3. Medicines Design Flashcards

Question

Give 3 examples of Vinca Alkaloids

Answer 1

Vincristine (R=CHO) Vinblastine (R=ME) Vindesine

Answer 2

- Taxols bind to taxol-binding sites on the inside surface of the microtubule, preventing disassembly - Inappropriate microtubules remain - Concentration of free tubulin dimers decreases - The low concentration of free tubulin dimers means that new microtubules cannot be assembled Paclitaxel (taxol), Docetaxel (taxotere)

Answer 3

- Colchicine binds to cholchicine-binding sites on the b-tubulin, disfavouring assembly of protofilaments - Colchicine bound at colchicine-binding sites on b-tubulin in microtubules disfavours disassembly of inappropriate microtubules

Answer 4

- After DNA and RNA, poly(ADP-ribose) [PAR] is the third nucleic acid in the mammalian cell - First observed in 1963; structure determined in 1967 - Polyanionic polymer built from ADP-ribose units derived from NAD+ - Usually built onto Glu side-chains in target proteins - MW varies with PARP isoform : upto 100KDa for PAR built by PARP-1 - Linear or branched

Answer 5

- Enzyme mainly found in the nuclei of cells - Abundant in most cells (ca. 2x10^6 molecules cell^-1) - 116 KDA protein

Answer 6

1. Radiotherapy of cancer causes DNA strand breaks 2. Electrophilic cytotoxic drugs (e.g mustards) cause DNA damage 3. Inhibitors of topoisomerase II (e.g doxorubicin) cause DNA single-strand breaks by inhibiting the strand re-joining step 4. If the tumour cells can repair the DNA before it is required, then cells survive 5. Inhibition of PARP-1 inhibits DNA repair 6. Inhibition of PARP-1 potentiates radiotherapy and DNA-targeted chemotherapy

Answer 7

1. When the supply of blood to an organ is interrupted, the cells become hypoxic 2. Reperfusion with blood causes rapid resupply of O2 to the hypoxic cells 3. O2 is an oxidising diradical and damages DNA 4. PARP-1 is over-activated 5. Cells are depleted of NAD+ (also important in production of energy) 6. Cells die 7. Organ failure

Answer 8

- through Zn fingers - The thiols of three Cys and the imidazole of one His in the DNA-binding domain of PARP-1 bind to a Zn2+, fixing the conformation of the protein - The NAD+ binding domain is at the C-terminal of the protein - Inhibitor olaparib binds at the NAD+ binding site

Answer 9

Therapy 1. Radiotherapy : radiation, bleomycin 2. Mono-alkylators : alkylsulfonates, nitrosoureas, temozolomide 3. Cross-linkers : N-mustards, mitomycin C, platinum drugs 4. Topoisomerase inhibitors : camptothecins, etoposide 5. Replication inhibitors : aphidicolin, hydroxyurea

Answer 10

- Inhibits PARP-1, PARP-2, PARP-3 - Clinical trials as a single agent started 2005 - Approved for BRCA-mutant ovarian cancer

Answer 11

- Inhibits PARP-1, PARP-2, Tankyrase-1, Tankyrase-2 - Clinical trials started in 2003, in combination with temozolomide - Approved for BRCA-mutant ovarian cancer

Answer 12

- Inhibits PARP-1, PARP-2, not PAPR-3, Tankyrases - Phase 1-3 clinical trials, in combination and as single agent - Approval expected in 2018/2019

Answer 13

Classical tyrosine kinase receptor - EGF or TGFa binds to the extracellular domain of EGFR - Ligand-EGFR complex forms an asymmetric dimer - Signalling cascades trigger proliferation, migration, adheision

Answer 14

- EGFR is implicated in the development and progression of cancer in two main ways : Overexpression of EGFR : Activating mutation in extracellular or intracellular domains - Mutations in the extracellular domain can lead to constitutive (EGF-independent) activity of EGFR and are frequently found in flioblastoma - Mutations in the kinase domain are found in a subset of non small-cell lung cancers (NSCLCs) - Most common kinase domain mutation is L858R (40% mutations) - These mutations are driver mutations (i.e they confer a growth advantage on the cells and so drive cancer) - The particular mutation occuring in an individual tumour is important as it can determine the sensitivity of the tumour to different drugs - Selecting drugs based on tumour mutation status is an example of personalised medicine in cancer - Targeted cancer therapy places a huge selective pressure on the target to evolve, and resistance mutations often emerge. Thus we move from first line therapies, which target the initial state, to second line therapies, which target the new mutant etc.

Answer 15

1. Active conformation - bound to AMP-PNP 2. Inactive conformation - bound to Lapatinib EGFR kinase domain is found in two conformations - active and inactive Inactive conformation has two hallmarks found in many inactive kinase structures - alphaC helix moved away from kinase body (aC out) - New helix at beginning of region of kinase known as the activation loop Physiologically, asymmetric dimerisation promotes the active conformation by stabilising aC helix 'in'

Answer 16

- The inactive conformation of EGFR is stabilised by a hydrophobic cluster - In the active conformation, the sidechain of Leu858 is solvent exposed - Two of the hydrophobic residues form active hydrophobic spine with conserved Phe and His - Mutating Leu858 to Arg destabilises this cluster and promotes active conformation

Answer 17

- EGFR is a crystallographic dimer (dimerised in crystals), so is normally observed in the active conformation in crystal structure - EGFR is only observed in the inactive conformation : in the presence of the inhibitor lapatinib : in the presence of the V948R mutation (which disturbs dimer interface) - Crystallography gives us atomic resolution information on the arrangement of the protein in the crystal, but gives no information on conformational heterogeneity or interconversion

Answer 18

- Binding data shows that Gefitinib binds more tightly to the L757R mutant than WT

Answer 19

- Targeted cancer therapy places a huge selective pressure on the target to evolve, and resistance mutations often emerge - Eventually patients develop resistance to Gefitinib, usually through a mutation of a structurally conserved residue called the 'gatekeeper' to a bulkier residue - In EGFR, the gatekeeper residue is Thr790 and the T790M mutation is the most common resistance mutation - Once T790M mutation occurs, patients must move from gefitinib to a second line therapy

Answer 20

11 6 C beta+ - 20.3mins 18 9 F beta+ - 110mins 99m 43 Tc gamma - 6hrs 32 15 P beta- - 14.3 days 35 16 S beta- - 86.5 days 226 88 Ra alpha - 1600yrs 235 92 U alpha - 7 x 10^8 yrs

Answer 21

- 4 2 He2+ - Weakly penetrating - Short path length - Brachytherapy

Answer 22

- e- - Penetration mm-cm - Radiotracers in e.g biodistribution & drug metabolism studies

Answer 23

- Photon (hv) - Highly penetrating - Imaging, radiotracers, radiotherapy

Answer 24

- positron e+ - Annihilation with e- gives 2xgamma - 2 x gamma detected for imaging

Answer 25

- proton - Short/medium path length - External beam therapy

Answer 26

- Neutron - short/medium path length - BNCT

Answer 27

Units of radioactivity - 1.0 Bq = 1.0 disintegration per sound Units of radiation - Dose - 1.0 Gy = 1.0 J Kg-1 Units of radiation - Relative Biological Dose - RBD = dose x RBE - RBE = Relative Biological Effectiveness

Answer 28

- instrument used for detecting and measuring ionising radiation - it detects ionising radiation such as alpha particles, beta particles, and gamma rays using the ionisation effect produced in Geiger-Muller tube.

Answer 29

- an instrument for detecting and measuring ionizing radiation by using the excitation effect of incident radiation on a scintillator material, and detecting the resultant light pulses. - Sample and scintillant molecules in the same solution - beta-particle from radioactive molecule strikes scintillant molecule, transferring energy - Energy re-emitted by scintillant molecule as flash of light - Flash of light detected by photomultiplier tubes

Answer 30

- image on an x-ray film or nuclear emulsion produced by the pattern of decay emissions from a distribution of a radioactive substance - The film or emulsion is apposed to the labeled tissue section to obtain the autoradiograph

Answer 31

- imaging technique using gamma rays | - requires delivery of a gamma-emitting radioisotope into the patient, normally through injection into the bloodstream

Answer 32

- nuclear medicine functional imaging technique that is used to observe metabolic processes in the body as an aid to the diagnosis of disease - The system detects pairs of gamma rays emitted indirectly by a positron emitting radioligand, most commonly fluorine-18, which is introduced into the body on a biologically active molecule called radioactive tracer

Answer 33

1. DNA is damaged 2. Damage is recognised by a protein called XPC, which is stably bound to another protein called R23 3. The binding of the XPC-R23 is followed by the binding of several other proteins (XPA, RPA, TFIIH, XPG) Of these, XPA and RPA are believed to facilitate specific recognition of base damage. TFIIH consists of six subunits and contains two DNA helicase activities (XPB and XPD) that unwind the DNA duplex. This local denaturation generates a bubble in the DNA, the ends of which comprise junctions between duplex and single-stranded DNA 4. The subsequent binding of the ERCC1-XPF heterodimeric subcomplex generates a completely assembled NER multiprotein complex 5. XPG is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 3' to the site of base damage. Conversely, the ERCC1-XPF heterodimeric protein is a duplex/single-stranded DNA endonucleases that cuts the damaged strand at such junctions 5' to the site of base damage 6. This fragment is removed from the genome, and a new section is synthesised including the damaged base 7. Collectively, these biochemical events return the damaged DNA to its native chemistry and configuration

Answer 34

Step 1 - First the N-glycosidic bond of the damaged base is cleaved by a DNA glycosylase leaving an abasic site in the DNA Step 2 - The sugar-phosphate backbone of the abasic site is then cleaved by a bi-functional glycosylase and/or an AP-endonuclease. If necessary the 3' strand break end is converted to hydroxyl allowing DNA polymerases to reinsert new bases Step 3 - Synthesis of a single base is referred to as short patch (SP) BER and synthesis of several bases is referred to as long patch (LP) BER Step 4-5 - The 5' single strand end of the single strand break intermediate is then processed to allow for ligation by DNA ligases

Answer 35

- also known as abasic site - AP site (apurini/apyrimidinic site) is a location in DNA that has neither a purine nor a pyrimidine base, either spontaneously or due to DNA damage

Answer 36

- process by which methyl groups are added to the DNA molecule - Methylation can change the activity of a DNA segment without changing the sequence. - When located in a gene promoter, DNA methylation typically acts to repress gene transcription.

Answer 37

- Covalent (PBD's, CPI's, Mitomycin C) and Non-covalent (Distamycin, Netropsin) - Flat (Planner) poly-aromatic structures - Many have natural twist to fit minor groove - Alkylation centre a base of minor groove - Secondary non-covalent interactions important in covalent binding - Non-covalent compound have been modified with DNA alkylation moieties (mustards, epoxides) to give experimental covalent compounds - Many covalent compound have been linked to give dimeric cross-linkers (inter- and intra-strand.

Answer 38

- Ethano bridges cause DNA over-winding and lead to dose limiting toxicity and delayed death

Answer 39

- Use of pro-drugs to restrict damage to specific tumour location - Size: based on tumour cell increased permittivity (addition of PEG chains) - Hypoxia based targeting - DNA specific structural targets - Antibody based targeting

Answer 40

- Bleomycin is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus and is freely soluble in water - Bleomycins are a group of related basic glycopeptides which differ in the terminal amine substituent of the common structural unit, Bleomycin acid. The main components of Bleomycin for injection are Bleomycins A2 and B2

Answer 41

- Bleomycins are used clinically in combination chemotherapy against lymphomas, squamous-cell carcinomas and germ-cell tumours

Answer 42

- The side effects of the bleomycins are dose-dependent and involve lung inflammation that often proceeds to lung fibrosis

Answer 43

- Bleomycins bind transition metals Fe(II) or Cu(I) and oxygen, in the presence of a one-electron reductant, can catalyse formation of single-stranded (ss) and double-stranded (ds) DNA lesions

Answer 44

- In vitro studies indicate that a single molecule of bleomycin is sufficient to generate lesions on both strands of DNA, the proposed source of cytotoxicity - Studies on a large number of bleomycin analogues, made possible by total synthesis of bleomycin, have indicated that the whole molecule is much greater than the sum of its parts : the linker between the metal and the bithiazole DNA-binding domain anad the flexibility of the bithiazole moiety itself are essential for efficient dsDNA cleavage. - The cellular response to bleomycin treatment are ccomplex and are cell-line and genotype-dependent. Extended cell-cycle arrest, apoptosis and mitotic cell death are most common outcomes of bleomycin treatment - Bleomycins are hydrophillic molecules that are unable to cross cell membranes by free diffusion. Studies with modified analogues indicate that the positively charged tail of bleomycin might play a key role in cellular uptake

Answer 45

- Metal-binding region - Linker region - Bithiazole tail

Answer 46

- Several pathways ensure the repair of DSBs in eukaryotic cells. - Recombination is the only inherently error-free pathway to accomplish this and it involves a complex series of events which are now beginning to be understood in eukaryotes. - Other pathways like Non-Homologous End Joining (NHEJ) and Break-Induced Replication (BIR) are error-prone. leading to mutations and loss of heterology - These DSB repair pathways are conserved in all eukaryotes. Recent work with transgenic mice has also provided conclusive evidence that recombinational repair is active and important in mammalian cells.

Answer 47

- Platinum-based drugs are effective against cancer because at their centre is a platinum atom joined to two ammonia molecules and two chloride ions. - The compound is negatively charged, but when it enters the cancer cell it becomes positively charged because the chloride ions are replaced by water molecules.

Answer 48

1. Platinum might enter cells using either transporters : a significant one being the copper transporter CTR1 : or by passive diffusion. - Loss of CTR1 results in less platinum entering cells and, consequently, drug resistance - Once inside cells, cisplatin is activated by the addition of water molecules to form a chemically reactive aqua species. This is faciliated by the relatively low chloride concentration that are found within cells 2. In the cytoplasm, the activated aqua species preferentially reacts with species containing high sulphur levels by virtue of their containing many cysteine or methionine amino acids. These species include tripoptide glutathine or metallothioneins. In some platinum-resistant cancer cells, glutathione and metallothionein levels are relatively high, so activated platinum is effectively mopped up in the cytoplasm before DNA binding can occur, therefore causing resistance 3. Finally, active export of platinum from the cells through the copper exporters ATP7A and ATP7B as well as through the glutathione S-conjugate export GS-X pump can contribute to platinum drug resistance

Answer 49

1) loss of DNa mismatch repair 2) Bypassing of adducts by polymerase beta and n 3) Through down regulation of apoptotic pathways

Answer 50

Resistance can be tackled by - increasing levels of platinum reaching tumours thereby in greater killing - combining existing platinum drugs with molecularly targeted drugs - using novel platinum drugs such as oxaliplatin that are capable of circumventing cisplatin-mediated resistance mechanisms - using other drugs either alone or in combination which exploit particular cisplatin-mediated resistance mechanisms

Answer 51

These targeted drugs block the growth of new blood vessels to tumours - Avastin (bevacizumab) for example, if a monoclonal antibody that binds with vascular endothelial growth factor (VEGF) which tumour cells release to stimulate blood-vessel growth. - The binding of the drug to the growth factor prevents VEGF from interacting with its receptors on the endothelial cells that line blood vessels. - Activation of these receptors normally leads to endothelial-cell growth and the formation of new blood vessels to the tumour - Preventing this growth also inhibits metastasis and may improve sensitivity to cytotoxic drugs

Answer 52

- Topoisomerase II (TOP2) is the target of several important classes of anticancer drugs, including the anthracycline doxorubicin - most clinically active drugs that target TOP2 kill cells by trapping an enzyme intermediate termed the covalent complex - TOP2-mediated DNA damaged is repaired by multiple pathways. This DNA damage includes DNA strand breaks and proteins that are covalently bound to DNA. Repair of TOP2-mediated damage requires double-strand break repair pathways and other pathways that are specific for the removal of protein-DNA adducts - Anthracycline use is limited by cardiotoxicity although the mechanism of the cardiotoxicity is poorly understood - An important side effect of targeting TOP2 with TOP2 poisons is the formation of secondary malignancies that arise from drug-induced translocations - Catalytic inhibition of TOP2 could also be a useful anti-cancer strategy. New compounds are being developed to test this possibility.

Answer 53

- Doorubicin and SN-38 interact with, and stabilise, the topoisomerases (topo)-II-DNA or topo-I-DNA complexes, respectively, to produce produce a 'cleavable complex'. - This results in DNA strand breakage that is associated with the protein-DNA complex - Pluramycin binds peripherally to the TATA-binding protein (TBP)-TATA box complex. - Alkylation by pluramycin is enhanced by TBP binding to the TATA box, and as result TBP is immobilised on the DNA

Answer 54

- Telomerase is an enzyme that adds DNA sequence repeats (TTAGGG in all vertebrates) to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes - This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from chromosome ends - Examples of DNA sequences that can form G-quadruplexes include telomeres and promoters that contain a polypurine-rich strand - Equilibrium between dsDNA structures and the G-quadruplexes is dependent on helicases that unwind the quadruplex and chaperone proteins that are required for its formation - G-quadruplexes-interactive drugs can either inhibit helicases or facilitate formation of new quadruplexes or can isolate newly formed G-quadruplexes

Answer 55

- substances that function as chemical messengers in the body - they affect the actions of cells and tissues at various locations in the body, often reaching their targets through the bloodstream

Answer 56

- produced by the ovaries in premenopausal women and by some other tissues, including fat and skin, in both premenopausal and postmenopausal women and men. - Oestrogen promotes development and maintenance of female sex characteristics and the growth of long bones - Progesterone plays a role in the menstrual cycle and pregnancy - Oestrogen and progesterone also promote the growth of some breast cancers, which are called hormone-sensitive breast cancers - Hormone-sensitive breasst cancer cells contain receptors that become activated when hormones bind to them. The activated receptors cause changes in the expression of specific genes, which can stimulate cell and tumour growth

Answer 57

- Hormone therapy slows or stops the growth of hormone-sensitive tumours by blocking the body's ability to produce hormones or by interfering with effects of hormones on breast cancer cells - Tumours that are hormone insensitive do not have hormone receptors and do not respond to hormone therapy

Answer 58

- Biopsy is performed and the sample tested - If the tumour cells contain Oestrogen receptors, the cancer is called : Oestrogen Receptor Positive (ER positive) : Oestrogen sensitive : Oestrogen Responsive - Similarly, if the tumour cells contain progesterone receptors, the cancer is called : Progesterone receptor positive (PR or PgR positive) - Approximately 80% of breast cancers are ER positive. Most of these ER-positive breast cancers are also PR positive - Breast tumours that contain oestrogen and/or progesterone receptors are sometimes called : Hormone Receptor Positive (HR positive)

Answer 59

- Oestrogen Receptor Negative (ER-negative) - These tumours are oestrogen insensitive, meaning that they do not use oestrogen to grow - Breast tumours that lack progesterone receptors are called Progesterone Receptor Negative (PR or PgR negative) - Breast tumours that lack both Oestrogen and Progesterone receptors are sometimes called : Hormone Receptor Negative (HR negative) For this reason, when a women taking HRT is diagnosed with HR-positive breast cancer, she is normally asked to stop HRT (or oral contraceptives) therapy.

Answer 60

- Some breast cancers have high numbers of receptors for the protein HER2 (Human Epidermal Growth Factor 2) - They are called HER2 positive breast cancers - About 1 in 7 women (15%) with early breast cancer have HER2 positive cancer. - A drug called trastuzumab (Herceptin) is an effective treatment for this type of breast cancer

Answer 61

- If the cancer does not have receptors for either HER2 or the hormones Oestrogen and Progesterone, it is called triple negative breast cancer - It affects around 13% of women with breast cancer and is more common in younger women

Answer 62

Several strategies are used to treat hormone-sensitive breast cancer 1. Blocking Ovarian function 2. Blocking Oestrogen production 3. Blocking Oestrogen's effects

Answer 63

- Because the ovaries are the main source of Oestrogen in premenopausal women, Oestrogen levels in these women can be reduced by eliminating or suppressing ovarian function. - Blocking ovarian function is called ovarian ablation - Ovarian ablation can be done surgically in an operation to remove the ovaries (called oophorectomy) or by treatment with radiation. This type of ovarian ablation is usually permanent. - Alternatively, ovarian function can be suppressed temporarily by treatment with drugs called Gonadotropin-releasing hormone (GnRH) agonists, which are also known as luteinizing hormone-releasing hormone (LH-RH) agonists. - These medicines interfere with signals from the pituitary gland that stimulate the ovaries to produce oestrogen - An example of ovarian suppression agent is Goserelin (Zoladex)

Answer 64

Drugs called Aromatase inhibitors are used to block the activity of an enzyme called aromatase, which the body uses to make oestrogen in the ovaries and in other tissues. Aromatase inhibitors are used primarily in postmenopausal women because the ovaries in premenopausal women produce too much aromatase for the inhibitors to block effectively. However these drugs can be used in premenopausal women if they are given together with a drug that suppresses ovarian function - Examples are Anastrozole (Arimidex) and Letrozole (Femara) both of which temporarily inactivate aromatase - Exemestane (Aromasin) permanently inactivates aromatase

Answer 65

- by aromatizing androgens - Aromatase is the only known enzyme in vertebrates capable of catalysing the aromatization of a six-membered ring - Aromatase converts androstenedione to oestrogen and testosterone to oestradiol

Answer 66

- Several types of drugs interfere with oestrogen's ability to stimulate the growth of breast cancer cells Selective Oestrogen Receptor Modulators (SERM) - bind to oestrogen receptors, preventing oestrogen from binding - examples are Tamoxifen (Nolvadex) and Toremifene (Fareston) Other antioestrogen drugs - Fulvestrant (Faslodex) binds to oestrogen receptor and functions as an oestrogen antagonist

Answer 67

There are three main ways that hormone therapy is used to treat hormone-sensitive breast cancer 1. Adjuvant therapy for early-stage breast cancer 2. Treatment of advanced or metastatic breast cancer 3. Neoadjuvant treatment of breast cancer

Answer 68

- Tamoxifen is approved for adjuvant hormone treatment of premenopausal and postmenopausal women with ER-positive early-stage breast cancer, and the aromatase inhibitors anastrozole and letrozole are approved for this use in postmenopausal women - A third aromatase inhibitor, exemestane, is approved for adjuvant treatment of early stage breast cancer in postmenopausal women who have not received tamoxifen previously

Answer 69

- Several types of hormone therapy are approved to treat metastatic or recurrent hormone-sensitive breast cancer. - Hormone therapy is also a treatment option for ER positive breast cancer that has come back in the breast, chest wall, or nearly lymph nodes after treatment - Tamoxifen and Toremifene are approved to treat metastatic breast cancer. - The anti-oestrogen fulvestrant is approved for postmenopausal women with metastatic ER-positive breast that has spread after treatment with other antioestrogens. - The aromomatase inhibitors Anastrozole and Letrozole are approved for use in postmenopausal women as initial therapy for metastatic or locally advanced hormone-sensitive breast cancer

Answer 70

- Use of hormone therapy to treat breast cancer before surgery has been studied in clinical trials - Goal of neoadjuvant therapy is to reduce the size of a breast tumour to allow breast-conserving surgery

Answer 71

- yes, but most breast canccers are ER positive, and clinical trials have tested whether hormone therapy can be used to prevent breast cancer in women who are at increased risk of developing the disease A large US randomized clinical trial called the “Breast Cancer Prevention Trial” found that tamoxifen, taken for 5 years, reduced the risk of developing invasive breast cancer by about 50% in postmenopausal women who were at increased risk. Long-term follow-up of another randomised trial, the “International Breast Cancer Intervention Study I”, found that 5 years of tamoxifen treatment reduces the incidence of breast cancer for at least 20 years.

Answer 72

- depends largely on the specific drug or the type of treatment - The benefits and harms of taking hormone therapy should be carefully weighed for each woman - A common switching strategy used for adjuvant therapy, in which patients take tamoxifen for 2 or 3 years, followed by an aromatase inhibitor for 2 or 3 years, may yield the best balance of benefits and harms of these two types of hormone therapy Hot flahses, night sweats, and vaginal dryness are common side effects of hormone therapy. Hormone therapy also disrupts the menstrual cycle in ppremenopausal women

Answer 73

- Certain drugs, including several commonly prescribed anti-depressants (SSRI) inhibit the enzyme CYP2D6. This enzyme plays a critical role in the use of tamoxifen by the body because it metabolises, tamoxifen into metabolites, that are much more active than tamoxifen itself - The possibility that SSRI might, by inhibiting CYP2D6, slow the metabolism of tamoxifen and reduce its effectiveness is a concern given that as many as 1 in 4 breast cancer patients experience clinical depression and will often be treated with SSRIs - Might change to weaker inhibitor such as sertraline or no inhibitory activity such as citalopram