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MEDCHEM 562 > Oncology Midterm #2 > Flashcards

Oncology Midterm #2 Flashcards

1
Q

Oncology Agents

A

Selectivity is incredibly important but the ability to only kill cancer cells is impossible.

Cytotoxic agents: kill cancer cells, first agents developed. Cause necrosis

Cytostatic agents: inhibit the growth of cancer cells. Less toxic. Cause apoptosis

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2
Q

Carcinogenesis

A
  1. Under normal circumstances cells in the human body are under strict control in terms of growth and differentiation, which are stimulated by growth factors.
  2. apoptosis: organized and programmed cell death. Normal cell maintenance in healthy tissue
  3. Hallmark of cancer is uncontrolled growth of abnormal cells which consume nutrients and energy within the host, and the cancer cells lose their ability to perform their normal functions1
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3
Q

Solid vs Liquid

A

solid tumors: cancer cells are located in solid tissues, not as responsive to radiation

liquid tumors: cells in the blood, responsive to radiation

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4
Q

Oncogenes vs Tumor suppressor genes

A

Oncogenes: mutation that occurs in proto-oncogenes, which promote cancer. Regulate the communication between cells and their outside environment

Tumor suppressor genes: mutations occur in these genes these genes normally suppress cancer, and when mutated they lack the ability to “turn off” cancer

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5
Q

Types of mutations

A

inherited germ line mutations, spontaneous point mutations, chromosomal rearrangements or augmentation of gene expression

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6
Q

Chronic myelogenous leukemia (CML) mutation

A

bcr-abl translocation (oncogene), Philadelphia chromosome. Liquid tumor. gene rearrangement, part of chromosome 22 is translocated to chromosome 9 to turn on cell growth. Chromosome 9 gets longer and chromosome 22 gets shorter.

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7
Q

Cell Cycle stages

A

somatic cell division through mitosis

G0: resting phase

G1: initial phase of mitosis; synthesis of enzymes required for DNA synthesis (about 20 hours)

S: DNA synthesis and replication of DNA (about 20 hours)

G2: synthesis of RNA, protein and formation of mitotic spindle for duplication of the cell (2-10 hours)

M: mitosis (1 hour) forming 2 daughter cells that are clones of the mother cell.

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8
Q

Polytherapy

A

Combining drugs that work at different phases of the cell cycle for greater cell kill

Cell cycle specific drugs: anti-cancer drugs that are specific for a certain phase in the cell cylce.

Antimetabolites: damage cells in the S phase

Antimitotics: Damage cells in the M phase

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9
Q

Metastasis

A

process by which cancer cells leave the location of the parent tumor and spread to distant sites.

Bloodstream and lymphatic system are the primary distributors.

Primary tumor must slough off enough cells to allow one to travel to another site.

Liver is common, highly perfused. Same with lung, brain and bone marrow.

Most cancer patients die from the consequences of metastatic lesions rather than the parent tumor.

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10
Q

Circulating tumor cells (CTCs)

A

type of cell that is sloughed from the primary cancer tumor. Measurement is used as a prognostic factor and a diagnostic factor and they are considered biomarkers or surrogate markers.

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11
Q

Chemotherapy as treatment

A

One of the four major forms: surgery, radiotherapy, biological (bone marrow transplantation or stem cell transplantation) and chemotherapy

Cancer cells are not “intelligent” but they are “adaptive”. They survive by clonal selection and they use many mechanisms to survive. This is why we use polytherapy in treatment of cancer. Single agent therapy may be successful in early stage hormone dependent cancers like breast and prostate.

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12
Q

Premedications

A

Minimize the occurrence of side effects and hypersensitivity

H1 antagonist: diphenhydramine

H2 antagonist: ranitidine

Corticosteroids: dexamethasone

Antiemetics for N/V

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13
Q

Drug Resistance

A

Occurs because not all cancer cells in a given tumor are exactly alike.

Clonal selection: the cells most sensitive to the initial drug dies but the resistant cells survive and continue to grow and replicate

Prostate cancer example: Androgen dependent cells and androgen independent cells. With hormone withdrawal kill all of the AD cells but leave the AI cells. Tumor returns containing mainly AI cells.

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14
Q

Clinical trials:

A

Phase 1 focus on PK and dose-limiting toxicities (10-25 subjects).

Phase 2 focus on signs of efficacy (30 patients).

Phase 3 focuses on proof of efficacy and frequency of side effects (100’s or 1000’s subjects).

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15
Q

Response criteria in early phase trials (Phase 1 and 2):

A

Complete response (CR): no sign of cancer 1 month after completion of therapy

Partial response (PR): reduced tumor size of 30% or more

Stable disease (SD): tumor size has not increased more than 20% and decreased less than 30%

Progression (P): tumor has grown by more than 20% and/or formation of new lesions

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16
Q

Response criteria for final stage trials (phase 3)

A

Overall survival (OS): how much longer do patients survive on average. gold standard.

Progression free survival (PFS): how much longer patients survive without progression (worsening) of disease.

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17
Q

Personnel:

A

surgical oncologists, radiation oncologists, hematologic oncologists (largely liquid tumor), medical oncologists (largely solid tumor), oncology pharmacists, oncology nurses, oncology histopathologists and geneticists. Oncology pharmacists should pay attention to drug interactions and combined toxicities.

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18
Q

Incidence

A

Use American Cancer Society for incidence and mortality

Most common: breast cancer, colorectal cancer, lung cancer and prostate cancer

Most lethal cancers: esophageal, glioblastoma (type of brain cancer), liver and bile duct and pancreatic. Also very rare cancers have high mortality because it is hard to conduct clinical trials for new treatment.

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19
Q

Hematopoeisis

A

the process by the blood cell components are produced in the body.

Different cell types are produced down different paths and can be stimulated or inhibited differently

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20
Q

Amount of cell types in body

A

Humans normally have approximately 5 million RBCs, 150,000-400,000 platelets and 4,000-11,000 WBC (which are subdivided into different populations). Low numbers of WBC make them vulnerable to depletion and they are necessary to prevent infection.

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21
Q

Formation of hematopoetic cells

A

Hemocytoblast forms all the different blood cell types. Leukocytes are white and include granulocytes and agranulocytes. Erythrocytes are red. Thrombocytes are platelets.

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22
Q

RBCs (erythrocytes)

A

Primary function is oxygen transport, Very rich in the oxygen carrier hemoglobin

Production can be stimulated by low oxygen content in blood which is detected in the kidneys. The kidney stimulates secretion of erythropoietin (Epo) which increases RBC production

Life-span is 120 days

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23
Q

WBC (leukocytes)

A

Primary function is to fight infection, and there are many subtypes

life-span is hours to several days or a weeks

Granulocytes and Agranulocytes

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24
Q

Granulocytes:

A

have the appearance of granules in their cytoplasm.

Granules are packets of digestive enzymes. Three subtypes:

  1. Neutrophils: target bacteria and fungi and destroy these pathogens by phagocytosis
  2. Eosinophils: target parasites and involved in allergic inflammatory responses
  3. basophils: store histamine for release during inflammation response. Hives, anaphylaxis
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25
Q

Agranulocytes:

A

appear not to have granules. Three subtypes:

  1. Lymphocytes: large subset of cell types that includes B cells, T cells and NK cells. More abundant in the lymphatic fluids than in blood.
  2. Monocytes: similar role to neutrophils and capable of phagocytosis but can also present pieces of pathogens to T cells
  3. Macrophages: monocytes that are in the tissue.
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26
Q

Lymphocyte T cells

A

A. Four types of T cells, just know that the T cell can recognize cancer cells through MHC and attack the cancer cells.

B. However, cancer cells over time have adapted a B7 protein to recognize T cells and inactivate the T cells (cancer cell survives). Interacts with CTLA4 on T cell
PD-L1 protein on the cancer cell can also interact with the T cell and inactivate the T-cell through PD-1 receptor on T cell.

C. Recent development of antibodies to prevent inactivation of the T cell by the cancer therapy. Called immunotherapy.

D. Ipilumumab: Yervoy. anti-CTLA4 mAb that prevents interaction of B7 with CTLA4. Approved for metastatic melanoma

E. Pembrolizumab: Keytruda. anti-PD1 mAb that prevents interaction of PD-L1 with PD-1.

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27
Q

Platelets:

A

very important in clot formation. Average life span 8-9 days. Not as big of a concern.

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28
Q

Neutropenia:

A

low levels of neutrophils

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29
Q

Leukopenia:

A

low level of leukocytes

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30
Q

Thrombocytopenia:

A

low levels of platelets. Not as big of a concern in therapy.

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31
Q

Anemia:

A

the condition of abnormally low functional hemoglobin. Usually has a low red blood cell count.

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32
Q

Polycythemia:

A

condition of abnormally high RBC which can occur with overdose of erythropoietin

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33
Q

DNA cross-linkers and alkylating agents

A

General mechanism: DNA is electron rich and these agents are electron poor, causing the interaction.

These agents are non-cell cycle specific

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34
Q

Platinum Agents

A

Cisplatin, carboplatin, oxaliplatin

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35
Q

Cisplatin: uses

A

lung cancer, testicular cancer, ovarian cancer, bladder cancer. IV only

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36
Q

Cisplatin: Dose

A

20-100 mg/m2 but dependent on disease and renal function. Hydration before and after therapy.

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37
Q

Cisplatin: MOA

A

reacts with DNA bases, especially nitrogen 7 of guanine. Cis geometry is essential for activity

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38
Q

Cisplatin Structure

A
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39
Q

Cisplatin: Toxicity

A

quite toxic. Includes nephrotoxicity, ototoxicity, myelosuppression (loss of WBC and usually neutrophils), severe N/V. Sodium thiosulfate can be administered to reduce nephrotoxicity. Amifostine can be used to reduce ototoxicity.

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40
Q

Cisplatin: ADME

A

High renal excretion predisposes to renal toxicity, this can impact other drugs that are excreted by the kidneys. Plasma half life less than 30 minutes.

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41
Q

Cisplatin: Distribution

A

Distribution: Outside cells with high chloride concentration cisplatin remains intact, and neutral and can penetrate cells. Once inside cells the chloride concentration drops and water molecules replace chloride atoms and this aquated form is charged and locked inside the cell.

Diluent: must be saline to prevent “aquation” reaction.

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42
Q

Carboplatin Structure and Class

A

Platinum. Paraplatin

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43
Q

Carboplatin: Uses

A

mainly for ovarian cancer (often with cyclophosphamide), also used in prostate cancer (with docetaxol) and lung cancer (with paclitaxel).

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44
Q

Carboplatin: MOA

A

Similar to cisplatin but chemically more stable and less active, also less toxic.

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45
Q

Carboplatin: Toxicity

A

Less toxic than cisplatin. Myelosuppression, nephrotoxicity, ototoxicity, N/V.

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46
Q

Carboplatin: ADME

A

Main route of excretion is renal. Longer half-life than cisplatin, 3 hours. For patients with renal impairment dosing is guided by creatinine clearance

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47
Q

Carboplatin: Dilution

A

Can be diluted with D5W or NS. So less reactive than cisplatin.

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48
Q

Oxaliplatin Class and Structure

A

Eloxatin. Platinum Agent

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49
Q

Oxaliplatin: Uses

A

mainly colorectal cancer.

FOLFOX regimen: folinic acid/fluorouracil/oxaliplatin

FOLFIRINOX regimen: folinic acid/fluorouracil/irinotecan/oxaliplatin. effective but highly toxic. More agents you combine the more risk for toxicity. Used in pancreatic cancer.

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50
Q

Oxaliplatin: MOA

A

Similar to cisplatin and carboplatin. More lipophilic so more penetration into tissues. The need for pre-hydration and evaluating renal function is less critical.

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51
Q

Oxaliplatin: toxicities

A

peripheral neuropathy (occurs in cisplatin and carbo as well but not the major toxicity). Unknown mechanism for peripheral neuropathy. Myelosuppression.

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52
Q

Oxaliplatin: ADME

A

Elimination largely renal. Longer half-life than cisplatin and carboplatin.

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53
Q

Oxaliplatin: Dilution

A

dilution of oxaliplatin should not include saline (chloride ions) or agents that make the solution alkaline. Chloride addition produces dichloro form which is more active and much more toxic

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54
Q

Pipeline Platinums

A

Picoplatin and Satraplatin have been studied but have failed in recent clinical trials. Very active but too toxic, compared to the agents on the market

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55
Q

Busulfan Structure and Class

A

Busulfex or Myleran. Methyl Sulfates.

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56
Q

Busulfan uses

A

mainly IV for myeloablation prior to bone marrow or stem cell transplantation for CML. Has been used in combination with cyclophosphamide (BuCy regimen). IV or PO. PO used for palliative treatment of CML.

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57
Q

Busulfan MOA

A

bifunctional and direct alkylator of DNA.

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58
Q

Busulfan: Toxicities

A

extreme myelosuppression, hepatotoxicity

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59
Q

Busulfan: ADME

A

lipophilic and can penetrate the CNS. PK monitoring of busulfan level is common and is the best way to deliver the most precise dose to the patient, in order to avoid seizures.

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60
Q

Treosulfan: structure, class

A

Methyl sulfates. approved in Europe but not the US

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61
Q

Treosulfan: Uses

A

historically for ovarian cancer but now being studied for myeloablatiion prior to allogenic stem cell transplantation, in place of busulfan. Potentially has no need to do PK monitoring.

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62
Q

Treosulfan: Toxicity

A

more polar than busulfan so less seizures due to lower CNS penetration. Similar toxicities otherwise.

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63
Q

Treosulfan: MOA

A

Alkylator that forms epoxides intramolecularly prior to reacting with DNA. Is also a more potent immunosuppressant than busulfan so it has the potential for replacing busulfan in allogeneic transplants.

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64
Q

Treosulfan: ADME

A

More polar than busulfan so less penetration into CNS.

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65
Q

Thio-triethylenephosphoramide

A

Thiotepa. methyl sulfate

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66
Q

Thio-triethylenephophoramide: uses

A

breast cancer, ovarian cancer, myeloablative agent prior to allogeneic and autologous stem cell transplantation. IV. Used for bladder cancer but administration is intravesical (directly into the bladder)

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67
Q

Thio-triethylenephophoramide: Mechanism

A

direct alkylator of DNA but more active following conversion to Tepa, the FMO enzyme is responsible for this conversion. Parent drug and metabolite are active, therefore not a prodrug. Tepa contains a double bonded oxygen instead of sulfur. Sites of DNA binding are any of the three-membered ring carbons.

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68
Q

Thio-triethylenephosphoramide: Toxicity

A

When given IV, severe myelosuppression, infections and N/V

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69
Q

Thio-triethylenephosphoramide: ADME

A

elimination half life is 2 hours and Tepa is nearly 20 hours. Both can penetrate the CNS and cause dizziness, headaches, etc. Most excretion is renal

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70
Q

Thio-triethylenephosphoramide: Dose

A

administered as initial dose followed by maintenance doses every 1-4 weeks. Delayed or slow response does not necessarily indicate a lack of effect. Increasing frequency of dosing causes increases toxicity.

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71
Q

Dacarbazine

A

DTIC. methyl sulfate

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72
Q

Dacarbazine: Uses

A

Hodgkin’s lymphoma as part of ABVD regimen (adriamycin/bleomycin/vinblastine/dacarbazine). Also used for melanoma. IV only

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73
Q

Dacarbazine: Mechanism

A

prodrug following N-dealkylation by cytochrome P450, the molecule tautomerizes to the more reactive form which reacts with DNA, specifically the O-6 position on guanine. DNA attacks on the methyl group outside the two nitrogens. See mechanism.

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74
Q

Dacarbazine: Toxicities

A

Myelosuppression, hepatotoxicity (severe and may cause death), N/V

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75
Q

Dacarbazine: ADME

A

metabolized by liver CYP1A2, but nearly half the drug excreted unchanged

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76
Q

Other methyl sulfates

A

procarbazine and Temozolomide

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77
Q

Mechlorethamine

A

Nitrogen Mustard/alkylating agents. Mustargen.

Very old agent, initially was a chemical warfare agent

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78
Q

Mechlorethamine: uses

A

formerly for various leukemias but used less today because of better agents. Palliative treatment for late stage Hodgkin’s lymphoma.

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79
Q

Mechlorethamine: Mechanisms

A

Binds to DNA after formation of reactive aziridine ring which is very electrophilic and is a 3 membered ring. Bifunctional activity because both ethyl chlorides are reactive and can bind DNA.

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80
Q

Mechlorethamine: toxicities

A

highly toxic, myelosuppression, severe N/V, severe vesicant (hits skin or lungs and causes severe blistering) and local toxicity if extravasation occurs (leakage of solution around vein), hepatotoxic, rare secondary cases of hemolytic anemia or leukemia many years later

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81
Q

Mechlorethamine: ADME

A

So reactive that it reacts with water and biomolecules very quickly after administration

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82
Q

Chlorambucil

A

Leukeran. Alkylating agents/Nitrogen Mustards.

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83
Q

Chlorambucil: Uses

A

chronic lymphocytic leukemia (CLL), lymphosarcoma, Hodgkin’s lymphoma. Administered PO

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84
Q

Chlorambucil: Mechanism

A

Active intact but less active than mechlorethamine. The electrons on the aromatic nitrogen are not as basic and the formation of the aziridinium ion is slower. Must be activated by N-dealkylation to form the aziridine ion.

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85
Q

Chlorambucil: Toxicities

A

Myelosuppression, hepatotoxicity (patients with impaired liver function should be closely monitored). Several CNS toxicities including seizures, tremors, hallucinations because the drug is non-polar (lipophilic) and can enter the CNS

86
Q

Chlorambucil: ADME

A

Beta oxidation (chain shortening) important form of metabolism, and the metabolite retains anti-tumor activity

87
Q

Melphalen

A

Alkeran. Alkylating agents/nitrogen mustards

88
Q

Melphalen: Uses

A

Multiple myeloma. Palliative treatment for non-resectable ovarian cancer. IV or PO

89
Q

Melphalen: Mechanism

A

active intact but less active relative to mechlorethamine. The electrons on the aromatic nitrogen are not as basic and the formation of the aziridinium ion is slower. Higher polarity due to the Nitrogen group on the right is charged (designed to hopefully improve uptake through amino acid recognition but that didn’t work). Need N-dealkylation before able to form the aziridinium ion.

90
Q

Melphalen: Toxicities

A

Myelosuppression, hepatotoxicity and less severe N/V. Rarely see pulmonary fibrosis and interstitial pneumonitis. CNS toxicities are rare because the drug is polar and does not enter the brain well.

91
Q

Cyclophosphamide

A

Cytoxan. Alkylating agents/nitrogen mustard.

92
Q

Cyclophosphamide: Uses

A

lymphomas, leukemias, multiple myeloma, breast cancer, myeloablation prior to transplantation. Administered IV and PO occasionally.

93
Q

Cyclophosphamide: Mechanism

A

phosphorous withdrawals electrons from N even stronger than chlorambucil. Prodrug, activated by P450 dealkylation to hydroxylate. The hydroxy group collapses forming the aldehyde which tautomerizes to eliminate acrolein and a phosphoramide mustard which is capable of forming an aziridine and reacting with DNA.

94
Q

Cyclophosphamide: Toxicities

A

myelosuppression, hemorrhagic cystitis (bladder toxicity due to acrolein). CNS toxicities

Patients should be well hydrated to protect against bladder toxicity. MesNA can also be used because it concentrates in the urine, binds to and inactivates the acrolein.

95
Q

Ifosfamide

A

Ifex. Alkylating agent/nitrogen mustard.

96
Q

Ifosfamide: Uses

A

Mainly testicular cancer. IV

97
Q

Ifosfamide: Mechanism

A

Prodrug with same bioactivation mechanism as cyclophosphamide
Toxicities: myelosuprression, nephrotoxicity, hemorrhagic cystitis (bladder toxicity), CNS toxicities. Need to well hydrate prior to administration due to metabolite. Enhanced CNS toxicity can induce a coma and even death

98
Q

Ifosfamide: ADME

A

similar to cyclophosphamide but CYP metabolism is slower so higher doses are needed. Dose-dependent PK, renal excretion.

99
Q

Ifosfamide: Minimizing Toxicity

A

Hydration and MesNA prior to therapy to reduce bladder toxicity. The sulfur agent N-acetylcystein (NAC) may provide protection from nephrotoxicity. There is no agent for protection against CNS toxicity

100
Q

Lomustine

A

CeeNU. Alkylating agents, nitrosoureas.

101
Q

Lomustine: Use

A

Brain cancer (glioblastoma), Hodgkin’s lymphoma. Administered PO

102
Q

Lomustine: Mechanism

A

Prodrug that ultimately forms a diazonium ion that reacts with DNA. Also reacts with proteins and RNA. Might have some G1 or S phase specificity.

103
Q

Lomustine: toxicities

A

Myelosuppression, hepatotoxicity, pulmonary toxicity, seizures. Leukemias and myelodysplasias have occurred years later.

104
Q

Lomustine: ADME

A

Non-polar (lipophilic) drug that can enter the CNS. This explains its efficacy and CNS toxicities. Levels in CSF can reach 50 times the levels in the blood.

105
Q

Carmustine

A

BiCNU or BCNU. Alkylating Agents/Nitrosourea

106
Q

Carmustine: Uses

A

brain cancer (glioblastoma), multiple myeloma, NHL. Administered IV

107
Q

Carmustine: Mechanism

A

Similar to lomustine, but can lead to additional electrophiles.

108
Q

Carmustine: Toxicities

A

Similar to lomustine; myelosuppression, hepatic toxicity, acute pulmonary toxicities (pulmonary fibrosis), seizures. Leukemias and myelodysplasias have occurred years later.

109
Q

Carmustine: ADME

A

Very unstable and degrades quickly when added to aqueous solution. Like lomustine, it is a non-polar (lipophilic) drug that can enter the CNS. This explains its efficacy and CNS toxicities. Levels in CSF can reach 50 times the levels in the blood.

110
Q

Bendamustine

A

Treanda. Fake nitrosourea but is an alkylating agent

111
Q

Bendamustine: Uses

A

CLL, NHL. IV. Being studied for the treatment of rare sarcomas.

112
Q

Bendamustine: Mechanism

A

Not actually a nitrosourea, instead is an alkylating of the nitrogen mustard type. It causes inter- and intra- strand crosslinks with DNA bases.

113
Q

Bendamustine: Toxicities

A

Nausea, fatigue, vomiting, diarrhea, constipation, fever, loss of appetite, unintentional weight loss, headache, difficulty breathing, rashes. Immunosuppression is common. Low incidence of alopecia.

114
Q

Bendamustine: ADME

A

metabolized by CYP450 and excreted renal.

115
Q

Streptozocin

A

Zanosar. alkylating agent/nitrosourea

116
Q

Streptozocin: uses

A

Pancreatic cancer. IV

117
Q

Steptozocin: Mechanism

A

prodrug that ultimately forms a diazonium ion. Sugar moiety (glucopyranose) helps to target to pancreatic cell, and makes the drug more polar to offset CNS toxicities.

118
Q

Streptozocin: Toxicities

A

N/V, renal toxicity rarely associated with diabetes insipidus, mild myelosuppression

119
Q

Streptozocin: ADME

A

substantial excretion by the kidneys.

120
Q

Streptomocin: CNS

A

drug is non-polar and does not penetrate CNS very well.

121
Q

Antimetabolites: general concept

A

Cell Cycle Specific for S-phase
Antimetabolites mimic endogenous molecules and in many cases target enzymes are irreversibly inhibited.

122
Q

Methotrexate

A

Trexall : folate analog of the antimetabolites.

123
Q

Methotrexate: uses

A

metastatic breast cancer, epidermoid head and neck cancer, lung cancer (squamous cell), pancreatic cancer and in combination with other agents for late stage non-Hodgkin’s lymphoma. IV, IM, PO

124
Q

Methotrexate: Mechanism

A

mimics the vitamin folic acid and therefore inhibits the enzyme dihydrofolate reductase (DHFR). Binding to and inhibiting DHFR prevents reduction of folate to Methenyl tetrahydroflorate which is a two carbon donor to TS. Two structural changes between methotrexate and folic acid: methyl group on the amine and an NH3 group instead of double bonded oxygen.

125
Q

Methotrexate: Toxicities

A

myelosuppression, hepatotoxicity, nephrotoxicity. Lipophilic molecule and some penetration into CNS with consequent toxicities

126
Q

Methotrexate: ADME

A

Actively taken into cells by the reduced folate carrier (RFC1). Once inside cells the molecule is polyglutamated by FPGS which adds negative charges to trap the molecule inside the cell. Polyglutamates are removed prior to excretion by the kidneys.

127
Q

Methotrexate: Overdose

A

Intentional high doses can be corrected by administration of leucovorin and is called a “leucovorin rescue”. In the body leucovorin is easily converted to methenyl tetrahydrofolate thus eliminating the need for the folate cycle completely.

128
Q

Methotrexate: Other uses

A

RA and psoriasis

129
Q

Pemetrexed

A

: Alimta. Antimetabolite, folate analog

130
Q

Pemetrexed: Uses

A

non-small cell lung cancer (non-squamous) in combination with cisplatin or gemcitabine. Also used for mesothelioma in combination with cisplatin. IV

131
Q

Pemetrexed: Mechanism

A

Similar to methotrexate but inhibits folate cycle at 3 steps including DHFR, TS and GARFT.

132
Q

Pemetrexed: Toxicities

A

myelosuppression, liver toxicity, renal toxicity, less CNS penetration compared to methotrexate.

133
Q

Pemetrexed: ADME

A

uptake and polyglutamation similar to methotrexate but the enzyme but is an even better substrate for polyglutamation by FPGS and thus is trapped in target cells better than methotrexate.

134
Q

Pralatrexate

A

Folotyn. Newer folate analog being studied for use in peripheral T-cell lymphoma. It appears to have superior tumor uptake and efficacy, but further trials are necessary

135
Q

5-FU

A

Pyrimidine Analog, antimetabolite

136
Q

5-FU: uses

A

metastatic breast cancer, colorectal cancer in FOLFOX (folinic acid/5-FU/oxaliplatin) and FOLFIRI regimen (folinic acid/5-FU/irinotecan). Folinic acid serves to potentiate the activity of 5-FU by stimulating the turnover of TS which is the target enzyme of 5-FU.

137
Q

5-FU: Mechanism

A

prodrug and mimic of uracil that is initially converted to ribosyl form and then specifically inhibits thymidylate synthestase (TS). Normal mechanism is that dUMP interacts with methylene tetrahydrofolate through TS to form thymidine and dihydrofolate. With F-dUMP binding to TS is halted because the flourine atom is a poor leaving group, this leads to no production of thymidine and irreversible inactivation of TS

138
Q

5-FU: Toxicities

A

myelosuppression, mucositis, diarrhea.

139
Q

5-FU: ADME

A

elimination from plasma is about 10-15 minutes and about 20% of the dose is excreted unchanged in the urine.

140
Q

5-FU: Polymorphic

A

a route of catabolic metabolism is by dihydropyrimidine dehydrogenase (DPD). Deficiency in the activity of this enzyme can lead to elevated levels of 5-FU and consequent toxicities. Female African Americans are more likely to be deficient. There is a genetic test available for determining DPD status of a patient.

141
Q

Floxuridine

A

pyrimidine agent like 5-FU but the ribose sugar is already attached. One step away from 5-F-dUMP. Used for liver metastasis from GI cancers. Given slowly as intra-arterial infusion to limit toxicity, conversion to 5-FU and circumvent DPD issues.

142
Q

Capecitabine

A

Xeloda. Pyrimidine Analogs, antimetabolites

143
Q

Capecitabine: uses

A

metastatic breast cancer, colorectal cancer, pancreatic cancer, gastric cancer. PO

144
Q

Capecitabine: Mechanism

A

prodrug of 5-FU, mimic of uracil that specifically inhibits TS. Breakdown to 5-FU exploits the fact that critical enzymes are preferentially located in tumors.

145
Q

Capecitabine: toxicities

A

similar to 5-FU and hand-foot syndrome because the drug has increased levels in the skin of hands and feet.

146
Q

Capecitabine: ADME

A

Can inhibit CYP2C9 and clinically relevant interaction can occur with warfarin and phenytoin.

147
Q

Cytarabine

A

AraC. Antimetabolite/pyrimidine analog

148
Q

Cytarabine: Uses

A

various leukemias: acute lymphocytic leukemia (ALL), non-lymphocytic leukemia, chronic myelocytic leukemia (CML), meningeal leukemia. IV or IT for meningeal leukemia

149
Q

Cytarabine: Mechanism

A

Inhibitor of DNA polymerase. Sugar moiety is arabinose and can be inserted properly into DNA but cannot by reduced to the deoxy form by ribonucleotide reductase preventing DNA elongation. Fools body into thinking it is cytosine.

150
Q

Cytarabine: Toxicities

A

Myelosuppression, mucositis, AraC syndrome (fever, myalgia, bone pain)

151
Q

Cytarabine: ADME

A

excreted in urine.

152
Q

Gemcitabine

A

Gemzar. Antimetabolites/pyrimidine analogs

153
Q

Gemcitabine: uses

A

pancreatic, NSCLC with cisplatin, breast cancer with paclitaxel, ovarian with carboplatin. Synergistic effects with other agents.

154
Q

Gemcitabine: mechanism

A

Difluorinated sugar similar to cytosine. Dual mechanism: inhibits ribonucletide reductase the enzyme that converts ribonucletides into deoxy-ribonucleotides and the second mechanism is that the triphosphate form (dGTp) competes with dCTP for incorporation into DNA.

155
Q

Gemcitabine: Toxicity

A

myelosuppression, paresthesias (numbness and tingling) and severe rash

156
Q

Gemcitabine: ADME

A

Elimination is renal and both gender and age dependent. Elimination decreases with age and if you are female.

157
Q

6-Mercaptopurine

A

: Purinethol. Antimetabolite, purine analog

158
Q

6-mercaptopurine

A

ALL and acute myelogenous leukemia. PO

159
Q

6-mercaptopurine: Mechanism

A

mimic of hypoxanthine, the precursor of adenine and guanine and therefore inhibits de novo purine synthesis. Specifically competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribiosyltransferase (HGPRTase)

160
Q

6-mercaptopurine: toxicities

A

Myelosuppression, hyperuricemia (can be reduced with hydration, alkanalization and xanthine oxidase inhibitors like allopurinol), hepatotoxitiy

161
Q

6-mercaptopurine: ADME

A

patients with low TPMT activity are at increased risk for severe toxicity. Genotypic and phenotypic tests are available.

162
Q

Thioguanine

A

Tabloid. Antimetabolite, purine analog

163
Q

Thioguanine: Uses

A

Acute non-lymphocytic leukemia. PO

164
Q

Thioguanine: Mechanism

A

competes with hypoxanthine and guanine for HGPRTase. Essentially competes for the synthesis of guanine nucleotides.

165
Q

Thioguanine: Toxicities

A

myelosuppression, N/V, hepatotoxicity

166
Q

Thioguanine: ADME

A

Rapid. Same TPMT issue as with mercaptopurine and cross-resistance is high in cancer cells between mercaptopurine and thioguanine.

167
Q

Fludarabine

A

Fludara. Antimetabolite, purine analog

168
Q

Fludarabine: Uses

A

Chronic lymphocytic leukemia (CLL). IV or PO

169
Q

Fludarabine: Mechanism

A

Both the base and the sugar are chemically modified relative to normal adenosine. Base is fluorinated and the sugar is an arabinose. The triphosphorylated form of the drug inhibits DNA polymerase, DNA primase and ribonucleotide reductase. Phosphate group is cleaved before entering cell and then once inside the cell is added back on.

170
Q

Fludarabine: Toxicities

A

myelosuppression, hemolytic anemia, CNS toxicities at high dose

171
Q

Fludarabine: ADME

A

high renal excretions so use in caution in patients with renal impairment

172
Q

Cladribine and Clofaribine

A

both are purine analogs used in leukemias. Cladribine along with myelosuppression can cause hemolytic anemia and CNS toxicities.

Clofaribine can cause tumor lysis syndrome (TLS) due to the rapid death of leukemia cells. This can lead to respiratory and cardio toxicity due to the rapid release of cytokines.

173
Q

Topoisomerase

A

Topo I and II are very important in the process of DNA replication. Only two Topo I agents have been approved (irinotecan and topotecan)

174
Q

Irinotecan

A

Camptothecins: Topo I Inhibitors - Cell cycle specific (S and G2)

175
Q

Irinotecan: use

A

colorectal cancer as a component to FOLFIRI (folinic acid/5-FU/ininotecan) also in FOLFIRINOX for pancreatic cancer.

176
Q

Irinotecan: Mechanism

A

prodrug of SN-38. Enzymatic hydrolysis by esterase enzymes convert it into SN-38, which is the molecule that binds reversibly in the ternary complex that includes DNA and Topo 1. More of the esterase enzymes are present in tumor tissues than plasma and liver

177
Q

Irinotecan: toxicities

A

myelosuppression, severe and unpredictable diarrhea with neutropenia which can lead to sepsis and death

178
Q

Irinotecan: ADME

A

Polymorphism in the elimination of SN-38 which is glucuronidated by UGT1A1. 7/7 polymorphisms express low levels of enzyme and have higher AUC compared to 6/6 genotypes. Commercial genetic assays exist for the UGT1A1 status

179
Q

Topotecan

A

: Hycamtin Camptothecins: Topo I Inhibitors - Cell cycle specific (S and G2)

180
Q

Topotecan: uses

A

SCLC and ovarian cancer. IV and PO

181
Q

Topotecan: mechanism

A

not a prodrug and does not require activation. Binds directly to Topo I enzyme. Is NOT extensively glucuronidated like SN-38 and is therefore no complicating factor of UGT1A1.

182
Q

Topotecan: toxicites

A

myelosuppression, thrombocytopenia, diarrhea, N/V, leukocytes.

183
Q

Topotecan: ADME

A

closed lactone ring has to undergo hydrolysis to the open carboxylate form which is inactive. Co-administration of oral cyclosporine A can increase the AUC over 2 fold.

184
Q

Doxorubicin

A

: Adriamycin. Anthracyclines: No cell cycle specific but S phase sensitive

185
Q

Doxorubicin: uses

A

acute lympoblastic leukemia (ALL), acute myelogenous leukemia (AML), soft tissue and bone sarcomas, Wilm’s tumor, neuroblastoma. Also for breast, ovarian, bladder, thyroid, gastric cancers and Hodgkin’s lymphoma. IV

186
Q

Doxorubicin: mechanism

A

intercalates into DNA and inhibits Topo II. Can also generate reactive oxygen species which contributes to its efficacy but also cardiotoxicity

187
Q

Doxorubicin: Toxicity

A

myelosuppression, cardiotoxicity (CHF), N/V, alopecia, peripheral neuropathy

188
Q

Doxorubicin: ADME

A

quick distribution, half life 30-40 hours

189
Q

Doxorubicin: preventing cardiotoxicity

A

dexrazoxane can be used to minimize cardiotoxicity

190
Q

Doxil

A

pegylated liposomal form of doxorubicin. Extravasation and cardiotoxicity are less than doxorubicin but it can cause palmar-plantar erythrodyesesthesia (hand-foot syndrome) due to a change in drug distribution.

191
Q

Daunorubicin

A

: Cerubidine. Anthracyclines: No cell cycle specific but S phase sensitive

192
Q

Danunorubicin; uses

A

remission induction for acute non-lymphocytic leukemia and acute lymphocytic leukemia. IV only

193
Q

Daunorubicin: Mechanism

A

intercalates into DNA to inhibit Topo II. Can also generate reactive oxygen species.

194
Q

Daunorubicin: toxicitie

A

similar to doxorubicin. myelosuppression, cardiotoxicity, N/V, alopecia, peripheral neuropathy

195
Q

DaunoXome

A

: liposomal formulation that is less toxic and is used mainly for Kaposi’s sarcoma associated with HIV

196
Q

Idarubicin

A

: Idamycin. Anthracyclines: No cell cycle specific but S phase sensitive

197
Q

Idarubicin: use

A

AML, metastatic breast cancer. IV

198
Q

Idarubicin: mechanism

A

Intercalates into DNA and inhibits Topo II. Can also generate reactive oxygen species

199
Q

Idarubicin: toxicity

A

myelosuppression, cardiotoxicity, N/V, alopecia, peripheral neuropathy

200
Q

Idarubicin: ADME

A

quick distribution, half life 22 hours. Metabolites remain active and can contribute to cardiotoxicity

201
Q

Etoposide

A

: VP-16. Podophyllotoxins

202
Q

Etoposide: uses

A

SCLC, sarcomas (Kaposi’s and Ewing’s), testicular cancer, lymphomas, non-lymphocytic leukemia, glioblastoma multiforme (brain cancer). IV or PO

203
Q

Etoposide: mechanism

A

binds to topo II, but does not possess a quinone moiety and therefore does not generate reactive oxygen species or cardiotoxicity.

204
Q

Etoposide: toxicity

A

myelosuppression, N/V, alopecia, serious hypotension if given IV too quickly. Hydration is important to prevent renal and bladder toxicity. Caution with cisplatin

205
Q

Etoposide: ADME

A

elimination through kidneys and bladder

206
Q

Teniposide

A

: VM-26. Podophyllotoxins

207
Q

Teniposide: use

A

Childhood acute lymphoblastic leukemia. IV

208
Q

Teniposide: mechanism

A

similar to etoposide, binds to topo II but does not possess a quinone moiety and therefore does not generate reactive oxygen species or cardiotoxicity

209
Q

Teniposide: toxicity

A

myelosuppression, mucositis, hypersensitivity, N/V, alopecia, potential hypotension if given IV too quickly.

210
Q

Teniposide: ADME

A

less polar than etoposide and there is less renal secretion.

MEDCHEM 562 (4 decks)

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