6,7 - Introduction to Anemias, hemolytic anemias, other anemias, Chemotherapies Flashcards

Question

Hereditary Pyropoikilocytosis (Membrane/cytoskeletal defects)

Answer 1

* Inherited (autosomal dominant) * Defect (qualitative) in a cytoskeleton protein (often doubly heterozygous for two different mutations) * Thermal instability (erythrocytes fragment at lower temperatures) * Marked anisopoikilocytosis (similar to thermal burn) * Anemia most severe in childhood

Answer 2

* Acquired (liver disease) or inherited (abetalipoprotenemia) * Excess cholesterol in outer leaflet of plasma membrane * Increased membrane rigidity (spike-like projections) * Extravascular hemolysis (mild)

Answer 3

* Normocytic anemia and reticulocytosis (mild) * Acanthocytes (spur cells) on blood smear - Hyperchromic (no central pallor) with irregular spiky projections

Answer 4

* Enzyme defects - Glucose-6-phosphate dehydrogenase (G6PD) deficiency - Pyruvate kinase deficiency

Answer 5

G6PD Deficiency * Inherited (X-linked recessive) * Hexose monophosphate shunt * Decreased reduced glutathione, susceptibility to oxidative stress * Hemoglobin (Fe2+) oxidized to methemoglobin (Fe3+) * Extravascular hemolysis

Answer 6

* Episodic normocytic anemia with reticulocytosis * Heinz body formation * Bite cells/polychromasia on blood smear

Answer 7

* Males express the disease, females are carriers * Episodic hemolysis following oxidative stress (drugs, infections) * A(-) variant – 10-15% of African-Americans - Unstable molecule (10% activity) * Mediterranean variant - Essentially absent enzyme activity - More severe hemolysis - Favism

Answer 8

* Inherited (autosomal recessive) * Conversion of phosphoenolpyruvate to pyruvate * Decreased ATP generation * Failure of membrane pumps, K+ loss (hypotonicity) with water loss * Extravascular hemolysis

Answer 9

* Normocytic anemia with reticulocytosis (variable) * Echinocytes/polychromasia on blood smear

Answer 10

* Hemoglobinopathies - Hemoglobin S - Hemoglobin C - Hemoglobin E - Methemoglobin

Answer 11

* Immune (antibody)-mediated hemolysis - Warm autoantibody - Cold autoantibody (cold agglutinin) - Paroxysmal cold hemoglobinuria (PCH) - Transfusion reactions (immediate/delayed) - Hemolytic disease of the newborn (HDN)

Answer 12

* Antibodies that bind at warm temperatures (37oC) * IgG, bind to global Rh proteins * Do not fix complement * Progressive loss of membrane with spherocyte formation * Extravascular hemolysis (most often)

Answer 13

* Normocytic anemia with reticulocytosis * Spherocytes/polychromasia on blood smear * Positive direct antiglobulin (Coombs) test

Answer 14

* 80% of AIHA (women > men) * Causes - Idiopathic - Infections (viruses, mycoplasma) - Collagen vascular disease (SLE) - Lymphoproliferative disease (CLL) - Drug-induced * Treatment with immunosuppression, transfusions, splenectomy (refractory)

Answer 15

* Antibodies that bind at cold temperatures (4oC) * IgM, bind to i/I antigens * May fix complement * Red cell agglutination peripherally, occasionally intravascular hemolysis * Extravascular hemolysis (liver, spleen)

Answer 16

* Variable anemia * Interference with CBC parameters (RBC, MCV, HCT, MCH, MCHC) – warm the blood sample * Red cell agglutination on blood smear * Positive direct antiglobulin test (only complement) * Occasionally evidence of intravascular hemolysis

Answer 17

* Peripheral vaso-occlusion (Raynaud phenomenon) * Causes - Idiopathic - Infections (EBV, mycoplasma) - Collagen vascular disease (SLE) - Lymphoproliferative disease - Drug-induced * Cold avoidance, immunosuppression/transfusion for more severe anemia

Answer 18

* Biphasic antibody (Donath-Landsteiner), binds in cold and activates complement upon warming * IgG, bind to P antigens * Fixes/activates complement * Intravascular hemolysis

Answer 19

* Severe anemia with reticulocytosis * No agglutination (IgG) * Decreased haptoglobin with hemoglobinemia and hemoglobinuria * Positive direct antiglobulin test (only complement) * Associated with viral infections, syphilis * Cold avoidance, transfusions

Answer 20

* Mechanical trauma – turbulent flow blood/increased sheer stress causes red cell fragmentation (intravascular hemolysis) * Macroangiopathic (larger vessel) - Prosthetic heart valve, vascular graft, vigorous exercise, malignant hypertension, vasculitis * Microangiopathic (capillary) - Microcirculatory thrombosis by platelets/fibrin (DIC, TTP, HUS)

Answer 21

* Variable anemia with reticulocytosis * Schistocytes on blood smear * Decreased haptoglobin * Thrombocytopenia (DIC, TTP, HUS) * Coagulation abnormalities (DIC only)

Answer 22

* Miscellaneous causes - Paroxysmal nocturnal hemoglobinuria (PNH) - Hypersplenism - Thermal burns - Erythrocytic parasites (malaria, babesiosis)

Answer 23

* Decreased erythropoietin synthesis * Normochromic, normocytic anemia * Low reticulocyte count * Recombinant erythropoietin for treatment * Renal transplant, if feasible, to correct underlying kidney disease

Answer 24

* Selective suppression of erythropoiesis * Causes - Parvovirus B19 infection (aplastic crisis) - Thymic lesions (thymoma, thymic hyperplasia) - Diamond-Blackfan syndrome (congenital) - Transient erythroblastopenia of childhood * Normocytic, normochromic anemia * Low reticulocyte count

Answer 25

* Bone marrow replacement by an infiltrating process * Disruption of bone marrow-blood barrier * Causes - Myelofibrosis - Primary or metastatic malignancy - Granulomatous disease * Extramedullary hematopoiesis (spleen, liver)

Answer 26

* Normocytic, normochromic anemia * Low reticulocyte count * Leukoerythroblastosis (circulating nucleated red cells and immature granulocytes) * Teardrop cells

Answer 27

* Sudden disruption of vascular integrity * Blood loss greater than ability of bone marrow to compensate * Degree of anemia may not initially be apparent (loss of whole blood) * May require transfusion support * One unit of red cells should raise hematocrit by 3% and hemoglobin by 1g/dl

Answer 28

general term for any treatment involving the use of chemical agents to treat several diseases including cancer, viral, microbial and parasitic infections ## Footnote 1971 National Cancer Act Pres. Richard Nixon Find a cure for cancer by 1976 $1.6 billion dollars

Answer 29

1. Primary induction CCT * Drugs given as primary treatment in patients with advanced cancer and no alternative treatment options Goals: Palliation: Relieve tumor related symptoms, improve QOL, delay tumor progression. Curative: Elimination of all known tumor mass. Eliminate small subset of diseases 2. Adjuvant CCT * Drugs given with/after primary therapy, when primary therapy is less than completely effective * Goals: reduce incidence of local and systemic recurrence, improve survival 3. Neoadjuvant CCT * Chemotherapy offered prior other primary treatment (e.g. prior to surgery).

Answer 30

* The initial description of hematological tumors described that leukemias and lymphomas tumor grew exponentially (blue curve) * Studies using mathematical models suggested that most solid tumors growth using different kinetics but rather using a Gompertzian model of tumor growth (red curve). * The Gompertz curve or function, is a type of mathematical model for a time series. It is a sigmoid function which describes growth as being slowest at the start and end of a given time period. 1. Initially, at #1, the tumor grows exponentially until crossing the inflection point (at #2). 2. After #2 whereupon its growth decelerates. 3. As the tumor grows its core lacks oxygen and becomes necrotic. When the rate of growth equals the rate of death (necrosis) tumor size remains (at 3)

Answer 31

* Growth fraction model suggests that tumors consist of pools of both proliferating and non-proliferating cells * Growth rate depends on the growth fraction (GF), which is the percent of proliferating cells within a given system * In Burkitt's lymphoma nearly 100% of the neoplastic cells are actively undergoing division concurrently, rendering them highly responsive to cytotoxic chemotherapy. * In colon carcinoma, the growth fraction is less than 5% of cells, leading to its comparatively diminished sensitivity to chemotherapy. * However, metastases originating from colon carcinoma and deposited in organs like the liver initially exhibit a high growth fraction, making them more susceptible to cytotoxic anticancer drugs.

Answer 32

* The cell cycle is susceptible to the effects of both cell cycle-specific and non-cell cycle-specific cytotoxic anticancer drugs. * Tumor cells, whether normal or neoplastic, display heightened responsiveness to specific drugs during particular phases, such as vinca alkaloids affecting mitosis in the M-phase. * Conversely, cell cycle nonspecific drugs (alkylating agents) influence tumor cells during both active cycling and the resting phase (G0). * Cell cycle-specific cytotoxic drugs, like antimetabolites, are effective only when cells are in the appropriate phase during treatment. * Non-cell cycle-specific drugs, including alkylating agents, disrupt DNA structure through a 'hit-and-run' mechanism, with the timing of cell exposure being less critical, as the drug's impact becomes apparent when cells initiate division

Answer 33

Therapeutic index is the ratio between drug concentration or dose causing toxicity versus therapeutic effect.

Answer 34

Most cancer drugs have a “narrow” therapeutic index.

Answer 35

DLT: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. Bone Marrow Suppression (myelosuppression) following therapy is a common DLT for many CCT drugs

Answer 36

Bone Marrow (rapid turnover) * Myelosuppression is a serious consequence of of CCT leading to severe neutropenia, thrombocytopenia, and sometimes anemia. * These hematological consequences may restrict the drug dosage that an individual can tolerate. * They can produce high risk of both infection (neutropenic sepsis) and hemorrhage Gastrointestinal Tract (rapid turnover) * CCT drugs may induce anorexia, mucosal ulceration (oral mucositis), or diarrhea. * Symptoms may include nausea, vomiting, diarrhea, and loss of appetite. * Use of alkylating drugs and cisplatin can limit an individual's ability to tolerate an optimal dosage regimen Reproductive Organs * Several CCT drugs have teratogenic activity due to their mechanisms of action. * Pregnant patients should avoid exposure to CCT drugs for treatment or as members of the healthcare team. * They can produce male infertility and/or adverse effects on sexual function. Peripheral Neuropathy * Pain, tingling, numbness, and cold sensations may occur in the hands and feet due to sensory nerve damage, with effects on motor and autonomic nerves also possible. * CCT Drugs producing are (some): vinca alkaloids (vincristine), platinum compounds, etc.

Answer 37

A given dose/unit time of chemotherapy will kill a constant percentage of cells, not a constant number). – Same dose is needed to decrease the tumor burden from 10^6 to 10^3 cells as from 10^3 to 10^0 cells.

Answer 38

“Classic View” Each exposure to a useful cancer drug treatment kills a constant fraction of “susceptible” cells until all cancer cells are killed OR remaining cells are “dormant” OR are eliminated by the immune system

Answer 39

* Primary resistance * Absence of response on initial exposure * Acquired resistance * Develops during treatment in response to drug exposure * Can be highly specific to a single drug * Some of these responses are mediated by Multidrug resistance (MDR) mechanisms and MDR genes such as: * MDR1 (ABCB1): This gene encodes P-glycoprotein (P-gp), which is a major player in drug efflux. Overexpression of MDR1 can lead to decreased intracellular drug concentrations and contribute to multidrug resistance. * MRP (ABCC) Family: The Multidrug Resistance-Associated Protein (MRP) family includes several genes (e.g., MRP1, MRP2, MRP3) that encode transport proteins involved in drug efflux. These proteins contribute to the resistance against a variety of anticancer drugs. * BCRP (ABCG2):Breast Cancer Resistance Protein (BCRP) is encoded by the ABCG2 gene. It acts as a drug efflux pump and is associated with resistance to certain chemotherapeutic agents.

Answer 40

(C) Increased expression of a P-glycoprotein transporter

Answer 41

There are different types of alkylating agents based on the chemical structures: 1. **Nitrogen mustards: cyclophosphamide, ifosfamide, chlorambucil, melphalan, bendamustine, mechlorethamine** 2. **Nitrosoureas: streptozocin, carmustine (BCNU), lomustine (CCNU)** 3. **Platinum agents: cisplatin, carboplatin, oxaliplatin** 4. Alkyl sulfonate: busulfan 5. Ethylenimine: Triethylenethiophosphoramide (thiotepa), altretamine 6. DNA-methylating drugs/Triazine: Procarbazine (?), dacarbazine, temozolomide. The main mechanism of action would include generation of H2O2 and oxygen free radicals that cause DNA strand scission. Most of these alkylating agents are metabolized hepatically and excreted in the urine; dose adjustment for renal dysfunction and severe hepatic dysfunction is often required.

Answer 42

* Major site of alkylation is N7 position of guanine * Bind to and cross link DNA (single strand or double strand breaks) * Not cell cycle specific (most susceptible in G1 and S phases)

Answer 43

* Develops rapidly when given as single agents * Mechanisms * Increased capability to repair DNA damage * Decreased transport of alkylating agents into cell * Increased activity of glutathione - needed to conjugate alkylating agent * Increased Glutathione S-transferase, which catalyzes the inactivation of alkylating agents. ## Footnote Please note that both elevated glutathione levels and increased activity of the enzyme glutathione S-transferase have been associated with the resistance of cells to alkylating agents.

Answer 44

C. Oxaliplatin

Answer 45

* Folic acid is an essential nutrient, which acts as a supplier of methyl groups to synthesize purines, pyrimidines, and certain amino acids. When able to donate methyl groups, folic acid exists as a reduced, methylene folate known as “5,10-methylenetetrahydrofolate” (Me-THF). * Trade Names: Rheumatrex, Methotrex (MTX), Trexall ® * Drug Class: Antimetabolite / Immunosuppressant / Antineoplastic * Dose: The oral dose is 7.5 to 20 mg **once weekly.** * Contraindications: – **Methotrexate can cause fetal death or teratogenic effects when administered to pregnant patients.** – Methotrexate is contraindicated in patients with hepatic damage

Answer 46

* Methotrexate (MTX) (MOA) * Folic acid analog that binds to catalytic site of dihydrofolate reductase (DHFR) -> inhibits synthesis of tetrahydrofolate (THF, FH4), a cofactor needed for synthesis of precursors for DNA, RNA, and de novo DNA synthesis * S - phase specific activity * Analogs used are: – Pemetrexed (PMX) – Pralatrexate (PTX)

Answer 47

The primary toxicities are: * Bone marrow suppression * Intestinal epithelium (mucositis, stomatitis) The supportive care for high dose MTX include: * Hydration (during infusion and 48 hours after) * Urine alkalinization (i.e. sodium bicarbonate to maintain urinary pH >7) * Leucovorin (folinic acid) serves as "rescue agent" in methotrexate therapy. *** Leucovorin is a reduced form of folic acid, and it bypasses the blocked enzyme (dihydrofolate reductase) targeted by methotrexate.**

Answer 48

1. Decreased methotrexate transport into cells 2. Decreased ability to synthesize methotrexate polyglutamylates 3. Production of altered forms of DHFR that have decreased affinity for methotrexate 4. Increased levels of target enzyme DHFR through gene amplification or altered gene regulation 5. Increased expression of a drug efflux transporter of the MRP class (P-Glycoproteins)

Answer 49

C. Leucovorin

Answer 50

* Azathioprine (AZA) is a prodrug of mercaptopurine (MP). *** Thioguanine (TG) and MP can be converted by hypoxanthine phosphoribosyl transferase (HPRT or HGPRT) to thioguanine nucleotide (TGNs) metabolites.** *** TGN metabolites are incorporated into DNA and RNA leading to cell death. However, DNA incorporation is believed to be the primary mode of cytotoxicty** * MP can also be converted to the methyl-thioinosine monophosphate (meTIMP) by thiopurine methyltransferase (Tpmt) which inhibits purine synthesis. * The neoplastic cell become resistant by blocking its activation by HPRT

Answer 51

* Pyrimidine analog used in AML * MOA * Converted to mono-, di-, and triphosphate metabolites * Triphosphate metabolite competitively inhibits DNA polymerase α and β -> blocking DNA synthesis and repair * Also incorporated into DNA -> interferes with chain elongation and defective ligation of newly synthesized DNA fragments Cytosine arabinoside (Cytarabine) * Primary toxicities: myelosuppression, mucositis, nausea, vomiting

Answer 52

* Cytarabine is an antimetabolic agent and blocks the function of DNA polymerase. * Pyrimidine analog used in AML * After cellular uptake, cytarabine is converted to cytarabine-5 ́-triphosphate, which is the active metabolite incorporated into DNA during DNA synthesis. * This results in a cell cycle arrest in the S phase.

Answer 53

* 5-Fluorouracil (5-FU) undergoes cellular conversion to 5- fluoro-2'-deoxyuridine-5'-monophosphate (5-FdUMP). * 5-FdUMP inhibits thymidylate synthase in cells. * The incorporation of 5-FdUMP into DNA hinders DNA synthesis and functionality * 5-FU also produces ananother metabolite, 5- fluorouridine-5'-triphosphate (FUTP). * FUTP disrupts RNA processing and function. * Resistance mechanisms in tumor cells include : * Decreased sensitivity of this enzyme to the drug. 5-Fluorouracil (5-FU) *** Toxicity: Severe Bone marrow suppression**

Answer 54

Topoisomerases: * Topoisomerase I and II are enzymes needed for DNA replication and cell division. * They create temporary nicks in DNA to relieve torsional strain, allowing the DNA to untangle so replication machinery can access the genome. * Topoisomerase I cuts one strand of DNA, Topoisomerase II cuts two strands of DNA *** These enzymes reseal DNA strands after replication. * Topoisomerase activity is increased in cancer cells.** Topoisomerase Inhibitors: * In the United States, approved topoisomerase inhibiting chemotherapeutics include **irinotecan and topotecan (topoisomerase I inhibitors) and etoposide and teniposide (topoisomerase II inhibitors).** * They are given intravenously in 3-4 week cycles combined with other agents. * Major dose-limiting toxicities are myelosuppression and GI issues like diarrhea and nausea.

Answer 55

This category of antineoplastic drugs is made up of several structurally dissimilar microbial products and includes these3 drugs that belong to two main groups: **1. Doxorubicin (Anthracyclines) 2. Bleomycin (Non- Anthracyclines) 3. Mitomycin (Non- Anthracyclines)**

Answer 56

*** They intercalate between DNA base pairs, inhibit topoisomerase II, and generate free radicals.** ** They block the synthesis of RNA and DNA and cause DNA strand scission.** *** Membrane disruption also occurs.** * Toxicity is **myelosuppression and cardiotoxicity** * Cardiotoxicity: including acute transient ECG changes (reversible) and chronic cardiomyopathy leading to the development of heart failure. **Cardiotoxicity develops slowly ( typically becomes symptomatic 5-15 years after therapy is completed)**

Answer 57

*** Bleomycin, which include bleomycinic acid, BLMA2, and B2, are a family of glycopeptide derived antibiotics isolated from the Streptococcus verticullis species.** *** Bleomycin must be given parenterally** *** Their mode of action is metal-dependent oxidative cleavage of DNA and RNA in the presence of oxygen** * They produce early drug resistance *** Pulmonary toxicity is very relevant** The toxicity profile of bleomycin includes pulmonary dysfunction (pneumonitis, fibrosis), which **develops slowly** and is dose limiting

Answer 58

*** Mitomycins are a class of broad-spectrum antibiotics that function as alkylating agents.** * They covalently bind to DNA and generate crosslinks between complementary strands as well as single strand alkylations. * Activation of mitomycins occurs under acidic conditions found in tumor tissue. * Mitomycins also produce reactive oxygen species that contribute to antitumor effects. *** Mitomycin causes severe myelosuppression and is toxic to the heart, liver, lung, and kidneys.**

Answer 59

(A) Bleomycin

Answer 60

* Antimetabolite. It is specific to impairing DNA synthesis (during S-phase) by inhibiting ribonucleotide reductase (which converts ribonucleotides to deoxyribonucleotides ) * Ribonucleotide reductase (RNR) is responsible for synthesizing deoxyribonucleotides, which is the sugar building block of DNA. * Hydroxyurea exploits the sensitivity of highly proliferative myeloproliferative neoplasms and leukemias given their dependency on abundant deoxyribonucleotide (dNTPs) pools to support brisk cell division rates.

Answer 61

GLUCOCORTICOIDS (GCs) Naturally occurring compound is cortisol which is released by the adrenal gland * What is their mechanism of action? * GCs exert their effects either genomically (slow pathway) or non-genomically (fast pathway). * GCs binds to the cytoplasmic GC Receptor (GR) which undergoes dissociation from accessory proteins (heat shock proteins (HSPs), and translocate into the nucleus. * In the nucleus, GR activates or represses transcription of genes by directly binding to glucocorticoid-response elements (GREs) or negative GREs, or by tethering to other transcription factors (TFs) * GCs act via the mitochondrial pathway to cause caspase activation to promote apoptosis of lymphocytes and eosinophils *** End result: decrease in cytokine release, including decreases in IL-2 and TNF α**

Answer 62

* GCs are used to induce cell apoptosis in malignant lymphoid cancers, such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLLetc * In non-hematologic malignancy, GCs monotherapy or combined therapy with other cytotoxic drugs, such as 5- fluorouracil (5-FU), had shown modest benefit in breast and prostate cancers, but not in other cancer types. * However, the addition of GCs to other therapy does not change the long-term survival in advanced breast cancer. * Dexamethasone used to reduce edema from tumors in areas like the brain, spinal cord (review in SMS course) * There are some adverse effects also described in specific tumors. GC may enhance breast and prostate cancer progression. * GCs are widely accepted as an adjuvant during chemotherapy or radiotherapy for reducing side effects in many cancer types. Treatment of GCs increases appetite, decreases weight loss, reduces fatigue, etc.

Answer 63

In 1965, Holland et al suggested the use of combination chemotherapy as the best strategy for cancer chemotherapy. Cancer cells could mutate to become resistant to a single agent, but by using different drugs concurrently it would be more difficult for the tumor to develop resistance to the combination. Requirements for Combination Chemotherapy **1. Each drug should target a different phase in the cell cycle to achieve maximum cell death and reduce resistance. 2. Each drug should have a different mechanism of action within the cancer cell; this will maximize the chance of synergistic effects. 3. Each drug should have activity against the cancer when used alone; a second drug would not be given simply to increase the formation of an active metabolite of the first, although sometimes drugs are given to reduce the development of toxicity or resistance to another drug. 4. Each drug should have a different toxicity; some common toxicity is almost inevitable because nearly all these drugs affect tissues with a high growth fraction.**

Answer 64

most common in young or middle-aged men (15-35 years old). **Average diagnosis is 33 years-old - In fact, testis cancer is the most common malignancy among men 20 to 40 years old (Hopkins)** - About 1 of every 250 males will develop testicular cancer at some point during their lifetime. - Estimated new cases and deaths (Hopkins): New cases: 8,000-10,000, and Deaths: approx. 400/year Combination Chemotherapy Protocols in Testicular Cancer (some examples): **VBP: Vinblastine, Bleomycin, Cisplatin** BEP: Bleomycin, Etoposide, Cisplatin EP: Etoposide and Cisplatin

Answer 65

D) Targeting different phases in the cell cycle and having different mechanisms of action

6,7 - Introduction to Anemias, hemolytic anemias, other anemias, Chemotherapies Flashcards

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