Session 10: Anti-arrhythmics and Cancer Drugs Flashcards

Question

Describe the uses and side effects of Calcium channel blockers

Answer 1

Uses * Control ventricles during supraventricular tachycardia * Convert supraventricular tachycardia (re-entry around AV) * Main clinical uses are for hypertension, angina, rate-controlled AF but only when beta-blockers are contra-indicated. Contra-indications for their use include heart failure, bradycardia and AV node block. Side effects: * Caution when partial AV block is present. Can get asystole if Beta-blocker is on board. * Caution when hypotension, decreased CO or sick sinus * Some gastrointestinal problems

Answer 2

Administration: rapid IV bolus, very short half life (seconds) Mechanism: natural nucleoside that binds A1 receptors and activates K+ currents in AV and SA node – leading to decreased APD, hyperpolarization =\> decreased HR (transient temporary heart block). Then normal rhythms start again from the SA. * Decreased Ca2+ currents – increased refractory period in AV node Cardiac effects: slows AV conduction (used for termination of natural arrhythmias) Uses: convert re-entrant supraventricular arrhythmias. It can be used to distinguish SVT as if given as the tachycardia continues, then the re-entry loop is likely to occur between the atrium and the ventricles, and not at the AVN. Also used for hypotension during surgery, diagnosis of Coronary Artery Disease, but can cause bronchospasm in asthmatics

Answer 3

Mechanism * Enhances vagal activity (increased K+ currents, decreased Ca2= currents, increased refractory period) * Slows AV conduction and slows HR * It also inhibits the action of Na+-K+-ATPase thus leading to a reversion sodium-calcium exchanger =\> increased store of Ca2+ in sarcoplasmic reticulum =\> positive inotrophic effect. Uses: treatment of rapid AF and atrial flutter Normally requires a loading dose (given in 2 doses) for rapid onset and is quite lipid soluble so has a large volume of distribution, reflecting in its half life of 36-48 hours. As it is excreted renally, any renal impairment should result in altered dosing in the patient. Main adverse effects are with cardiac toxicity, yet any severe digoxin toxicity can be treated with Digiband.

Answer 4

Atropine: normally given whilst waiting to put a pacemaker as an emergency * Mechanism: selective muscarinic antagonist * Cardiac effects: block vagal activity to speed AV conduction and increase HR * Uses: treat vagal bradycardia Magnesium: treatment for tachycardia resulting from long QT

Answer 5

Either rate control (slow action potential) or rhythm control (slow AV conduction =\> then SA wakes up and starts generating normal rhythms) Consider Beta-blocker (slows AV node), Calcium Channel Blockers, Flecainide, Digoxin, Amiodarone or Sotalol (the latter two would also affect conduction and slow HR)

Answer 6

Which IV drug first for VT * Lidocaine Should flecainide be used alone for atrial flutter? * Flecainide slows down conduction but creates flecainide flutter (‘organises’ AF into atrial flutter with 1:1 conduction) * The first response would be give Beta-blocker or (possible calcium channel blocker or digoxin) – target AV node conduction Best drug for WPW? * Flecainide - Slows conduction (bundle of Kent) (slows AV conduction)

Answer 7

List drugs used in re-entrant SVT * Adenosine – blocks AV, terminates rhythm - IV verapamil for asthmatics * + slow conduction e.g. Flecainide (weight-limited) or Amiodarone Which drugs for ectopic atrial tachycardia? * Beta-blockers (phase 4), Calcium Channel blockers, can use Flecainide possibly if heart structure is normal * Use drugs that affect automaticity Which drugs for sinus tachycardia? * Target automaticity – so use Beta-blockers, Calcium channel blockers (rate control)

Answer 8

Around 1 in 3 people will experience cancer in their lifetime, with about 350,000 new cases of cancer in the UK annually. Overall, cancer is the second most frequent cause of death in the UK with about 160,000 deaths in 2011, or about 25% of all UK deaths. The scale of the challenge cancer presents is due in part to the survival of many more people into older age, when the ability of the body to deal with cancer on its own is much reduced. For effective treatment of cancer, chemotherapy is often employed as part of a carefully planned treatment program that often involves surgery and radiation therapy. The combination depends on the type of cancer and its stage of progression. Over 80 chemotherapeutic drugs are currently in use in the UK and this number continues to increase as new treatments are approved for use.

Answer 9

In the 1940s, investigators used nitrogen mustard to treat lymphoma. Some agents were found by chance e.g. Cisplastin (platinum electrodes stopped E coli growth) Screening of compounds e.g. trabectedin (extract from the sea squirt) Chemical engineering e.g. Taxotere (follow up molecule from tubulin poison in Pacific Yew stem bark). Molecular targeting approaches: Imatinib (magic bullet) * Rationally designed targets and inhibitors * Tumour selective * More efficacious * Fewer side effects

Answer 10

Cancerous cells arise due to one or more mutations in the normal genome that result in a profound change in the cell’s behaviour, Both the internal and external environment plays a well-documented role in driving these genetic changes, providing a host of carcinogenic factors e.g. radiation exposure from UV light or X-ray, free radical generators, viral triggers, fatty diet etc. The two main categories of genes acted upon by mutation are recognised as: * Proto-oncogenes (inactive) transformed by mutation to oncogenes (active). * These genes control cell division apoptosis and differentiation * Tumour suppressor genes. The loss of function of these suppressor genes can be critical in triggering carcinogenesis.

Answer 11

Structure of DNA: * Nucleotide = sugar-phosphate-base * DNA = double helix of nucleotides * Purines = adenine and guanine * Pyridimines = cytosine and thymine (uracil in RNA) Tumour growth * 10^9 = clinically detectable * 10^12 = exponential tumour growth * Exponential tumour growth in between.

Answer 12

Loss of cell growth control * The key feature is that the normal mechanism controlling proliferation and ordered cell death (apoptosis) is lost. This does not mean that the cancer cells are necessarily proliferating faster than normal cells, but that the ordered control of cell division balanced by apoptosis is lost in cancer cells. De-differentiation and loss of specific function * Normal cells have a specific function to fulfil, which is lost when they turn cancerous. The degree of de-differentiation in cancers varies considerably but the greater this loss of original identity, the worse the malignant challenge to the body generally is.

Answer 13

Blood Supply: * As the cancer cells proliferate to reach the dimensions of a clinically discernible tumour, there is a natural limit to growth due to limited blood supply. * This would restrict tumour growth to about 1-2mm in diameter. * To overcome this limitation, the tumour cells produce their own local angiogenesis factors to promote vessel growth into the tumour so it can continue to develop. Metastasis and invasiveness * If they didn’t metastasise, they could be targeted through direct surgery and irradiation. However, malignant cells may lose the very specific positional sense and identity within their parent tissue. This arises due to changes in cell surface proteins. These changes allow them to migrate or metastasise throughout the body. * This takes place via the lymphatic or vascular system or more locally by invasion of an adjacent body cavity. They can then proliferate further afield and produce new tumours. * In addition as the cancer progresses over time, further mutations in cancer cells result in increased heterogeneity, with distinct cell lines arising that increase the malignant challenge to be met by chemotherapy.

Answer 14

Given the physiological limitations on tumour growth, not all cells in a tumour are involved in active proliferation and normally belong to one of three compartments. These compartments tend also to relate to their spatial position in the body of the tumour. Compartment A: Dividing cells receiving adequate nutrient/vascular supply * May represent between 5-20% of the actual tumour cell population and is the one most susceptible to chemotherapy targeting cells at one or more stages in the cell cycle. Compartment B: Resting cells remain in ‘G0’ phase but able to re-join Compartment A if there are changes in cell signalling or the local environment – e.g. following surgery. More likely to be situated in the middle of the body of the tumour. * Therapeutically the cells present a real problem. They may be affected to some degree by chemotherapy as some resting RNA and protein synthesis will be taking place. But the proportion of chromosomal DNA in G0 that is open to attack is much more limited. * This makes the effective kill ratio attainable in this compartment much lower. They will thus be available to re-enter Compartment A, even following intense chemotherapy. Compartment C: Cells no longer able to divide, but act to contribute to the overall bulk of a tumour. These present no challenge. * NB: cancer cells can still die off on their own if minimal nutrient supply is not maintained. In addition, surgery and radiation can only be effective on dealing with identified tumour sites and not on those smaller metastatic tumours or rogue cancer cells that have evaded detection. The above proportions of compartmentalisation also relate to tumour types’ susceptibility to chemotherapy. For example, rapidly proliferating lymphomas are more sensitive than breast, ovarian or bladder tumours that grow at a moderate rate. These in turn are more sensitive than slow growing prostate cancer.

Answer 15

Cell proliferation variation in cycle 9-43 hours between cancer cells

Answer 16

Typically a tumour needs to consist of a cluster of about (10^9) cells before it is clinically detectable or to reach the side of a small group. A log kill ratio means that if a given treatment kills 10^4 cells or 99.99% of cancer cells, then for a population of 10^9 cells, this would mean a reduction to 10^5 cells or to 0.01% of the original population of 10^9 cells. The 10^5 cancer cells remaining would resemble a sphere the size of a full stop. This would be four log kill ratio and further treatment would be warranted so another dose of the same four log kill therapy would then result in only 10^1 or just 10 cancer cells remaining. In this theoretic model this sounds really good, but the factors outlined earlier mean that of the 10^9 cells, perhaps only 10^7-10^8 may be available for direct attack (Compartment A) with the more resistant resting Compartment B cells able to revert hydra like, to aggressive ‘A’ types post therapy. In reality, more modest kill rations may be attained that require repeated chemotherapy. The kill rate for cancer cells has to be weighed up against the kill rate for healthy cells in susceptible tissue.

Answer 17

The fractional cell kill hypothesis (reason for intermittent chemotherapy) * Bone marrow recovers before tumour cells so need to make sure bone marrow has recovered before second dose (bolus) but give second bolus before tumour cells have recovered =\> leads to a reduction in tumour cells * After successive rounds of chemotherapy, bone marrow cells take longer and longer to recover. The ‘art’ of chemotherapy therefore is to try and ensure that this kill ratio does not lead to mortality, and that in between each chemo session, the rate of regrowth of healthy tissues is sufficiently ahead of that of tumour cells. This means that the clinical team must work to improve the odds ratio in favour of healthy cells. If this cannot be maintained, then the prognosis is poor.

Answer 18

Classification of tumours according to chemo-sensitivity * Highly sensitive (so majority of treatment is chemotherapy): lymphomas, germ cell tumours, small cell lung, neuroblastoma, Wilm’s tumour * Modest sensitivity (surgery plays the main part of treatment, chemotherapy given before to minimise the size of the tumour – neoadjuvant – or afterwards to kill any remaining cancer cells – adjuvant): breast, colorectal, bladder, ovary, cervix * Low sensitivity: prostate, renal cell, brain tumours, endometrial

Answer 19

There are a wide range of agents that act at particular phases of the cell cycle but they all aim to try and drive a therapeutically higher rate of apoptotic death in cancer cells over that caused in normal cells. Their therapeutic indexes are frequently quite small due to their paradoxical therapeutic effect being dependent on their cytotoxicity. They have significant side effect profile

Answer 20

**DNA Intercalation and Topoisomerase II inhibition** * The anthracycline antibiotics are used in synergistic combination with other drugs with different mechanisms to reduce the risk of additive ADRs. * Members of this group include **doxorubicin and daunorubicin**. Their discrete molecular ring structure enables to intercalate between the spaces between DNA base pairs. This **intercalation would interfere with normal transcription and replication**. The anthracyclines particularly affect the activity of Topoisomerase II. * Topoisomerase II enables the breaking, rotation and re-ligation of DNA strands during DNA replication and repair. The intercalated antibiotic molecule physically interferes with this. This action is further augmented by the anthracycline binding to the Topoisomerase II thus forming a tripartite DNA – anthracycline-Topoisomerase II complex. * This hinders its available for deployment elsewhere. The resulting non-ligated free strands of DNA act as a trigger to apoptosis. * As a secondary action, the anthracycline are able to generate free radicals by binding free Fe2+. The locally produced free radicals then go onto further damage the DNA. Overall, the damage caused by anthracyclines is detected by DNA damage sensing mechanisms in the cell which then trigger apoptosis. In contrast to bleomycin, their action is non-cell cycle specific.

Answer 21

**DNA Scission** Bleomycin is a glycopeptide antibiotic derived from Streptomyces fungi. * Bleomycin can both bind with DNA and chelate with free Fe2+ ions. Its structure allows it to closely align itself within DNA by both intercalation but also by binding via its terminal NH2 group to DNA. * When it chelates with free cytoplasmic Fe2+ ions, this reaction site then catalyses production of both superoxide and hydroxide free radical species. * These highly free radical species then attack phosphodiester bonds in the DNA strand resulting in a cutting or scission of DNA strands. * This scission is considered to be the primary mechanism underlying its cytotoxicity and is comparable with the anthracyclines in this respect. The production of free radicals is also considered to underlie its pulmonary toxicity. * Bleomycin is most effective during G2 but also has some effect in non-replicating G0 cells.

Answer 22

Alkylating Agents Related Compounds and the Platins Lots of variation in naming which can cause some confusion. For example nitrosourea and the platinum based agents have no alkyl group. However, they are also referred to or commonly considered alongside and grouped with, the ‘alkylating agents’. Clinically the name is often used to refer to compounds used in chemotherapy that **covalently bind to DNA**. The primary underlying mechanism for these related agents is that they typically possess two highly labile or ‘leaving’ groups such as Cl, that are necessary for instigating the covalent reaction with the DNA.

Answer 23

Nucleophile target sites for these agents are spread along the whole length of DNA. Along the length of DNA strands the specific molecular target sites are nucelophilic or positive charge attracting, groups. These are very common and their locations are very well defined. These include: * N7 and O6 atoms in guanine * N1 and N3 in adenine * N3 in cytosine These all have spare electron pairs to donate to a vacant electron orbital. They can therefore, make a covalent bond with those agents the alkylating group. The reactive group on alkylating agents are therefore electrophilic or ‘electron attracting’.

Answer 24

Mechanistically the alkylating agents undergo a common sequence of chemical reactions with DNA. What these apparently disparate compounds have in common are the steps outlined below Step 1: the ‘alkylating’ agent is administered IV to allow fine control of the delivery of these cytotoxic drugs delivered to the body Step 2: in the plasma compartment, the –Cl groups remain attached to the parent molecule via carbon, as the relatively high concentration of plasma Cl-, reduces the degree of dissociation from the parent molecule. Step 3: the molecules enter the cell where the labile negatively charged – Cl groups are easier to lose, due to the lower cytoplasmic concentration of free Cl-. Step 4: when close to their exposed DNA target site, the loss of the Cl- groups results in a net positively charged carbonium ion, or in the case of the platins, a positively charged Pt2+. Step 5: whether it is a single unit positively charged alkyl associated with a carbonium R-C+ ion or a Pt2+ group that remains after the Cl leave, these are able to then react with the nucleophilic (positive charge attracting) groups on the DNA bases referred to above. These nucleophilic groups donate electron pairs to form the stable covalent bonds.

Answer 25

Step 6: the existence of two sets of individual electron pair accepting sites on each carbonium ion enables cross-linking at two spatially separate nucleophilic sites on DNA strands. * In the case of the platins, the two electron pair accepting orbital sites are located on the platinum Pt2+ or other similar chemotherapeutic electrophilic compound, also enables crosslinking at two spatially separate nucleophilic sites on DNA strands. * The key point is even though the single charge carbonium ion is distinct to the double charged Platinum ion, they both react as electrophiles accepting the electron pair from the DNA nucleophilic bases. Step 7: These can then form inter-strand or intra-strand links to form DNA adducts with the DNA. For example with cis-platin, these covalent links are typically about 55% G-G and 30% A-G adducts with intra-strand linking being most favoured. In addition, cross-linking can also occur between DNA and proteins. The physical disruption of DNA interferes with both DNA replication and RNA transcription. It is the inhibition of DNA replication that is the primary cause of cell death.

Answer 26

The maximal effect of alkylating agents is during ‘S’ phase. The action of alkylating agents is considered to be non-cell cycle specific and they can interact with DNA at any point. However, they have maximal effect in cells undergoing a greater rate of replication and exert their greatest effect in ‘S’ phase when DNA is replicating and large sections of DNA strands will be exposed and unpaired. Similarly, attack can occur at G1 when enzymes, especially those for DNA synthesis, are being transcribed. Disruption here will further interfere with the process of cell division by reducing this enzyme pool.

Answer 27

Platinum compounds: formation of platinated inter- and intrastrand adducts leads to inhibition of DNA synthesis. DACH platinum adducts are bulky and thought to be more effective in inhibiting DNA synthesis than platinum adducts.

Answer 28

Antimetabolites – interference with precursors to purine and pyrimidine synthesis. Antimetabolites used in cancer chemotherapy are structurally related to precursors involved in DNA synthesis. They act to interfere with the production of purine or pyrimidine nucleotides. This is by acting as a direct competitive analogue in DNA or RNA synthesis such as 6-Mercaptopurine (a purine analogue), 5-Fluorouracil or 5-FU (a pyrimidine analogue). In addition inhibition of key enzymes involved in precursor synthesis is a common therapeutic option, with methotrexate used as a highly potent inhibitor of Dihydrofolate Reductase or DHFR. Antimetabolites are cell-specific in their action – ‘S’ phase * Predictably the antimetabolites are most effective during the period of maximal DNA synthesis or ‘S’ phase. * They would have less effect in cells in the resting state and would not be indicated for use in malignancies with a low growth fraction.

Answer 29

Methotrexate acts by inhibiting DHFR to interfere with folate metabolism Folates are vital for production of purine nucleotides and thymidilate. These feed into the pathway that enables DNA and RNA synthesis. After being actively taken up into the cell, folate is converted into a polyglutamate. Then the polyglutamated folate is reduced in two steps by the enzyme DHFR to produce a tetradhydrofolate, or FH4. Polyglutamated FH4 acts as a co-factor acting as a methyl group carrier. This methyl group is then used in the transformation of 2-deoxyuridylate or DUMP into 2-deoxythymidylate or DTMP. This transformation is carried out by the Thymidylate Synthase enzyme. Along with other related pathways, the production of DTMP contributes to the production of the purines and pyrimidines that act as molecular building blocks for both DNA and RNA.

Answer 30

Methotrexate is structurally very similar to folic acid and is actively transported into the cell and also polyglutamated. Methotrexate on its own has a much higher (x1000) affinity for DHFR. The polyglutamated form of Methotrexate also has a very long half-life within the cell of weeks to months and also has a very high affinity with DHFR. As a result, both Methotrexate alone and its polyglutamated form act to vastly reduce the metabolism of folate to reduce nucleotide production. The decrease in thymidine levels is the most marked. The controlled dosages used in cancer chemotherapy are much higher than used in RA and the aim is to reduce cancer cell growth as rapidly as possible by effectively removing nucleotide precursors from the cell metabolite pool.

Answer 31

Metabolised 5-FU acts to irreversibly inhibit Thymidylate synthase 5-FU is an analogue of the pyrimidine base uracil and is actively transported into the cell. As a close analogue of uracil, it is converted in FDUMP the fluoro-analogue of the precursor DUMP used in Thymidilate synthesi. FDUMP then competes with DUMP for access to the binding site on Thymidilate Synthase. At the active site FDUMP combines with a further coenzyme to produce a stable complex that cannot release any product. This effectively irreversibly inhibits the enzyme and if enough are affected, then cell undergoes ‘thymidine-less cell death’.

Answer 32

Normal cell division proceeds by the cells complement of chromosomes aligning themselves along the equator of the pre-mitotic cell. The mitotic spindle organises this alignment and is responsible for the synchronous separation of the replicated chromosomes into their respective new daughter cells. The mitotic spindle is made up of special protein subunits, alpha and beta tubulin. The existence of the spindle is dependent on the subunits polymerising to form microtubules. These tubulin proteins are the specific target sites for two groups of plant derived compounds: the vinca alkaloids and taxanes. The action of both vinca alkaloids and taxanes are cell cycle specific and their action is apparent in the M (mitotic phase).

Answer 33

Vinca alkaloids acts by inhibiting polymerisation of tubulin * There are a number of vinca alkaloids, which are indicated for use in treating different tumour types, but they all act to inhibit microtubule formation. * Two examples of this are vincristine and vinblastine. **They do this by specifically binding with the Beta-tubulin subunit that then prevents formation of the microfilaments that make up the microtubule.** This means the mitotic spindle does not form and the cell cycle is arrested in mitotic metaphase. * The chromosomes cannot segregate and affected cells cannot proliferate with the arrest of the normal replication cycle leads to apoptotic cell death.

Answer 34

Taxanes promote and stabilise formation of tubulin polymer into microtubules but prevent depolymerisation (prevents tubules dissolving) Whilst the mechanism for taxanes is different to the vinca alkaloids, the final effect is effectively the same. An example of a taxane is paclitaxel. The taxanes reversibly bind at a separate site to that of vinca alkaloids on the Beta-tubulin subunit. Binding at this site stabilises the microtubules and inhibits their disassembly. These microtubules are rendered non-functional and they cannot disassemble to pull the chromosome apart, which means the cell is stuck in metaphase. This again triggers apoptotic cell death in both cancer cells and normal cells.

Answer 35

Clinical use of all the agents requires very careful consideration by clinicians. This is because these agents are cytotoxic and each patient will vary considerably in their pharmacokinetic profile. This is especially as they may already present with compromised organ function and the treatment may well take them close to death by precipitating organ failure. **Routes of administration – IV most common** With many of these drugs, their toxicity rules out oral delivery, as they would severely damage the GI tract. In addition bioavailability is often variable and only a few agents are given orally. The patient is more likely to experience nausea and vomiting throughout treatment further limiting practicability of the oral route. The most practical route for systemic administration of these agents is intravenous. This allows fine control of delivery by injected bolus an infusion bag or continuous pump infusion. If an emergency arises due to appearance of adverse effects, the infusion can be stopped immediately. If a tumour is localised, then direct intralesional delivery may be possible. If it is within a defined space for example the bladder or lung effusion may be performed. Intrathecal (by lumbar puncture) and intraventricular (ommaya reservoir =\> directly into ventricles) delivery is used for treating tumours in the CNS. Other routes of administration include: * PO: convenient, dependent on oral bioavailability * SC: convenient in community setting * Into a body cavity: bladder, pleural effusion * Intralesional – directly into a cancrous area – consider pH * Topical – medication will be applied onto the skin * IM rarely NB: PICC line (peripherally inserted central catheter) can be used for a prolonged period of time, patient is able to go home. For many types of cancer, chemotherapy regimen will consist of a number of different drugs – combination chemotherapy – usually given an acronym. A drug may be given as a single agent.

Answer 36

Factors affecting distribution and elimination following administration * The general assumptions made about distribution in body compartments with many other drugs do not apply in cancer chemotherapy. * The plasma compartment may be proportionately larger due to the patient having experienced very significant weight loss with an accompanying reduction in body fat. * Liver and renal function along with cardiac output, may also be significantly lower and heavily compromised and drugs in combination may cause changes in Phase I and II pathways by either inhibition or induction. * In addition, many agents are proportionately bound to plasma proteins and presence of other non-chemotherapeutic drugs that associate with plasma proteins will affect free levels.

Answer 37

Using Body Surface Area and Renal Clearance to Optimise Dosing * The above factors can be partly addressed by calculating dose according to body surface area and with reference to their BMI. This normalises, in part, variations due to height and weight as for example, a lean person will have a smaller surface area. * These measures are best employed with measures of both renal function and plasma/urine drug levels. * These can be used to establish clearance and the expected concentration time curve (AUC) to better approximate overall and peak exposure to a drug.

Answer 38

Abnormalities in absorption * Nausea + vomiting, compliance, gut problems Abnormalities in distribution * Weight loss, reduced body fat, ascites etc Abnormalities in elimination * Liver and renal dysfunction, other medications Abnormalities in protein binding * Low albumin, other drugs

Answer 39

Primary and Acquired Resistance * Traditional agents used in cancer chemotherapy are, by definition, cytotoxic. * Neither healthy or cancer ‘know’ these drugs are being used to defeat a systemic threat to the whole body. * Consequently they will treat many of these agents in the way they would deal with any other potentially toxic xenobiotic molecule. The terms primary and acquired resistance are respectively defined as resistance being present prior to drug exposure and subsequent to drug exposure. These resistances in tumour cells can be due to their adapting and up-regulating responses to repeated ‘xenobiotic’ chemotherapeutic challenge, or they can arise as a result of mutations in the cancer cell genome driving increased MDRP expression/activity.

Answer 40

Multidrug Resistance Protein –MDRP: This P-Glycoprotein (P is for ‘permeability’) is generally expressed throughout most healthy cells at low levels. High levels are notably expressed in the kidney, liver and GI tract. It is a transporter and can lead to decreased entry or increased exit of an agent. MDRP functions to generically remove hydrophobic (i.e. charged) large xenobiotics. If cancer cells repeatedly encounters one or more of the chemotherapeutic drugs described here than expression of MDRP may increase as a result. Importantly, as MDRP activity is non-specific, it can then act to remove structurally dissimilar molecules used in combination chemotherapy. For example, prior exposure to doxorubicin can then also increase efflux and resistance to vinblastine or cis-platin to limit efficacy of future dosing.

Answer 41

Other inducible mechanisms: drug exposure can also act to decrease the rate of active uptake of drugs such as methotrexate or cis-platin by down-regulation of the active carrier. Conversely, drug target enzymes expression can be upregulated to offset the decrease in production of metabolites e.g. DHFR (increased) with methotrexate. Further examples include increased rate of repair of drug induced lesions in DNA or membrane following increased expression of repair enzymes in cancer cells. For example, this is seen with use of the alkylating agents or belomycin, which act to damage DNA. There could also be inactivation of agent in cell e.g. Glutathione binds to drug and neutralises its effect so drug is no longer cytotoxic (e.g. for alkylating agents).

Answer 42

Chemotherapy – Clinical Indications * Aim is very different in different malignancies * Predicted response is also different within the same cancer based on: * Performance score (an assessment of the performance status of that patient based on WHO Scoring Tool (0-5); also influenced by comorbidities; poor performance score indicates patient is less likely to recover. * Clinical Stage: can they be cured or is it palliative? Consider quality of life. May accept increased toxicity if going to be cured at the end of the day. * Prognostic factors or score (often involving biological factors) * Molecular or cytogenetic markers * Side effects vs anticipated or best outcome Clinical Strategies to Offset Drug Resistance The problem of acquired resistance arises with suboptimal and repeat doses that allow the cells time to manifest those responses. To counter the effects of resistance on therapy and to give the immune system time to recover, the clinician will often use a high dose, short term intermittent repeated therapy with drugs given in optimal combination to treat a specific tumour type.

Answer 43

There are a wide range of ADRs associated with use of these agents. As they are primarily targeted at rapidly dividing cells, they also affect normal cells with a higher rate of proliferation. This includes most of the GI tract, especially the buccal mucosa, and hair follicles. There are however other ADRs, which are manifest with specific groups or drugs. Common ADRs These include severe nausea, vomiting and diarrhoea. Mucositis, alopecia and myelosuppression, impaired wound healing, lethargy, myalgia, local reaction, phlebitis skin toxicity are also common. More specific within group ADRs include neurotoxicity (e.g. neuropathy), cardio, bladder (e.g. cystitis), lung (e.g. pulmonary fibrosis) and renal toxicity. The latter three are irreversible. Of the ADRs, the most frequent dose limiting is haematological toxicity and is the most frequent cause of death during chemotherapy e.g. patients could die of neutropenic sepsis so patient education is very important – need to present earluy rather than late. Different agents have varying effects in both degree and lineage e.g. neutrophils and platelets. Acute renal failure is also an expected ADR – often multifactoral. Hyperuricaemia caused by rapid tumour lysis during treatment can result in a large increase in purines being released into the circulation. The subsequent increase in purine metabolism generates urates. This can lead to precipitation of urate crystals in renal ubules and in extreme cases subsequent kidney failure and death. GI perforation at site of tumour – reported in lymphoma. Disseminated intravascular coagulopathy e.g. onset within a few hours of starting treatment for acute myeloid leukaemia. Predicting the risk in each individual patient can be difficult, especially with combination therapy and the aim must be to minimise this by close observation during monitoring.

Answer 44

Vomiting * Multifactorial but includes direct action of chemotherapy drugs on the central chemoreceptor trigger zone. * Patterns of emesis * Acute phase: 4-12 hours * Delayed onset: 2-5 days later * Chronic phase: may persist up to 14 days Alopecia * Hair thins at 2-3 weeks * May be total body hair loss * May re-grow during therapy * Marked with doxorubicin, vinca alkaloids, cyclophosphamide * Minimal with platinums * Help sometimes with scalp cooling (but these caps can lead to terrible headaches, not very well tolerated)

Answer 45

Skin toxicity Local * Photosensitivity, irritation and thrombophlebitis of veins * Extravasation (never should have happened, chemotherapy has gone into surrounding tissues not the veins – tissue is not necrotic – needs to be removed) General * Bleomycin * Hyperkeratosis * Hyperpigmentation (particularly in Asian patients – with a degree of pigmentation already) * Ulcerated pressure sores * Bulsulphan, doxorubicin, cyclophosphamide, actinomycin D * Hyperpigmentation \*Beau’s lines: deep grooved lines that run from side to side on the fingernail or toenail (chemotherapy caused delayed growth of the nail)

Answer 46

Gastrointestinal tract epithelial damage May be profound and involve whole tract Most commonly worst in oropharynx Presents as * Sore mouth/throat (think mouth ulcers across the whole mouth) * Diarrhoea * GI bleed May require hospitalisation and morphine due to the damage.

Answer 47

**Cardio-Toxicity** Cardiomyopathy * Doxorubicin ++ (\>550 mg/m2) * High dose cyclophosphamide * Mortality approx. 50% Arrhythmias * Cyclophosphamide * Etoposide **Lung Toxicity** Bleomycin (used for testicular tumours) * Pulmonary fibrosis * Beware concurrent (do not give high flow O2 – makes it worse) * Other drugs such as Mitomycin C can also lead to pulmonary fibrosis **Haematological Toxicity of Cancer Therapy** * Most frequent dose limiting toxicity * Most frequent cause of death from toxicity * Different agents cause variable effects on degree and lineages: neutrophils, platelets

Answer 48

Antimetabolites: the example drugs already given largely exhibit all the general ones listed. With high dose methotrexate treatment, there is a higher risk of renal failure. Cytotoxic antibiotics – Cardiotoxicity: the anthracyclines doxorubicin and daunorubicin are especially cardiotoxic due to free radical generation Cytotoxic antibiotics – Pulmonary Toxicity: risk of pulmonary fibrosis with bleomycin is high at about 10% with a 1% fatality rate. These effects of both are cumulative and irreversible. Alkylating agents – Cis-platin at high dose, peripheral, sensory and motor neuropathy. High frequency ototoxicity is common. Mitotic spindle inhibitors: high dose neurotroxicity as ‘stocking and globe’ peripheral neuropathy is often reported.

Answer 49

: Drug-Drug Interactions The clinician would need to be fully aware of what other drugs the cancer patient may be taking during therapy e.g. diuretics, St John’s wort. Carefully planned therapeutic DDIs are central to treating cancer. Even though a number of ADRs are common across these agents the aim is to minimise the overlap of shared toxicity whilst delivering all agents at the highest dose for as short as possible with gaps between dosing. This decreases the risk of irreversible ADRs such as pulmonary toxicity or death whilst maximizing the kill ratio of cancer:normal cells. Because shared ADRs are common in chemotherapy, this means doses have to be adjusted downwards for some drugs. The gaps between dosing are necessary to allow the immune system to recover. High dose short interval treatment regimes also aim to offset the risk of drug resistance that would emerge with lower (but less toxic) regimes given over a longer period of time. Finally, as is evident from the above sections, the distinct target sites of these drugs means that there are more chances to kill heterogeneous cells in the tumour population.

Answer 50

An example combination would be methotrexate (target is DHFR in ‘S’ phase; highly myelosuppressive) with agents also having a lower myelosuppressive index * Vincristine (target is Tubulin in ‘M’ phase; high risk of peripheral neurotoxicity ‘stocking and glove pattern’) * Cis-platin (target is DNA synthesis, mainly ‘G1’/’S’ phase; mixed pathway neurotoxicity, ototoxicity common) * Bleomycin (target is DNA synthesis in ‘S’ phase; greater risk of pulmonary toxicity) Important drug interactions: other drugs may increase plasma levels of the chemotherapy drug (and therefore side effects) * Vincristine and itraconazole (a commonly used antifungal) leads to more neuropathy * Capecitabine (oral 5FU) and warfarin; Capecitabine and St Johns Wort, grapefruit juice * Methotrexate – caution with prescribing penicillin, NSAIDs

Answer 51

Monitoring during chemotherapy is vital to accurately establish the degree of therapeutic success and the development of side effects, especially if these may lead to compromised organ function and eventual death. Dose needs to be altered for the individual patient based on: * Their surface area and/or body mass index * Drug handling ability (e.g. liver function, renal function…dependent on the metabolism and excretion outes0 * General wellbeing (performance status and comorbidity). Treatment phasing needs to take into account the balance between: * Growth fraction * The ‘cell kill’ of each cycle of the chemotherapy regimen * Marrow and GI tract recovery before next cycle * How tolerable is the regimen – both short term organ toxicity and physical side effects and long term damage causing late effects Hence weigh up the role and dose of chemotherapy for every cancer patient individually and always remember the aim of the treatment. Response of the Cancer: this can be checked with radiological imaging, tumour marker blood tests, bone marrow sampling and cytogenic testing and pathology.

Answer 52

Pharmacokinetics: Blood/Urine/CSF/Tissue samples for assay allow estimates of half-life and clearance to be made. With repeated measures, AUC estimation can give better individualised estimation of how the patient is handling their chemotherapy to maximise beneficial effect and minimise toxicity. * For example, given the unusual kinetics of methotrexate, additional post course rescue therapy with folinic acid to increase normal cell purine synthesis back to normal may be appropriate – methotrexate drug assays taken on serial days to ensure clearance from the blood after folinic acid rescue. Organ functional deficit (check for end organ damage) – Carry out cardiac testing by ECG, echocardiogram, - pulmonary function – FEV, FVC. Hepatic enzyme levels in plasma. Renal function – creatinine clearance in blood/urine etc. Evoke neural responses for conduction time for peripheral neurotoxicity, audiogram with cis-platin.

Answer 53

In current clinical practice many refined protocols exist for specific neoplastic states. These are usually given an acronym that identified the main agents in use. These protocols will and be validated from many clinical trials carried out globally. In the UK, media coverage often focuses on new treatments that employ novel molecular targeting agents not receiving NICE approval. This is even though these new treatments offer reduced side effects and moderate improved median survival times of 6-12 months. This is in large part due to drug companies pricing yearly courses of treatments beyond the market limit. The NHS ‘market limit’ is currently about £50,000 per year of additional life gained by a treatment. This is doubly unfortunate, as the UK has been at the forefront of research for developing novel treatments. It is not amongst the first countries to reap the clinical benefit due to market forces. NB: Kaplan-Meier curve (survival analysis estimate) – overall survival is the ultimate measure Chemotherapy is the treatment of cancer with drug therapy. Traditionally this applies to cytotoxic drugs but over the years more classes of drugs have been introduced to treat cancer such as hormones and now targeted drug therapy e.g. * Monoclonal antibodies * Drugs inhibiting angiogenesis * Drugs targeting gene expression * Signal transduction inhibitors * Drugs interfering with the apoptotic pathways * Drugs interfering with cell cycle control * Cytokines

Answer 54

Neoadjuvant: given before surgery or radiotherapy for the primary cancer Adjuvant: given after surgery to excise the primary cancer, aiming to reduce relapse risk e.g. breast cancer Palliative: to treat current or anticipated symptoms without curative intent Primary: 1st line treatment of cancer…in many haematological cancers this will be with curative intent, initially aiming for remission Salvage: chemotherapy for relapsed disease