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Flashcards in GI: Cancer Therapy Drugs Deck (49)
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1

Alkylating Agents?

  • Melphalan
  • Chlorambucil
  • Cyclophosphamide
  • Lomustine
  • Carmustine
  • Cisplatin
  • Oxaliplatin
  • Carboplatin
  • Procarbazine

2

Nitrogen Mustard Alkylators?

Nitrogen Mustard Alkylators?

  • Melphalan
  • Chlorambucil
  • Cyclophosphamide

3

Melphalan

Chlorambucil

Cyclophosphamide

Nitrogen Mustard Alkylators

  • Cause Alkylation of DNA at the N-7 position of Guanine
    --> Misreading
    of DNA during Replication
    --> Lethal errors
    (depurination and strand breaks)
  • Hepatotoxicity
  • Immunosuppression
  • Alopecia
  • Carcinogenesis

4

What is special about

Cyclophosphamide?

Nitrogen Mustard Aklylator - Cyclophosphamide

  • Consolidation Therapy (Step 2)
    • Active Form + --> Guanine N7
    • Acrolein (toxic) form --> 'Hemorrhagic Cystitis'
      --> Mensa
       (Traps Acrolein)
  • No Hepatotoxicity
  • Requires activation by CYP450 w/in Liver
  • Tx: Non-Hodgkin, Ovarian, Breast cancer, Neuroblastoma, Solid tumors, Leukemia, Lymphomas
  • Side effects: Hemorrhagic cystitis (Mesna - protects Bladder, traps Acrolein and is protective)

5

Nitrosourea Alkylators?

Nitrosourea Alkylators?

"-mustine"

  • Lomustine
  • Carmustine

6

Lomustine

Carmustine

Nitrosourea Alkylators

  • Carmustine --> CNS
  • Lipid Soluble --> able to cross the BBB
  • Alkylation of DNA
  • DNA crosslinking and Carbomoylation of Proteins
  • Tx: Brain tumors
  • Toxic: CNS toxicity (Dizziness, Ataxia)
  • Delayed Severe Immunosuppression

7

Platinum Alkylators?

Platinum Alkylators?

"-platin"

  • Cisplatin
  • Oxaliplatin
  • Carboplatin

8

Cisplatin

Oxaliplatin

Carboplatin

Platinum Alkylators

  • Causes DNA crosslinks
  • Testicular, Ovary, Bladder, and Lung Cancer
  • Cisplatin causes Nausea and Vomiting (use Ondansetron)
  • Toxic:
    • Nephrotoxicity
      • Heavy metals are bad for Kidneys
      • Use Amifostine (protects Kidneys)
    • Ototoxicity (Deafness)
      • Listening to too many Platinum records will lead to Hearing Loss
      • Ears shaped like "C"s

9

"Natural" Microtubule Inhibitors?

"Natural" Microtubule Inhibitors

"Vin-"

  • Vincristine
  • Vinblastine

10

Vincristine


Vinblastine

"Natural" Microtubule Inhibitors

  • Microtubles are the Vines of the cells
  • Plant-derived; Bindds Beta-tubulin in Microtubles
    --> Inhibits polymerization
    --> Inhibition of Mitosis (M-phase) and Cytoskeletal movements (CNS)
  • Similar to Cochicine (used for Tx of Gout)
  • Induction Chemotherapy Agent for Solid tumors, Leukemias, Lymphomas
  • Side effects:
    • VinCriStiNe - CNS - (neurotoxicity), Wilms, Hodgkin
    • VinBlastine - Destruction of Blasts = Myelosuppression, Hodgkin, Testes, Kaposi
  • MDR - Mechanism of Resistance

11

"Natural" Microtubules Stabilizers?

"Natural" Microtubules Stabilizers

"Its TAXing to stay polymerized"

  • Paclitaxel
  • Docetaxel
  • Ixabepilone

12

Paclitaxel


Docetaxel


Ixabepilone

"Natural" Microtubules Stabilizers

  • Stabilize Polymerized Microtubules by Inhibiting Depolarization in Anaphase --> M phase Interruption
  • Side effects: Myelosuppression, Cardiotoxicity, Peripheral neuropathy (Ixabepilone only)
  • Ovarian and Breast Cancer
  • MDR - Mechanism of Resistance

 

  • Dont use Paclitaxel and Vincristine together.

13

"Natural" Chemotherapies?

"Natural" Chemotherapies

"-poside"

  • Etoposide
  • Teniposide

"-tecan"

  • Irinotecan
  • Topotecan

14

Etoposide

Teniposide

Irinotecan

Topotecan

"Natural" Chemotherapies

  • Podophyllotoxin derived - VP 16 and VP 25
  • Two Sides to every story = Topoisomerase II inhibitor
  • Leukopenia, Thrombocytopenia

Block S-phase supercoil uncoiling

  • Camptothecin derived
  • One tea can = Topoisomerase I inhibitor
  • Neutropenia
  • MDR is Mechanism of Resistance

15

"Natural" Anthracyclines?

"Natural" Anthracyclines

"-rubicin"

  • Doxorubicin
  • Daunorubicin
     
  • Dexrazoxane (iron Chelator)

16

Doxorubicin

Daunorubicin

"Natural" Anthracyclines

  • cin = antibiotic, rubbing alcolhol = Free Radicals
  • Anthraquionone ring --> DNA intercalator and Forms Free Radicals, Introduction of Single Strand Breaks and
    inhibits Topoisomerase II (S-phase halt)
  • Induce double stranded breaks --> cell death pathway
  • Induction Chemotherapy agent
  • Side effects:
    • Free radical disposition --> attacks cardiac cells
    • Rubbing alcohol = Dilated cardiomyopathy
    • Bone marrow suppression
    • Myelosuppression, Alopecia, Extravasation toxicity
  • MDR is Mechanism of Resistance
  • Antidote is Dexrazoxane - Iron chelator used to prevent Free Radical formation and Cardiotoxicity

17

"Natural" Antibiotic Chemotherapy?

"Natural" AntiBiotic Chemotherapie

  • Bleomycin

18

Bleomycin

"Natural" AntiBiotic Chemotherapy

  • Binds DNA and Iron (Fe2+ and O2)
    --> Uses Iron to Depurinate and Depyrimidate DNA
    --> Single and Double DNA Strand Breaks ('scission')
    --> Problem in G2 phase of cell cycle
  • Testicular, Hodgkin's Lymphoma, Head, Skin cancer
  • Side effects: Pulmonary fibrosis (lungs look like large B's, Skin changes, Minimal myelosuppression
  • NOT MDR - Mechanism of Resistance
    • Increased DNA repair enzymes, decreased cellular uptake, Inactivation by Bleomycin hydrolase overexpression

19

Antimetabolites?

Antimetabolites

  • Methotrexate (MTX)
  • 5-Fluorouracil (5-FU)

20

Methotrexate (MTX)

Methotrexate (MTX)

  • Folic acid analogue
  • Competitive inhibitor of DHFR (Dihydrofolate reductase)
    --> Cannot perform single carbon transfers
    --> Cannot synthesize DNA
  • Consolidation Therapy - for Leukemias, Lymphomas, Sarcomas, RA, Psoriasis, Abortion, Ectopic pregnancy
  • Side effects: Severe myelosuppression (requires Leucovorin rescue Bone marrow), Renal and Hepatotoxicity, Neurotoxicity, Teratogenicity, Mucositis
  • Mechanism of Resistance: Increased DHFR activity

21

5-Fluorouracil (5-FU)

5-Fluorouracil (5-FU)

  • Suicide inhibitor of TS (Thymidylate synthase)
    --> no dTMP produced --> 5-FUTP incorporated into RNA
    --> Defective transcripts
  • Pyrimidine antimetabolite (S phase)
  • Bioactivated Inhibit TS
  • CRC, Basal cell Carcinoma (Topical) and Keratoses
  • Bone marrow Myelosuppression (not reversible w/ Leucovorin), Photosensitivity
  • Mechanism of Resistance: Overexpression of TS or TS mutations

22

Pyrimidine Analogue Antimetabolites?

Pyrimidine Analogue Antimetabolites

"Cyt-"

  • Cytarabine
  • Gemcitabine
  • Azacitidine
  • Capecitabine

23

Cytarabine

Gemcitabine

Azacitidine

Capecitabine

Pyrimidine Analogue Antimetabolites

  • Cytidine analogues
    • Cytarabine - inhibition of DNA polymerase, defective ligation and Premature Chain termination
    • Azacitidine - inhibits DNA methyltransferase
      --> Hypomethylation
  • Consolidation therapy for Leukemias, Lymphomas, Myelodysplastic syndrome (Azacitidine)
  • Megaloblastic anemia, Leukopenia, Thrombocytopenia
  • Mechanism of Resistance: Decreased Cytosine Kinase activity, Increased Cytosine Deaminase activity

24

Purine Analogue Antimetabolites?

Purine Analogue Antimetabolites

"Pure As Gold" - "Purine Adenine Guanine"

  • 6-mercaptopurine
  • 6-thioguanine

25

6-mercaptopurine

6-thioguanine

Purine Analogue Antimetabolites

  • Converted to nucleoside monophosphates via
    HGPRT --> Inhibit de novo Purine synthesis
    --> Incorporated
     into DNA and RNA
    --> S phase inhibition
  • HGPRT def. --> Lesch-Nyhan syndrome (Purine recovery)
    • Hypoxanthine and Guanine --> IMP and GMP
  • Bioactivated by HGPR transferase
  • Consolidation CT treatment of ALL, Immunosuppression,
  • Side effects: Myelosuppression, Hepatotoxicity
  • Allopurionol - Increased toxicity when used w/ 6-mercaptopurine (6-MP), Oxidation by Xanthine Oxidase
  • Mechanism of Resistance: HPRT mutations

26

Kinase Inhibitors?

Kinase Inhibitors

"-nib"

  • Imatinib
  • Erlotinib
  • Gefitinib
  • Vemurafenib

27

Imatinib

Erlotinib

Gefitinib

Vemurafenib

Kinase Inhibitors

  • Imatinib Mesylate - c-abl TK blocker
    • Philidelphia + Chrom. t(9;22)
    • CML (always). ALL (sometimes), AML (rarely)
  • Erlotinib, Gefitinib - EGF TK, nsc Lung Cancer
  • Vemurafenib - BRAF Serine/Threonine Kinase w/ V600E mutation; Melanoma
  • Better side effect profile than other Chemotherapy drugs, except
    • Congestive Heart Failure - all except Vemurafenib

28

Antibody Chemotherapies?

Antibody Chemotherapies

"-mab"

  • Rituximab
  • Bevacizumab
  • Trastuzumab

29

Rituximab

Bevacizumab

Trastuzumab

Antibody Chemotherapies

  • Rituximab - anti-CD20 Ab - Non-Hodgkin's Lymphoma
  • Bevacizumab - anti-VEGF Ab, Solid tumors, Increased clotting risk
  • Trastuzumab - aka Herceptinanti-HER2 Ab (TK), HER2 positive Breast cancerCardiotoxicity

30

Biological Agents?

Biological Agents

  • All-trans-retinoic acid (Vitamin A)
    • Treatment for Promeyelocytic Leukemia
    • Differentiating agent, Promotes differentiation of Promyelocytes
    • t(15;17) - Auer rods - Acute myelogenous leukemia M3 type of AML
    • "Differentiation syndrome" w/ respiratory distress, Pleural and pericardial effusions, CNS symptoms
  • Vorinostat
    • Histone Deacetylase Inhibitor
  • Bortezomib
    • Proteasome inhibitor