HNI 333 - Cancer Chemotherapy 2024 SPRING BS (1) PDF

Cancer Chemotherapy HNI 333 – Pharmacology Kenneth M. Faulkner, PhD, RN, ANP Department of Undergraduate Studies  Objectives After completing this lecture and the assigned reading, the student should be able to: 1. Describe the cell cycle and how it relat...

Cancer Chemotherapy HNI 333 – Pharmacology Kenneth M. Faulkner, PhD, RN, ANP Department of Undergraduate Studies  Objectives After completing this lecture and the assigned reading, the student should be able to: 1. Describe the cell cycle and how it relates to chemotherapy 2. Describe growth fraction and name tissues that fall into high and low growth fraction categories 3. Describe why solid tumors do not respond well to chemotherapy 4. Describe how resistance occurs to chemotherapy 5. Describe how intermittent therapy improves effectiveness of chemotherapy 6. Describe how combination therapy improves effectiveness of chemotherapy 7. Describe the importance of determining appropriate dosing schedules 8. Describe the major toxicities of chemotherapy and describe why they occur  Objectives (cont.) 9. For each of the following drug classes: give an example, describe the mechanism of action, describe the effect of the drug, name the common side effects, describe clinical usefulness, and describe any nursing considerations (teaching, important interactions, dietary considerations, etc.) Alkylating agents Platinum compounds Antimetabolites – Folic acid analogs – Pyrimidine analogs – Purine analogs Topoisomerase inhibitors Antitumor antibiotics – Anthracyclines – Non-anthracyclines Mitotic inhibitors – Vinca Alkaloids – Taxanes Asparaginase  Objectives (cont.) 9. For each of the following drug classes: give an example, describe the mechanism of action, describe the effect of the drug, name the common side effects, describe clinical usefulness, and describe any nursing considerations (teaching, important interactions, dietary considerations, etc.) Antiestrogens Aromatase inhibitors Anti-HER2 antibodies Kinase Inhibitors GnRH agonists GnRH antagonists Androgen Receptor blockers CYP17 Inhibitors Angiogenesis inhibitors  Cancer Cancer – 2nd leading cause of death in the US Three modalities for treating cancer: – Surgery: mostly for solid tumors – Radiation – Drugs: Mostly for disseminated cancers (leukemias, metastases, etc.) Also used for several localized cancer (testicular cancer) Also used after surgery to kill the cells that were left behind  Four major classes of medications: 1. Cytotoxic agents: kill the cell (most used) The only one that “officially” qualifies for the term “cancer chemotherapy” 2. Hormones and hormone antagonists 3. Biologic response modifiers Modify the immune system 4. Targeted drugs Bind to a specific molecule that promotes cancer growth  Drugs can cure some cancers (5-year disease free interval following treatment) – Testicular cancer – Hodgkin’s lymphoma – ALL – AML  Characteristics of cancer cells: 1. Persistent proliferation (though not necessarily rapid) Do not respond to feedback mechanisms that control cell growth 2. Invasive growth 3. Metastases – through breaking away from primary source and traveling through lymphatics or circulation 4. Immortality  Abnormalities are due to alterations in DNA – Activation of oncogenes – genes that cause cancer – Deactivation of tumor suppressor genes – normally suppress replication of cells that are cancerous Changes lead to unregulated cell division and protection against cell death  The cell cycle Sequence of events that a cell goes through from one mitotic division to the next G1 – cell prepares to make new DNA S – DNA synthesis takes place G2 – cell prepares for mitosis M – Mitosis occurs Daughter cells can then re- enter G1 or enter the G0 phase (a resting phase)  Growth fraction Growth fraction: the ratio of proliferating cells to G0 cells. – Tissues with more proliferating cells than resting cells have a high growth fraction Responsiveness to chemotherapy is related to this – Generally, chemotherapy is more toxic to tissues with a high growth fraction – Most drugs act by blocking DNA synthesis or mitosis – Will also affect NON-cancerous cells with high growth fraction (bone marrow, GI epithelium, hair follicles, sperm-forming cells)  Two examples Suppose you have a tumor composed of 200 cells in which 150 are proliferating and 50 are in G0: 𝑝𝑟𝑜𝑙𝑖𝑓𝑒𝑟𝑎𝑡𝑖𝑛𝑔 𝑐𝑒𝑙𝑙𝑠 150 3 = = =𝟑 𝑐𝑒𝑙𝑙𝑠 𝑖𝑛 𝐺0 50 1 – Would chemotherapy be effective? Suppose you have a tumor composed of 200 cells in which 50 are proliferating and 150 are in G0: 𝑝𝑟𝑜𝑙𝑖𝑓𝑒𝑟𝑎𝑡𝑖𝑛𝑔 𝑐𝑒𝑙𝑙𝑠 50 𝟏 = = 𝑐𝑒𝑙𝑙𝑠 𝑖𝑛 𝐺0 150 𝟑 – Would chemotherapy be effective?  In general: – The more common cancers (solid tumors of breast, lung, prostate, colon) have low growth fraction Do not perform the activities targeted by these drugs Have time to repair during G0 What does this mean about effectiveness of chemotherapy? – Rarer cancers (ALL, Hodgkin’s lymphoma, testicular cancer) have a high growth fraction What does this mean about effectiveness of chemotherapy?  As cancer cells grow, more cells enter G0 – Less likely to be influenced by drugs – Poor blood supply to the core of the tumor Debulking – Reducing the size of the tumor by surgery or radiation – Increases effectiveness of drugs  Toxicity Damage to normal cells is dependent on growth fraction – These drugs are not selective Toxicity is dose selective – Often have to reduce dose of drug to minimize damage to normal cells We have not identified unique biochemical features of cancer cells that allow us to target them with chemotherapy exclusively  Major toxicities of chemotherapy 1. Bone marrow suppression – Neutropenia – Thrombocytopenia – Anemia 2. GI tract injury – Stomatitis – Diarrhea 3. Nausea and vomiting 4. Alopecia 5. Reproductive system toxicity  Major toxicities of chemotherapy 1. Bone marrow suppression: – Highly proliferating cells – Three major effects: a) Neutropenia – normally, absolute neutrophil count is 2500-7000 cells/mm2 Promotes risk of infection Opportunistic infections (candidiasis) can be life threatening In most cases, neutropenia is rapid Lowest neutrophil count (nadir) is between 10-14 days after dose – Highest risk of infection – Fever is the first sign Neutrophil count recovers in a week Can administer Filgrastim (Neupogen) to stimulate production of neutrophils Hospitalization increases risk of infection What teaching should take place? Major toxicities of chemotherapy b) Thrombocytopenia: normal = 150,000-450,000/mm3 Promotes risk of bleeding Nose and gums are most common What other drugs would be contraindicated? What teaching should take place? What nursing interventions should be performed with caution? c) Anemia: HGB < 12 for women, < 13.5 for men Less common than neutropenia or thrombocytopenia Can administer erythropoietin (epoetin alfa or darbopoetin alfa) to stimulate RBC production CANNOT be given in myeloid cancers (AML, CML) as it may stimulate those cancers Can shorten survival, so use is only palliative  Major toxicities of chemotherapy 2. GI tract injury – epithelial lining has very high growth fraction a) Stomatitis – inflammation of oral mucousa Develops days after onset of chemo Can last up to 2 weeks after end of therapy Ulceration can occur and infection can develop Painful Relieve symptoms with oral antifungals and mouthwash composed of anesthetic (lidocaine) and antihistamine (diphenhydramine) b) Diarrhea – by impairing absorption of fluids and other nutrients Can be slowed by administration of oral opioid agonist (loperamide) 3. Nausea and vomiting – from direct stimulation of the chemoreceptor trigger zone in the brain – Can be immediate and severe – More profound than other medications – Treat with ondansetron (Zofran)  Major toxicities of chemotherapy 4. Alopecia – from injury to hair follicles – Begins 7-10 days after onset of treatment – Maximized in 1-2 months – Regenerates 1-2 months after last course of treatment – May be able to slow by cooling the scalp 5. Reproductive system – high growth fraction of testes and developing fetus – Both highly susceptible, especially to alkylating agents – Risk of fetal abnormality is worst in 1st trimester – After 18 weeks, risk tends to be low  Resistance Can occur and can reduce effectiveness of therapy Mechanisms: – Reduced drug uptake – Increased drug efflux: p-glycoprotein – Reduced drug activation – Reduced target molecule sensitivity – Increased repair of drug-induced damage to DNA Promotes growth of resistant cells  Challenges to Chemotherapy Tumors are made of heterogenous cells – Cells may be different in morphology, growth rate, metastatic ability – Can influence effectiveness of drugs Core of solid tumors have poor vascularity – Difficult getting drugs into the core of the tumor BBB – Difficult to treat CNS tumors – What quality do drugs need to penetrate BBB?  Achieving maximum benefit from chemo 1. Intermittent chemotherapy – Permits normal cells to repopulate – However: normal cells must proliferate faster than cancer cells for this to be effective 2. Combination chemotherapy – Each effective on it’s own – Different mechanisms of action – more effective at killing – Resistance is less frequent when combination therapy is used – Minimally overlapping toxicities – can give maximal tolerated dose while improving effectiveness  Achieving maximum benefit from chemo 3. Optimizing dosing schedules – Need to maximize effect of drug – Need to consider phase specificity while considering inactivation time of drug – Single high dose: Some cells may not be in the appropriate phase for the drug to exert effect Inactivation of drug may be fast As a result, many will survive – Multiple smaller doses: Greater chance of drug affecting multiple cancer cells Increased likelihood of cell kill 4. Regional drug delivery – Direct delivery to the source  Cytotoxic agents Largest class Work directly to kill cancer cells Most toxic to tumors with high growth fraction Eight major groups!! – Most interfere with synthesis of DNA – Some block mitosis – One disrupts synthesis of proteins – Some are only effective during a particular phase of mitosis (a.k.a. “schedule dependent”) Only effective against cells in that phase at that time Often administered by prolonged infusion or by multiple doses at short intervals – Phase-nonspecific drugs can be given at any time Affect drugs in all phases As a rule, are more toxic to proliferating cells than resting cells  Nursing considerations Handling cytotoxic drugs – Most are mutagenic, carcinogenic, and teratogenic – Safe handling procedures must be followed to avoid contact with skin, eyes, etc. Vesicant drugs can cause severe tissue injury – Must have good IV flow – Should avoid locations that have been irradiated – Stop infusion immediately if infiltrate is identified  Cytotoxic agents 1. Alkylating agents – Nitrogen mustards – Nitrosureas 2. Platinum compounds 3. Antimetabolites – Folic acid analogs – Pyrimidine analogs – Purine analogs 4. Hypomethylating agents – we won’t talk about these 5. Antitumor antibiotics 6. Mitotic inhibitors – Vinca alkaloids – Taxanes 7. Topoisomerase inhibitors 8. Miscellaneous – we’ll only talk about asparaginase  Alkylating agents Two main groups: – Nitrogen mustards – Nitrosureas Shared qualities: Mechanisms of action: – Binding an alkyl group to a specific nitrogen atom in guanine – Some can form cross-links between strands of DNA – Result is DNA miscoding, scission of DNA strand or inhibition of DNA replication – Not phase specific, but more effective during replication Detrimental effects are seen when the DNA attempts to replicate – Resistance is common due to DNA repair enzymes Alkyl groups  Nitrogen mustards Cyclophosphamide (Cytoxan, Neosar) – Most widely used alkylating compound – Bifunctional alkylating compound – Broad spectrum – Pro-drug that is converted to active form in liver Delayed onset of action – Not vesicant – can be given IV or PO Administer with food  Nitrogen mustards – Adverse effects: 1. Acute hemorrhagic cystitis!! – Administer with mesna (Mesnex) and adequate hydration to minimize effect 2. Bone marrow suppression – may limit dose 3. Nausea, vomiting, diarrhea 4. Alopecia  Nitrosureas Carmustine (BiCNU, Gliadel) – Bifunctional alkylating compound – Broad spectrum – Highly lipophilic – what does that mean?  Nitrosureas – Adverse effects: 1. Bone marrow suppression – may limit dose – Nadir 4-6 weeks after dose 2. Nausea, vomiting, diarrhea 3. Alopecia 4. Pulmonary fibrosis – only in large doses – Administration in the form of a biodegradable wafer (Gliadel) or IV Wafer used for brain tumors  Platinum compounds (-platin) Cisplatin (Platinol-AQ) With paclitaxel is first-line therapy for ovarian cancer and non-small cell lung cancer Mechanism of action: – Forms cross-links between and with in strands of DNA – APPROVED ONLY for metastatic testicular and ovarian cancer and advanced bladder cancer Used off label for other indications  Platinum compounds (-platin) Adverse effects: 1. Kidney damage – may limit dose Can be reduced by hydration and diuretic therapy 2. Severe nausea, vomiting Within one hour of administration 3. Peripheral neuropathy 4. Mild-moderate bone marrow suppression  Antimetabolites Structural analogs of important natural substances Disrupt normal processes by mimicry ONLY EFFECTIVE AGAINST CELLS INVOLVED IN REPLICATION – Some inhibit enzymes – Some are incorporated into DNA  Antimetabolites Folic Acid Analogs: – Methotrexate (Rheumatrex, Trexall) Pyrimidine Analogs: – Cytarabine (cytosine arabinoside or Ara-C) Purine Analogs: – Mercaptopurine (Purinethol)  Folic acid analogs Methotrexate (Rheumatrex, Trexall) Mechanism of action: – Inhibits an enzyme in folic acid activation Prevents folic acid from being synthesized – Activated folic acid is necessary for DNA synthesis – Also functions by inducing apoptosis – S-phase specific “Me Thot Rex Ate…” Special thanks to Karen Zhu, BBP Class of 2024 Remember folic acid synthesis??  Methotrexate and leukovorin Administration: – Methotrexate requires transport protein that causes cell to uptake methotrexate – Some cancer cells lack this transport protein Large doses are required to FORCE methotrexate into the cell by diffusion Dangerous for normal cells due to high concentration – Co-administration with leukovorin “rescues” normal cells Leukovorin is a precursor of folic acid Does not require the enzyme that is being blocked by methotrexate to convert into folic acid Does NOT rescue cancerous cells Leukovorin requires the same transport protein as methotrexate Cancerous cells that lack the protein will not be able to take up leukovorin and will not be rescued  Adverse effects: 1. Bone marrow suppression – may limit dose 2. Pulmonary infiltrates and fibrosis 3. Oral and GI ulceration Can lead to perforation 4. Nausea, vomiting 5. Kidney damage Minimize by hydrating and alkylating urine 6. Fetal malformation  Side effects of folic acid analogues “Me Thot Rex Ate Burger King Fries": B=bone marrow suppression K=kidney damage F=fetal malformation – Sean Arthurs, BBP class of 2023 The side effects spell out FOLIK: F=fetal malformation O=oral and GI ulceration L=lung infiltrates and fibrosis I=intraosseous (bone marrow) suppression K=kidney damage – Skyler Baez, BBP class of 2023  Pyrimidine analogs Cytarabine (cytosine arabinoside or Ara-C) – Prodrug that converts to active form within cells Structurally similar to pyrimidines (cytosine, thymine, and uracil) Mechanism of action: – Incorporated into DNA – Suppresses further DNA synthesis – S-phase specific  Pyrimidine analogs (cont.) Adverse effects: 1. Bone marrow suppression – may limit dose 2. Pulmonary edema 3. Nausea, vomiting 4. Stomatitis 5. Liver damage 6. Kidney damage Lungs, liver and kidneys in here!  Pyrimidine analogs (cont.) To remember the side effects, think about flavors of pie… Blueberry, Lemon and Key lime: B=bone marrow suppression L=liver injury K=kidney injury – Sean Arthurs, BBP class of 2023  Purine analogs Mercaptopurine (Purinethol) – Prodrug that converts to active form within cells Structurally similar to purines (adenine, guanine, and hypoxanthene) Used for cancer, but may also be used for immunosuppression Mechanism of action: – Following activation, interferes with 1. Purine synthesis 2. Nucleic acid synthesis – S-phase specific  Purine analogs (cont.) Adverse effects: 1. Bone marrow suppression – may limit dose 2. Mild hepatotoxicity (high bilirubin and LFTs) is common 3. Nausea, vomiting 4. Oral and GI ulceration  Topoisomerase inhibitors Topoisomerase is an enzyme that cleaves the DNA – Permits relaxation of the coiled DNA – Promotes synthesis of RNA, DNA replication, and DNA repair – Later re-seals the strand  Topoisomerase inhibitors (cont.) Etoposide (Toposar) Mechanism of action: – Permits cleaving of the DNA but does not permit repair – Cell death occurs due to accumulation of DNA with multiple breaks Protein binding is high! – What other drugs are you concerned about?  Topoisomerase inhibitors (cont.) Adverse effects: 1. Bone marrow suppression – usually dose- limiting 2. Alopecia 3. Mucositis 4. Nausea, vomiting, diarrhea  Antitumor antibiotics Anthracyclines (most end in –rubicin) and non-anthracyclines (most end in –mycin) ONLY used to treat cancer Damage cells by direct interaction with DNA Conventional vs. liposomal – Liposomal associated with infusion-associated symptoms – Liposomal more likely to target cancer cells and avoid normal cells  Antitumor antibiotics (cont.) Anthracyclines – Doxorubicin (Adriamycin) – conventional – Doxorubicin (Doxil, Caelyx) – liposomal Mechanism of action: 1. Intercalation with DNA Slips between base pairs and binds to DNA Distorts structure of DNA 2. Inhibition of topoisomerase II Enzyme that cleaves and repairs DNA strands Doxorubicin allows cleaving of DNA but not repair Leads to apoptosis  Antitumor antibiotics (cont.) Adverse effects: 1. Bone marrow suppression – may limit dose 2. Cardiotoxicity (arrhythmias) leading to heart failure Can appear within minutes of dosing Lookout for palpitations, edema, and shortness of breath Transient in most cases Can be delayed – developing years after therapy resulting in cardiomyopathy Administration of dexrazoxane (Zinecard) may offer some protection, but increases bone marrow suppression 3. Liposomal form associated with infusion-related symptoms (chest pain, back pain, flushing) Disappear when infusion is stopped and don’t return when restarted at a slower rate  Antitumor antibiotics (cont.) "ABC Do XYZ" Anthracyclines have Bone marrow suppression and Cardiotoxicity so Do Xpect Your Zinecard I also like that it has DoX in the middle, which might remind you of doxorubicin  Antitumor antibiotics (cont.) Doxorubicin is red in color (hence the "rub" in the name, like “rubor”) and is nicknamed the "Red Devil." To remember the side effects: 1. It's red, like the heart, so there is cardiotoxicity 2. If you were running from the devil you'd have shortness of breath, palpitations, chest pain, back pain and flushing (like the infusion-related symptoms with the liposomal form) 3. If the Red Devil catches up to you, the only thing that will be left are your bones because you can't defend yourself (bone marrow suppression - so be on the lookout for fever, sore throat, etc.) – Special thanks to Judy Rodriguez, BBP Class of 2023  Antitumor antibiotics (cont.) Non-anthracyclines – Dactinomycin (Actinomycin D) Mechanism of action: – Intercalates with DNA and distorts structure – Inhibits RNA and protein synthesis Adverse effects: 1. Bone marrow suppression 2. Oral and GI mucositis 3. Nausea, vomiting, diarrhea 4. Alopecia  Mitotic inhibitors Drugs that act during M phase Two groups: 1. Vinca alkaloids Vincristine (Oncovin) – conventional Vincristine (Marqibo) – liposomal Vinblastine (Velban) 2. Taxanes Paclitaxel (Abraxane, Taxol)  Vinca alkaloids (Vin-) Derived from periwinkle plant Mechanism of action: – Block mitosis during metaphase – Disrupts assembly of microtubules by binding to tubulin (a component of microtubules) – Cell stops in metaphase – Promotes apoptosis  Vinca alkaloids (cont.) Vincristine (both forms) BONE MARROW SPARING! – Useful in combination therapy Adverse effects: 1. Peripheral neuropathy – dose-limiting toxicity Disrupts neurotubules in neurons (binds to tubulin) Necessary for transport of enzymes and organelles Sensory or motor nerves (↓reflexes, weakness, paresthesia, sensory loss) Minimal injury to brain – cannot cross BBB Almost all patients experience some neuropathy 2. Alopecia  Vinca alkaloids (cont.) Vinblastine (Velban) – Nearly identical to Vincristine, but toxicity differs – Neurotoxicity is less common and less severe – Bone marrow suppression is the major dose- limiting toxicity  Taxanes Paclitaxel (Abraxane, Taxol) Derived from the Pacific Yew tree In combination with cisplatin is first line therapy for ovarian cancer and non-small cell lung cancer Mechanism of action: – Promotes formation of microtubule bundles – Inhibits cell division – Promotes apoptosis  Taxanes (cont.) Adverse effects: 1. Bone marrow suppression – may be dose limiting 2. Severe hypersensitivity reaction with Taxol Hypotension, dyspnea, angioedema, urticaria Not as common with Abraxane Pretreat with: – glucocorticoid (Dexamethasone) – antihistamine (diphenhydramine) – H2 receptor antagonist (famotidine, cimetidine) 3. Peripheral neuropathy can occur 4. Can cause bradycardia and heart block  Taxanes (cont.) “When they tax all (taxol) your income, you severely hyper-react!!” – Thanks to Martina Robotham, ABP class of 2023  Asparaginase (Elspar) Mechanism of action: – Asparaginase is an enzyme that converts asparagine into aspartic acid Asparagine is an essential amino acid – Needed for protein synthesis Cells deprived of asparagine will not be able to synthesize proteins – Limited to Acute Lymphoblastic Leukemia (ALL) “ALL patients like Asparagus” – Patrice Babian, BBP class of 2020 Many other cells can manufacture their own asparagine  Asparaginase (cont.) Adverse effects: 1. Coagulation deficiencies – due to inhibition of protein synthesis 2. Liver, kidney, and pancreas damage – due to inhibition of protein synthesis 3. CNS depression 4. Nausea, vomiting, diarrhea  Drugs for breast cancer Anti-estrogens – Tamoxifen Aromatase inhibitors – Anastrozole Anti-HER2 Antibodies – Trastuzumab Kinase inhibitor – Lapatinib  Antiestrogens Drugs that block estrogen receptors – Only effective against cells that have these – Deprive tumor cells of growth-promoting influence of estrogen (estradiol) Tamoxifen (Nolvadex) – gold standard for endocrine treatment of breast cancer Indications: Estrogen receptor (ER) positive breast cancer in pre and post menopausal women  Mechanism of action: – Prodrug that is converted into an active metabolite – BLOCKS estrogen receptors in breast cancer cells Prevent estradiol from binding Estradiol normally stimulates growth and proliferation Blockage causes ↓ proliferation and ↑ tumor regression – ACTIVATES estrogen receptors in bone, liver and uterus Can ↑ bone density, ↑ clotting factors, and ↑ risk of endometrial cancer  Adverse effects: 1. Increased risk of endometrial cancer and thrombosis 2. Hot flashes – by blocking estrogen receptors 3. Fluid retention 4. Vaginal discharge and menstrual irregularities – due to alteration of estradiol 5. Endometrial cancer – due to activation of receptors in uterus 6. Teratogenic Precautions: – Use of CYP450 inhibitors can negate effect of tamoxifen  Aromatase Inhibitors Anastrozole (Arimidex) Indications: ER positive breast cancer in POSTMENOPAUSAL women Mechanism of action: – NORMALLY: adrenal androgens are converted into estrogen by aromatase in peripheral tissues – Anastrozole blocks aromatase, so estrogen synthesis from androgens is reduced to undetectable levels – This deprives estrogen-dependent breast cancer from growing – DO NOT block estrogen produced by ovaries (not effective in pre-menopausal women) Estrogen from Androgens  Adverse effects: 1. Musculoskeletal pain – probably due to estrogen deprivation 2. Osteoporosis and fractures Compared to tamoxifen: – Anastrozole appears to be more effective – Fewer side effects (fewer hot flashes, weight gain) – No risk of endometrial cancer or thromboemboli – There is a risk of fracture  Anti Human Epidermal Growth Factor Receptor 2 (HER2) Antibodies (-tuzumab) Trastuzumab (Herceptin) Indications: HER2 positive breast cancer in pre and post menopausal women Mechanism of action: – NORMALLY: HER2 is a receptor on the cell membrane that regulates cell growth – Overexpression of HER2 is associated with aggressive tumor growth – Trastuzumab is a monoclonal antibody that blocks HER2 receptors 1. Inhibits cell proliferation 2. Promotes antibody-dependent cell death  Adverse effects: 1. Cardiotoxicity – ventricular dysfunction and heart failure 1. Caution in women with heart disease 2. Caution when combining with paclitaxel (increased risk of cardiotoxicity) 2. Flu-like symptoms (fatigue, chills, fever, nausea) Occurs with most monoclonal antibodies 3. Can cause potentially fatal hypersensitivity reaction (urticaria, bronchospasm, angioedema, hypotension) 4. Infusion reaction (chills, fever, nausea) – fades with prolonged treatment No bone marrow suppression  Kinase inhibitor Lapatinib (Tykerb) Indication: HER2 positive breast cancer ONLY in combination with other drugs Mechanism of action: – Inhibits two enzymes involved in cell signal transduction: HER2 tyrosine kinase EGFR tyrosine kinase – Blocks signal promoting growth of tumor  Kinase inhibitor Adverse effects: 1. Diarrhea, nausea, vomiting 2. Fatigue 3. Rash 4. Rarely severe liver injury  Androgen deprivation therapy For use in prostate cancer Disease usually progresses after 18-24 months following therapy 90% of androgens come from testes 10% produced by adrenal and prostate Drug therapy more effective than castration – Block testosterone receptors – Lower testosterone production  Gonadotropin-releasing hormone agonists (GnRH agonists) Leuprolide (Eligard, Lupro) Synthetic analog of GnRH Administered daily, monthly, several times a year, or annually Mechanism of action: – Mimics GnRH and binds to receptors in the pituitary – INITIALLY cause release of hormones that stimulate INCREASED production of testosterone Transient “flare” in prostate cancer is seen – With continuous exposure, GnRH receptors become desensitized – Testosterone production begins to decline – Prostate cancer needs testosterone Reduction in testosterone leads to “chemical castration” – NO EFFECT on androgens produced by adrenal or prostate  Gonadotropin-releasing hormone agonists (GnRH agonists) Adverse effects: 1. Hot flashes – usually decline with time 2. Erectile dysfunction 3. Reduced libido 4. Gynecomastia 5. Reduced muscle mass 6. Increased risk of osteoporosis and bone fracture Coadministration with androgen receptor blocker (Flutamide) – Reduces the flare – Reduces activity due to adrenal and prostate produced androgens  Gonadotropin-releasing hormone antagonists (GnRH antagonists) Degarelix (Firmagon) Used for advanced prostate cancer Mechanism of action: – Block the GnRH receptors in pituitary – Reduces production of hormones that stimulate the testes to produce testosterone – NO INITIAL FLARE OF PROSTATE CANCER Administration: – Subcutaneous  Gonadotropin-releasing hormone antagonists (GnRH antagonists) Adverse effects: 1. Hot flashes – usually decline with time 2. Erectile dysfunction 3. Reduced libido 4. Gynecomastia 5. Reduced muscle mass 6. Increased risk of osteoporosis and bone fracture 7. Injection site reactions  Androgen receptor blockers Flutamide Only indicated for prostate cancer Often administered with GnRH Agonist to suppress initial flare and activity due to adrenal/prostate production of androgens Mechanism of action: – Blocks androgen receptors  Androgen receptor blockers Adverse effects: 1. Hot flashes – usually decline with time 2. Erectile dysfunction 3. Reduced libido 4. Gynecomastia 5. Reduced muscle mass 6. Increased risk of osteoporosis and bone fracture 7. Nausea, vomiting, diarrhea 8. Rare liver toxicity  CYP17 Inhibitor Abiraterone (Zytiga) Used in combination with prednisone to treat METASTATIC castration-resistant prostate cancer Mechanism of action: – Inhibition of CYP17 An enzyme necessary for androgen synthesis Synthesis of androgens and estradiol  CYP17 Inhibitor Adverse effects: 1. Hot flashes 2. Decreased libido 3. Decreased muscle mass 4. Erectile dysfunction 5. Gynecomastia 6. Hepatotoxicity 7. Hypokalemia – due to excessive secretion of aldosterone following blockade of androgen production 8. Edema – due to excessive secretion of aldosterone following blockade of androgen production 9. Joint swelling  Angiogenesis inhibitors Bevacizumab (Avastin) Suppress formation of new blood vessels Deprive solid tumors of blood supply Cannot KILL tumors that already exist Mechanism of action: – Monoclonal antibody – Binds to VEGF – a compound that stimulates vessel proliferation – Combination of Bevacizumab/VEGF cannot bind to receptors on vascular endothelium that promote vessel growth – New vessel growth does not occur  Angiogenesis inhibitors Adverse effects: 1. Nephrotic syndrome 2. GI perforation – if it occurs, stop the drug and never use again 3. Hemorrhage – brain, lung, GI, vaginal, etc. 4. Thromboembolism – if it occurs, stop the drug and never use again  Angiogenesis inhibitors To remember the side effects of angiogenesis inhibitors, they almost spell out the word NIGHT: N=nephrotic syndrome G=GI irritation H=hemorrhage T=thromboembolism – Sean Arthurs, BBP class of 2023 Next week: Drugs for CNS Disorders Thanks to Vivian Vuong, ABP Class of 2020