ONCOLOGY: PHARMACOLOGY

ONCOLOGY: PHARMACOLOGY

REVIEW NOTES

·         Mercaptopurine & Xanthine Oxidase:
Acute Lymphoblastic Leukemia case. Treated with 6-mercaptopurine
Which enzymes inactivates/degrades this drug? 
Xanthine Oxidase

[6-MP à HGPRT converts 6-MP to ACTIVE Cytotoxic Metabolites]
[6-MP broken down by XO to INACTIVE metabolites]

[Allopurinol inhibits Xanthine Oxidase so…6-MP gets converted by HGPRT to ACTIVE Cytotoxic Metabolites]

·         5-FU. 5-Fluorouracil:
2 Antineoplastic drugs inhibit Intracellular Thymidylate formation. Drug X is overcome by N-formyl-tetrahydrofolate supplementation, but Drug Y is not affected. What are the drugs?
A: Drugs X = Methotrexate,   Drug Y = Fluorouracil

·         Vincristine:
Diffuse Large B Cell Lymphoma stem. Treated with Drug. Now has Tingling in hands and feet. Drug cases cell cycle arrest at which stage?
A. 1. Vincristine AE
     2. Stops cell cycle at M-Phase – Mitosis/Microtubule formation inhibited

·         Methotrexate and Leucovorin:

Pt. recently on Methotrexate for psoriasis. Overdose…has mouth ulcers, pancytopenia. Best next step management?

A: 1. Methotrexate OD
     2. Folinic Acid [Leucovorin]

[Leucovorin – reduced form of folinic acid doesn’t require action of DHF-Reductase]

·         Chemo-induced-Vomiting:

Drug to treat Chemo-induced vomiting/nausea?

A.      1. Ondansetron, Granisetron, Dolasetron
2. Serotonin 5-HT3-Receptor Antagonist  [Prevents Chemo-Induced Vomiting]

[Location: Presynaptic nerve terminals of Vagus Nerve in GIT.  @Nucleus Solitary in Brain]

·         Chemo-Induced Vomiting:
Elderly F. Has Refractory Nausea and vomiting. Recently diagnosed with Ovarian Cancer. Emetogenic following Chemo. Additional therapy blocking which receptors would likely by helpful in this patient?
A: Listed: Neurokinin 1 [Neurokinin-1 Receptor Antagonists Tx: Chemo-induced vomiting]

[Neurokinin 1 Receptor Antagonists: Prevent Substance P Release…prevents vomiting]

·         Multidrug Resistant Gene   MDR1 gene
Tumor Cells Resistant post-exposure to Anticancer drugs. Cells express surface glycoprotein with which function?
A: 1. MDR1 Gene – P-glycoprotein….
     2. Glycoprotein has ATP-Dependent Transporter [efflux drug out] @GIT or Renal Epithelial  cells = cause Drug Resistance

MDR1 gene codes for P-Glycoprotein [Transmembrane ATP-Efflux pump protein for hydrophobic compounds]…Protein Reduces Drug Influx into cytosol & Increases EFFLUX from cytosol…prevents action of Chemo Drugs.

·         Etoposide:

Testicular cancer sensitive to Etoposide. MoA:

A: Targets Topoisomerase II à Topoisomerase II dysfunction

[Topoisomerase II relieve DNA supercoiling occurs during DNA replication as result of separation and unwinding of double helix…. Etoposide inhibits sealing activity of Topoisomerase II = causes Chromosome Breaks to accumulate in dividing cells…causing cell death]

·         MESNA Tx: Cyclophosphamide induced Hemorrhagic Cystitis

3 day frequent urination, suprapubic pain, dysuria, hematuria. She had Hx. Breast Cancer, a month ago got treated. Urinalysis lots RBC, no leukocyte esterase or bacteria seen. Which could prevent this pt’s current condition?
A: 1. Cyclophosphamide induced Hemorrhagic Cystitis

     2. Prevented with: MESNA

Pt had systemic chemo for breast cancer…now has HEMATURIA & SUPRAPUBIC TENDERNESS = Hemorrhagic Cystitis [DT: Nitrogen MUSTARD chemo: Cyclophosphamide or Ifosfamide its analog]. [Drugs get metabolized by KIDNEYS into ACROLEIN…then excreted to urine. Acrolein =toxic to uroepithelial cells…necrosis.]
Mesna prevents Hemorrhagic Cystitis case.  Mesna binds/inactivates Acrolein

·         Trastuzumab:

Female 3 weeks ago. Invasive Ductal Carcinoma – Biopsy – Estrogen Receptor positive, Progesterone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Positive. Therapy with a Monoclonal Antibody is started. Which is most likely target of this drug?

A: 1. Breast Cancer – HER2 positive
     2. Trastuzumab – targets Tyrosine Kinase Receptor

Trastuzumab: monoclonal antibody used to manage HER2 positive-Breast Cancer. Binds to extracell domain of HER2 and prevents activation of Transmembrane Tyrosine Kinase à Apoptosis

·         Hydroxyurea MoA:

African American female with history of Sickle cell anemia. Dr. adds Hydroxyurea. MoA?

A: Hydroxyurea à Increases Hemoglobin F Synthesis

Hydroxyurea increases Fetal Hb F synthesis unknown mechanism. – for pt in frequent pain crises
more Hb F will protect against polymerization of sickle cells

·         Methotrexate:

Female Ectopic Pregnancy. Given Methotrexate. Which substance likely accumulate in embryonic tissues?
A: Methotrexate à Build up Dihydrofolate Polyglutamate

DOC: Ectopic Pregnancy.  MOA: Inhibits Dihydrofolate Reductase… reduces DHF to tetrahydrofolate THF….. if blocked… DHF acid polyglutamate builds up in treated cells.

·         Rasburicase:
Elderly F, Enlarging painless neck mass. Bilateral cervical lymphadenopathy. Biopsy. Diffuse Large B-Cell Lymphoma. Received Chemo…leads to Rapid Loss of neoplastic cells. Receives Rasburicase. This medication helps to protect normal organs by which mechanism?
A: 1. Tumor Lysis Syndrome – Tumor cell turnover [hyperuricemia]
     2. Rasburicase à Converts Uric Acid into more soluble metabolites

Rasburicase or Allpurinol reduces Uric Acid Levels from tumor cell breakdown.

·         Vincristine AE: à Finger Numbness and tingling

CANCER DRUG Facts

·         Amifostine – Cytoprotective free radical scavenger to decrease nephrotoxicity DT: Ankylating drugs…to decrease dry mouth

·         Dexrazoxane: Chelates Iron. Prevents Antracycline-induced cardiotoxicity

·         Filgrastim: granulocyte CSF analog used to stim. Proliferation and differentiation of granulocytes in pt. with NEUTROPHENIA

·         Mesna: prevents hemorrhagic cystitis dt: Cyclophosphamide or ifosfamide. MESNA binds Acrolein [a toxic metabolited]

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PATHOLOGY

·         Apoptosis:
Caspases à Rapid Cell Death

·         Tumor Cells Detach from surrounding cells by DECREASING expression of adhesion molecules: E-Cadherins. 
Tumor Cells Adhere to Basement Membrane by INCREASING expression of LAMININ
Tumor Cells INVADE the Basement membrane by INCREASING secretion of METALLOPROTEINASES proteolytic enzymes & Cathepsin D Protease.

·         Dysplasia vs. Cancer:
Epithelial lesion. Dysplasia tissue vs. how Differentiate from Carcinoma
A: Reversibility of Changes

·         Anaplasia: Features
1. Unrecognizable tissue architecture.
2. Pleomorph: Vary size & shape of cells

3. Large Nuclei to cytoplasm ratio – deep stain hyperchromic – Clump
4. Lots Mitotic Figures.
5. Giant Cells Multi nucleated tumor cells

[Vs. Keratin Pearls by skin tumor = Dysplasia….can see Keratin means tumor cells is WELL DIFFERENTIATED – TRAP]

 

·         Monoclonality & Cancer:
Consistent with malignancy?
A: Monoclonal T-cell receptor gene rearrangement  TCR-Gene

[Lymphadenopathy – Abnormal architecture & Numerous Lymphocytes]
[Lymphadenopathy: Malignant = Monoclonal – single type of cell]
[Lymphadenopathy: NON-Malignant/Reactive Lymphoid Hyperplasia = POLYCLONAL – benign/reversible/proliferation of MANY Different cell types in LN.]

[Non specific as malignant: Pleomorphism, Abundant Mitotic figures in LN [↑Mitosis] = TRAP!, Nuclear Changes] = these do NOT Indicate Malignancy yet.

·         Bony Metastasis:
Elderly M, Persistent Back Pain for months. BP 145/85. Focal tender 10^th rib L1-L2 Vertebrae. Radionuclide Bone image: Increased Activity in Multiple Vertebrae & Ribs. [Sclerotic Bone Lesions matches bone scans areas of Increased uptake. Highly suspicious of Metastatic Cancer]

Additional finding likely seen in this pt?
A: 1. Prostate Cancer – Elderly Man. [Metastatic Prostate Cancer à bones]
     2. Nodular Prostate and Elevated Prostate-Specific Level  - PSA

·         Metastatic Prostate Cancer:
Elderly, M. 2mo Hx. Back pain-lower. Pain is constant and nagging. Urine Urgency & Frequency. Likely responsible for Back pain?
A: 1. Neoplastic 

[Metastatic Prostate Cancer à Vertebrae, Elderly – Constant Back Pain]

·         Pilocytic Astrocytoma:
12yo Boy. Headaches, Gait Instability, MRI: Medulla mass. Diagnosis?
A: Pilocytic Astrocytomas

[Pilocytic Astrocytomas MC – has Both CYSTIC & SOLID Components.  >> 2^nd MC: Medulloblastomas Always Sollid > Ependymomas]

·         Glioblastoma [Multiforme]:
New onset headache. Diagnosed with. Intracranial Mass. Biopsy pic.
Histo findings most characteristic of this lesion?
A: Necrosis and Vascular Proliferation

[Glioblastoma – MC Brain Tumor Adults]

·         Lung Mass: Hypercortisolism:
Smoker, Lung mass à Excess ACTH Production by lung mass à Cushing case: Bruises, skin darker etc. weight gain.

·         Stain Cytokeratin – Cells Belong to?
A: Epithelial Cells

·         Breast CA:
46yo F. Yellow-red skin rash on chest. Skin reveals brawny INDURATION and PITTING over the right breast. Biopsy shows carcinoma. Likely cause?
A: 1. Peau d’orange
     2. Lymphatic Obstruction

·         Bladder Cancer:
73yo man, blood in urine. No pain with urination, dysuria, or urine frequency. Hematuria, mass in bladder. Prognostic marker?
A: 1. Bladder Cancer
     2. Involvement of the Muscular Layer

[Bladder cancer arise from TRANSITIONAL Epithelium lining the bladder. – Painless GROSS HEMATURIA.  – 90%cases: Neoplastic cells look like those of NORMAL Bladder epithelium = “Urothelial (Transitional Cell) Carcinomas.]
[Tumor Stage – Degree of invasion into Bladder]

·         Liver Microsome – Procarcinogen:
Increased intracellular enzyme activity more susceptible to develop Benzopyrene induced lung cancer. Which enzymes likely Overreactive?
A: Liver Microsomal Monooxygenases [Liver p450 microsomes] converts Pro-cancer chemicals to cancer chemicals

[Procarcinogens chemicals enters liver…get converted to cancer type.]

·         Liver p450 microsomal oxidase:
Rats exposed to high Carbon Tetrachloride gets liver damage. See Fatty change and hepatocyte necrosis. These changes are result of:
A: Free Radical Injury

[Liver P450 microsomal oxidase – for detoxification.]
[CCl4 goes to Liver P450 à free radicals react with Lipids of cell membranes à Cycle of hepatic injury – by lipid degradation & hydrogen peroxide formation = Lipid Peroxidation]

·         Liver Hepatocellular Carcinoma  & HBV:
Man died of Liver disease. – Biopsy see hepatocytes have foreign DNA fragments integrated into their genome. Fragments likely belong to which organisms?
A: Hepatitis B Virus à Hepatocellular Carcinoma

[HBV integrates its DNA into host genome à increases risk for hepatocellular carcinoma]
[vs. Hep C virus = RNA Virus lacks Reverse transcriptase & doesn’t integrate into host genome]

·         Colon Cancer:
Colonoscopy solitary mass in sigmoid colon. If Tumor penetrates into Muscularis Propria = bad prognosis

·         Kaposi Sarcoma – Skin
Skin rash. Had Peumocystic pneumonia and painful oral ulcers 6 months ago. Widespread rash. Like cause of patient’s lesion?
A: 1. Kaposi Sarcoma – [pic+HIV infxn]
     2. Human Herpes Virus type 8

·         TNF-Alpha and Wasting Syndrome:
72yo, M. Progressive weakness, fatigue, anorexia, weight loss 22lb. Streak blood in sputum. 2 weeks ago. Smokes 50 years. Chest Xray: Irregular Right Mass [=Lung cancer]. Which contributes to this patient’s WASTING?
A. Tumor Necrosis Factor – alpha  [Pt has Cachexia]

[TNF-alpha from Macrophage causes necrosis of some tumors. TNF-alpha à Hypothalamus to suppress appetite]

·         Fibronectin:
Carcinoma cells – poor adhesion to extracellular matrix and basement membrane secondary to decreased integrin. Which molecules most important mediating the Adhesion mechanism in these cells?
A: Fibronectin

[Integrin mediated adhesion of cells to basement membrane and extracellular matrix involves binding of Integrins to Fibronectin Collagen Laminin]

·         GF & Angiogenesis:
Liver mass. Angiography shows a well demarcated, Highly vascularized tumor surrounded by normal liver parenchyma. Which Substances likely contributed to Blood Vessel Development?
A: Fibroblast Growth Factor

Angiogenesis = Blood Vessel Formation   KEY GF:   FGF-2 or VEGF!
[FGF-2 à endothelial cell proliferation, migration, differentiations, ANGIOBLAST Production.. Role in Embryo development hematopoiesis, wound repair]
[VEGF Vascular Endothelium Growth Factor: à Angiogenesis in different tissues. It increases endothelium cell motility and proliferation, new capillaries begin to sprout]

·         Keratin Stain – Marker:
Node biopsy stain positive for Keratin. Which is likely origin of cells?
A: Epithelial Surface

[Keratin stains EPITHELIUM]

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ONCOGENES:

·         Proto-Oncogenes & Tumor:
Chronic inhaled formaldehyde….develop Nasal squamous cell carcinomas: Decreased Activity of which genes likely to be found on cytogenetic studies of Tumor cells?
A: p53  [is inactive in many tumors.  If p53 on à Apoptosis]

·         BRCA Mutations & Cancer:
Lump in Breast. Mom died from Ovarian Cancer. Aunt died from Breast Cancer. Most likely inherited gene mutation responsible for which process?
A: 1. BRCA 1, BRCA 2
     2. DNA Repair

[Normal BRCA = Repairs dsDNA breaks]   Other functions: DNA Repair., Cell Differentiation, Checkpoint control cell cycle, Transcription factor regulation]

·         HER2:
Ovarian Cancer, Uterine Cancer. Protein spans cell membrane has Intracellular Tyrosine Kinase. Overexpressed Glycoprotein. Function of this Protein?
A: 1. Her 2/neu encodes Glycoprotein
     2. Accelerates Cell Proliferation

[Has Intracellular Tyrosine Kinase. Member of Epidermal GF-Receptors.  OVEREXPRESSION of this Protein will Increase rates of Breast Cancer, Ovarian Cancer, Endometrial Cancer – ON]

·         Breast Cancer – ERB-B2
Breast Lump. = HER-2 or aka ERB-B2 
[HER Human Epidermal Growth Factor Receptor-2 – OVEREXPRESSED]
[Tx: Trastuzumab = Anti-HER-2 Ab]

·         Retinoblastoma RB protein:
Hyperphosphorylated Retinoblastoma protein most likely perform which functions?
A: Prevention of G1/S cell cycle transition

·         RB protein:
Stimulus applied to a cell increases its activity of several enzymes including dihydrofolate reductase and DNA polymerases. Which immediately proceeds the observed effect?
A: Retinoblastoma Protein Phosphorylation

[Rb-Phosphorylated]

·         Li-Fraumeni Syndrome:
32yo, F. Breast lump. Osteosarcoma – limb amputated at age 17. Mom died of Adrenal tumor. Sister died of Leukemia. Gene mutation likely etiology?
A: TP53 mutated

[TP53 codes for p53.  Li-Fraumeni Sd.:  Sarcomas, Breast CA, Brain Mass, Adrenal cancer, Leukemia]
[NOT BRCA-1 bc NO LINK to sarcomas, Leukemias, brain tumors]

·         Oncogenes – Gain of function:
45yo, F. 2weeks persistent back pain. Excess fatigue, anorexia, wt. loss. Hx family cancer. Lytic Lesions in T10 Vertebrae. High replication potential lesion – biopsy. Single Nucleotide substitution causing Active Mutation. Which genes is most likely involved?
A: KRAS proto-oncogene

·         BCL-2 Gene:
Overexpression of bcl-2 gene which normally inhibits which?
A: Cell Death Cascade

[bcl-2 overexpressed à allows cell to NOT undergo apoptosis = lives forever/neoplastic growth]
[t14:18] = Follicular Lymphoma

For practice test please click the link below:

Oncology Practice Test

For answers and rationale click the link below: 

Oncology Practice Test - Answers and Rationale

For ONCOLOGY: PHARMACOLOGY REVIEW NOTES click the link below:
ONCOLOGY: PHARMACOLOGY