous therapeutic regimens. IV

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What are the side effects of clofarabine?

Capillary leak syndrome or systemic inflammatory response syndrome (SIRS), and bone marrow suppression

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What are the cautions for clofarabine?

Caution is recommended in mild to moderate renal and hepatic impairment, and complete avoidance advised in severe hepatic or renal impairment. Teratogenic (avoid pregnancy, men should not father children while being treated)

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What are the adverse reactions of clofarabine?

Jaundice, flushing, hypotension, pericardial effusion, haematoma, agitation, paraesthesia, peripheral neuropathy, restlessness, haematuria, hand-foot (desquamative) syndrome and pancreatitis

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Describe how nelarabine works (1)

Latest purine antimetabolite approved. Prodrug of 6-methylguanine arabinoside, metabolized by adenosine deaminase to the deoxyguanosine analogue ARA-G which then enters cells through a nucleoside transporter

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Describe how nelarabine works (2)

Once within a cell, the ARA-G is phosphorylated to ARA-GTP by cellular kinases, and then incorporated into DNA where it acts as a false substrate leading to a cytotoxic effect

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Describe how nelarabine works (3)

IV. Approved for use in ALL, and T-cell lymphoblastic lymphoma in patients who have relapsed or are refractory after receiving at least two previous regimens

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What are the side effects of nelarabine? (1)

Neurotoxicity (close monitoring, discontinuation of drug if required).

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What are the side effects of nelarabine? (2)

Can affect performance of skilled tasks (driving). Other S/E - GI/eating disturbances, hypotension, oedema, breathing problems, CNS problems, peripheral neurological disorders including hypoaesthesia/paraesthesia

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What are the side effects of nelarabine? (3)

Musculoskeletal effects, fatigue, blurred vision

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What are the cautions for nelarabine? (1)

Caution is also recommended in patients who have received, or are presently receiving, intrathecal chemotherapy or craniospinal irradiation as this can increase the risk of neurotoxicity

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What are the cautions for nelarabine? (2)

Monitor tumour (the formation of benign and malignant tumours resulting from treatment has been reported). Contraceptives are recommended in both males and females during treatment and for three months after

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How do pyrimidine antimetabolites work? (1)

Inhibit the synthesis of DNA in the S-Phase and block the movement of cells through the G1/S part of the cell

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How do pyrimidine antimetabolites work? (2)

5-fluorouracil (5FU, its prodrug is tegafur) and cytarabine (Cytosar®, ARA-C) are the two prototypic pyrimidine antimetabolites that work by interfering with pyrimidine synthesis

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Give examples of second generation agents

Gemcitabine, capecitabine, azacitidine (variations in structural modification)

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Describe features of Decitabine

A 2'-deoxycytidine analogue which becomes phosphorylated and is then incorporated into DNA. Has another mechanism of action involving inhibition of DNA methyltransferase enzymes (DNMTs)

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What is the most recent pyrimidine antimetabolite therapy introduced?

Trifluridine/tipiracil (Lonsurf®)

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Describe indications for 5-Fluorouracil (1)

Fluoropyrimidine. IV/infusion/intra-arterial. For the treatment of some solid tumours including gastro-intestinal tract and breast cancers, and in combination with folinic acid for advanced colorectal cancer. PO (unpredictable)

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Describe indications for 5-Fluorouracil (2)

Used topically for the treatment of superficial malignant and pre-malignant skin lesions, where a 5% cream (i.e., Efudex®) is highly effective

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Describe the mechanism of action for 5-Fluorouracil (1)

Metabolized to its 2′-deoxyribonucleotide form, 5-fluoro-2′-deoxyuridylic acid (FUdRP), which is a potent inhibitor of thymidylate synthase (TS)

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Describe the mechanism of action for 5-Fluorouracil (2)

Enzyme works by transferring a methyl group from the coenzyme methylenetetrahydrofolic acid to deoxyuridylic acid, which is converted to thymidylic acid and then incorporated into DNA

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Describe the mechanism of action for 5-Fluorouracil (3)

5-FU has a higher affinity for thymidylate synthetase (bioisosteric fluorine atom, van der Waals, high electronegativity, lower pKa).

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Describe the mechanism of action for 5-Fluorouracil (4)

Enables FUdRP to fit into the active site of the enzyme extremely well, although the fluorine cannot be removed, thus inhibiting the enzyme

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Describe the mechanism of action for 5-Fluorouracil (5)

Nucleophilic sulphydryl group at the active site forms a covalent bond to FUdRP, leading to a “dead end” adduct of the enzyme, coenzyme and 5-FU

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Describe the mechanism of action for 5-Fluorouracil (6)

SAR - increased size but lower electronegativity of other types of halogen atoms lead to reduced activity.

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Describe the mechanism of action for 5-Fluorouracil (7)

Overall, inhibition of TS causes depletion of dTTP resulting in an imbalance of the dATP:dTTP ratio, thus disrupting DNA synthesis and repair, and leading to a thymine-deficient death

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Why is 5-FU highly selective for cancer (malignant skin lesions)?

May be due to certain types of cancer cells lacking the relevant enzymes to degrade it

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5-FU used in combination with which drug provides a synergistic effect? (1)

Leucovorin. Proposed mechanism - folinic acid adds to the limited folate pool required for formation of the covalent ternary complex with TS to aid FdUMP binding but further conversion to dTMP is prevented

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5-FU used in combination with which drug provides a synergistic effect? (2)

Improved response rates are observed when this combination is used to treat metastatic colorectal cancer.

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What are the adverse effects of 5-FU? (1)

Myelosuppression, mucositis and, rarely, a cerebellar syndrome. On prolonged infusion, a desquamative hand-foot syndrome (also known as palmar-plantar syndrome) may also occur

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What are the adverse effects of 5-FU? (2)

Topical formulation Efudix® has to be handled with caution as it may cause local irritation, inflammatory reactions and photosensitivity, and more rarely erythema multiforme

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5-FU is used to treat which other condition? (1)

Actinic/solar keratosis. Condition of thick, scaly or crusty patches of skin usually on top of the head in older men

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5-FU is used to treat which other condition? (2)

Mostly associated with fair-skinned individuals who are frequently exposed to the sun, and caused by solar damage of the skin. The lesions are often pre-cancerous, and can progress to squamous cell carcinoma (SCC).

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5-FU is used to treat which other condition? (3)

Untreated lesions have up to a 20% risk of progression to SCC, therefore it is important that they are treated

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Describe features of Actikerall (1)

Topical solution containing fluorouracil (5 mg/g) and salicylic acid (100 mg/g) for the treatment of 33 palpable and/or moderately thick hyperkeratotic actinic keratosis (Grade I/II) in adult patients.

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Describe features of Actikerall (2)

The tolerability profile is good, and site- application events of only mild to moderate intensity occur.

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Describe features of tegafur

A prodrug of 5-fluorouracil in which a tetrahydro-2-furyl moiety is joined to the N1-position of 5-FU. Often given in combination with agents that modify its bioavailability and toxicity such as gimeracil, oteracil or uracil

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How do gimeracil and uracil work? (1)

Gimeracil and uracil work by inhibiting the enzyme dihydropyrimidine dehydrogenase (DPD) which is responsible for metabolizing fluoropyrimidines such as tegafur, 5- fluorouracil and capecitabine

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How do gimeracil and uracil work? (2)

Thereby reducing their degradation in the body and maintaining plasma and tissue levels

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How does oteracil work? (1)

Oteracil inhibits the enzyme phosphoribosyl transferase, thus decreasing the activity of fluorouracil in normal gastrointestinal mucosa and reducing potential toxicity to this tissue

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How does oteracil work? (2)

(Tegafur/gimeracil/oteracil combination used with cisplatin for solid tumours, advanced gastric cancer). Variations in CYP2A6 genotypes

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What are the side effects of tegafur?

Similar to 5-FU. myelosuppression, gastrointestinal toxicity (especially diarrhoea) and central neurotoxicity, with gastrointestinal toxicity dose-limiting. Central neurotoxicity is more common with tegafur than with fluorouracil

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Caution is required in what for tegafur?

Cardiac and hepatic impairment

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Describe features of genetic variations in the DPD gene (1)

Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are homozygous or heterozygous for these variations may have complete or partial DPD deficiency

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Describe features of genetic variations in the DPD gene (2)

Those patients with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines including myelosuppression, neurotoxicity and hand-foot syndrome

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Describe features of gemcitabine (1)

Metabolized to biologically active diphosphate and triphosphate nucleosides that are responsible for inhibiting DNA synthesis and inducing apoptosis

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Describe features of gemcitabine (2)

It is used alone intravenously in elderly patients or for palliative treatment, or in combination with cisplatin as first-line treatment for locally advanced or metastatic non-small-cell lung cancer

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Describe features of gemcitabine (3)

It is also used in locally advanced or metastatic pancreatic cancer

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Describe features of gemcitabine (4)

First-line treatment of locally advanced or metastatic non-small cell lung (as monotherapy or in combination with cisplatin), pancreatic, bladder (with cisplatin), epithelial ovarian (with carboplatin) and breast (with paclitaxel) cancers

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What are the side effects of gemcitabine?

Mild GI disturbances, musculoskeletal pains, renal impairment, pulmonary toxicity, influenza-like symptoms and rashes. Haemolytic uraemic syndrome. Microangiopathic haemolytic anaemia (discontinue)

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Is gemcitabine teratogenic?

Yes - contraceptives are required in both females and males during and after treatment

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Describe features of capecitabine (1)

A prodrug of doxifluridine, a fluorinated pyrimidine nucleoside with cytostatic activity which is no longer used clinically

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Describe features of capecitabine (2)

A multiple prodrug of 5-FU designed to be given orally and to be metabolized by a three-enzyme cascade specifically in cancer cells.

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Describe features of capecitabine (3)

Capecitabine is recommended by NICE for use as an adjuvant for Stage III colon cancer following surgery, metastatic colorectal cancer, first-line treatment of advanced gastric cancer

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Describe features of capecitabine (4)

And second-line treatment of locally advanced or metastatic breast cancer

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Describe features of capecitabine (5)

Of the general cytotoxic side effects, hand-foot (desquamative) syndrome and diarrhoea are the most prominent. Caution is required in patients with cardiac, liver, renal disease or diabetes

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Describe features of cytarabine (1)

The first pyrimidine antimetabolite analogue to be approved. It is converted by cellular kinases into the active metabolite, and can be administered subcutaneously, intravenously or intrathecally

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Describe features of cytarabine (2)

Cytarabine is recommended by NICE for the induction of remission in acute myeloblastic leukaemia, and for the treatment of lymphomatous meningitis

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Describe features of cytarabine (3)

A liposomal cytarabine–daunorubicin combination formulation (Vyxeos®) is also available and recommended by NICE as an option for therapy-related untreated acute myeloid leukaemia, or acute myeloid leukaemia with myelodysplasia- related changes

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What are the issues with cytarabine? (1)

S/E - potent myelosuppression (requires careful haematological monitoring). Cytarabine therapy relates to its rapid hepatic deamination by cytosine deaminase to an inactive uracil derivative thus leading to a short half-life

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What are the issues with cytarabine? (2)

This problem can be counteracted by using continuous infusion methods of administration, although a reduced dose must be used in patients with renal impairment.

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What are the issues with cytarabine? (3)

This rapid deamination led to a quest for deaminase-resistant analogues, and also pyrimidine nucleoside deaminase inhibitors that could potentially be co-administered

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What are the issues with cytarabine? (4)

However, of the many halogenated analogues investigated, only fluoro-derivatives appear to have any appreciable antitumor activity

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Describe features of azacitidine

DNA hypomethylating agent. SC. Treatment of CML, AML and intermediate-2 and high-risk myelodysplastic syndromes in adults who are not eligible for haematopoietic stem cell transplantation

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What is the mechanism of action for azacitidine (1)

It becomes incorporated into DNA and forms stable complexes with methyltransferase enzymes leading to their inhibition. Acts as a DNA methylation inhibitor

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What is the mechanism of action for azacitidine (2)

Blocks a number of essential cellular processes such as transcription by preventing the binding of regulatory proteins

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What are the cautions for azacitidine? (1)

Caution is necessary in patients with a history of severe congestive heart failure, unstable cardiac or pulmonary disease, or hepatic or renal impairment.

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What are the cautions for azacitidine? (2)

A rise in serum creatinine or blood urea nitrogen levels indicates that the next treatment cycle should be delayed, and patients should be monitored for bleeding

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What are the side effects of azacitidine?

GI disturbances, anorexia, hypotension, hypertension, dyspnoea, pneumonia, haematuria, hypokalaemia, arthralgia, myalgia, injection-site reactions, rash, haematoma and haemorrhage

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Is azacitidine teratogenic?

Yes - contraception is required for both males and females during and after treatment

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Describe features of decitabine (1)

A 2'-deoxycytidine analogue which becomes phosphorylated and is then incorporated into DNA, affects normal processing. Has another mechanism of action involving inhibition of DNA methyltransferase enzymes (DNMTs)

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Describe features of decitabine (2)

Functions in similar manner to azacitidine although can only be incorporated into DNA strands while azacitidine can incorporate into both DNA and RNA chains

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Describe features of decitabine (3)

Decitabine is incorporated into DNA strands upon replication, and when DNMTs such as DNMT1 are engaged to bind the DNA and to replicate the methylation pattern to the daughter strand, the decitabine binds to the enzyme irreversibly

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Describe features of decitabine (4)

Thus blocking disengagement from the DNA strand. Division-dependent - tumour cells replicate more rapidly

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Describe features of decitabine (5)

Methylation of CpG islands upstream of tumour suppressor genes in order to silence them seems to be critical for activity towards haematological cancers. Decitabine exerts its anticancer effect, at least in part, by blocking this type of methylation

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What are the indications for decitabine?

Treatment of newly diagnosed acute myeloid leukaemia in patients over the age of 65 who are not candidates for standard induction chemotherapy

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What are the side effects of decitabine?

Bone marrow suppression leading to thrombocytopenia and anemia, diarrhea, epistaxis and headaches

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Describe features of trifluridine/tipiraci (1)

Most recent pyrimidine antimetabolite therapy. Fixed combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase (TPase) inhibitor that enhances trifluridine concentrations

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Describe features of trifluridine/tipiraci (2)

Trifluridine was originally developed as an anti-herpes antiviral agent, primarily for the eye.

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Describe features of trifluridine/tipiraci (3)

Design concept based on the hypothesis that, as a modified form of deoxyuridine similar enough to be incorporated into viral DNA replication, the –CF3 group added to uracil ring should block viral DNA base pairing, interfering with replication

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Describe features of trifluridine/tipiraci (4)

PO (tablet), approved for metastatic colorectal cancer, in patients previously treated with (or unsuitable for treatment with) other therapies including irinotecan-, fluoropyrimidine- and oxaliplatin-based therapies, or anti-VEGF or anti-EGFR agents

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What are the side effects of trifluridine/tipiraci? (1)

blood disturbances (e.g., anaemia, decreased or increased leucocytes, neutropenia, thrombocytopenia), GI disturbances (e.g., nausea, vomiting constipation, diarrhoea, taste alterations, mucositis, gastrointestinal discomfort), appetite

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What are the side effects of trifluridine/tipiraci? (2)

Weight loss, alopecia, asthenia, peripheral neuropathy, hyperbilirubinaemia, hypoalbuminaemia, increased risk of infection, oedema and skin reactions

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How is trifluridine/tipiraci metabolised?

It has no tendency to accumulate in the body, and is metabolised by the enzyme thymidine phosphorylase to 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (FTY), and also by glucuronidation.

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What is adenosine deaminase?

An enzyme involved in the salvage pathway associated with purine synthesis

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Describe features of pentostatin

Initially isolated from Streptomyces antibioticus. IV, alternative weeks, approved for the treatment of hairy cell leukemia, and is capable of inducing prolonged remissions

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What are the side effects of pentostatin?

Myelosuppression, immunosuppression and several other side effects that can be severe

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State features of ribonucleotide reductase (1)

Ribonucleotide reductase, also known as nucleoside diphosphate reductase (or RNR), is involved late in both the purine and pyrimidine synthesis pathways

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State features of ribonucleotide reductase (2)

RNR catalyzes the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates by replacing a 2’-OH functionality with H

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State features of ribonucleotide reductase (3)

Its enzymatic activity is attributed to the formation of a tyrosyl free radical from tyrosine and iron atoms at the active site

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Give examples of ribonucleotide reductase inhibitors

Hydroxycarbamide, triapine and tezacitabine. (Gemcitabine possesses some RNR inhibitory properties in addition to its other mechanisms of action)

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Describe features of hydroxycarbamide (1)

PO. Inhibits ribonucleotide reductase by quenching the tyrosyl radical and causing depletion of the deoxynucleoside triphosphate pool, thus blocking DNA synthesis and repair at the G1-S interface

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Describe features of hydroxycarbamide (2)

Recommended by NICE for the treatment of polycythaemia vera, essential thrombocythaemia, chronic myeloid leukaemia and cervical cancer

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Describe features of hydroxycarbamide (3)

In the non-cancer area, because it induces foetal Hb production, hydroxyurea (Siklos®) is also used to treat sickle cell anaemia (Sickle-cell disease)

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What are the toxic effects of hydroxycarbamide?

Myelosuppression, nausea, and skin reactions

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Describe features of triapine (1)

Aminopyridine thiosemicarbazone. Synthetic inhibitor of ribonucleotide reductase with similar properties to hydroxyurea. In addition to quenching the tyrosyl radical at the active site of the enzyme, triapine also chelates iron atoms

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Describe features of triapine (2)

Enhancing potency. It also increases the uptake and antitumour activity of gemcitabine and cisplatin, a property which was potentially useful for combination therapies (didn't progress further)

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Describe features of tezacitabine (1)

Synthetic purine nucleoside. Analogue of ribonucleotide reductase. Dual MOA

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Describe features of tezacitabine (2)

Inhibits RNR in its diphosphate form and then becoming incorporated in the triphosphate form into DNA during replication, thus causing chain termination and cell death (trials in gastroesophageal cancer, colorectal cancer)

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Antimetabolites

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