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Oncology Medchem 2 Flashcards

0
Q

5-fluorouracil (5FU)

A

Converts to FdUMP (active metabolite)

Mimics UMP, Competes for thymidylate synthase,
Creates an irreversible ternary complex,
and immobilizes thymidylate synthase, no TMP formation

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1
Q

Tetrahydrofolic acid (THFA)

A

Central cofactors for DNA, thymidine and purine synthesis

Reduced twice from dietary folic acid by DHFR

Methotrexate mimics folic acid and binds to DHFR and prevents THFA formation (needed for thymidine synthesis) psuedo-irreversible

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2
Q

Antifolate resistance

A

Impaired transportation
Mutation of DHFR
Increased concentration of DHFR

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3
Q

Methotrexate, 5-FU antidote

A

Leucovorin (folinic acid salt)

Already reduced without DHFR and can serve to synthesize Purines and pyrimidines

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4
Q

UMP

A

Thymidylate synthase
THFA cofactor and PABA-GluAcid

Form TMP with methyl from N5N10 THFA

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5
Q

Capecitabine

A

Prodrug metabolizes to 5FU

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6
Q

Other UMP mimics

Pyrimidine antimetabolites

A

Competitively inhibit DNA polymerase

Azauridine
Cytarabine
5-azacytidine
Gemcitabine

-ine

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7
Q

Hydroxyurea

A

Inhibits ribonucleotide reductase and
Inhibits formation of all 2’deoxy analogs (remove OH)
Destroys tyrosine radical

Targets S phase

Synergize with radiation (targets G1 phase)

Unconverted base-phosphates can exert feedback inhibition of nucleotide synthesis

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8
Q

Alkylating agents

Methylchlorethamine
Chlorambucil
Cyclophosphamide
BCNU
Streptozotocin
A

Nitrogen Mustards, form mono/di-adducts

Form electrophilic positive charge -onium
Causes covalent interstrand cross linking of DNA bases by oxygen, nitrogen nucleophiles

Results in mutagenic and cytotoxic effects
Cell cycle arrest, p53 recognizes damaged DNA and causes apoptosis

P53 mutation leads to alkylating agent resistance

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9
Q

Chlorambucil

A

Decreased nucleophilicity and chemical reactivity due to aromatic ring
Can be taken orally

Compared to aliphatic nitrogen mustard gas

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10
Q

Cyclophosphamide

A

Prodrug mustard, alkylating species

Produces toxic acrolein and therapeutic metabolite

If aldehyde dehydrogenase oxidation is over expressed can lead to sub therapeutic drug resistance into inactive urinary metabolite

Resistance also by lack of CYP2B prodrug activation

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11
Q

Acrolein

A

Cyclophosphamide toxic metabolite

Susceptible to Michael addition and causes severe nephrotoxicity and neurotoxicity

Antidote = MESNA (good nucleophile to bind and inactivate acrolein)

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12
Q

Glutathione

A

Best antioxidant in the body
Good nucleophile to bind and inactivate NAPQI
Via Michael addition

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13
Q

Temozolamide

A

Triazine

Forms simple CH3+ electrophile as an alkylating agent

CH3+ methylates guanine for mutation

Resistance by AGT

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14
Q

Busulfan

A

1) alkylate SH group and interstrand crosslink
2) create abasic site - major mutation
3) denature DNA

Sulfur stripping. SH alkylation to cyclic sulfonium mostly with cysteine or glutathione

Resistance if glutathione is overexpressed
Altered transport of busulfan into cell

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15
Q

DNA repair pathways

A

NER (mono adduct) and NHEJ/HR (crosslink)

Acquired resistance mechanism to alkylating agents

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16
Q

Streptozotocin

A

Nitrosourea: Mustard alkylating agent
Forms toxic isocyanate
OH- base
And carbonium ion (leads to OMeG)

Streptozotocin self-neutralizes and does not form isocyanate - nontoxic

Effective against malignant insulinomas, sugar taken up by pancreas for aided targeting
Can cause diabetes

Resistance by AGT

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17
Q

O-alkylation from nitrosourea

A

From nitrosourea (BCNU, streptozotocin) and temozolamide

Forms o-methyl guanine (pairs with T instead of C)
Cause downstream replication pairing of A
Results in G to A transition mutation

Enhanced by methylation and silencing of AGT increased response to BCNU nitrosourea

Also enhanced by O6-benzylguanine via AGT inhibition

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18
Q

AGT

A

removes methyl (temozolamide, streptozotocin) and ethyl (BCNU) adducts from guanine

Resistance against alkylating agents

Adjunct therapy with O6-benzylguanine (AGT inhibitor)

Or ethacrynic acid to irreversibly inhibit glutathione via Michael addition (alkylating and busulfan)

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19
Q

Anti tumor antibiotics

A

Planar aromatic rings
Dactinomycin, doxorubicin, bleomycin

Inhibit DNA/RNA synthesis via
1) intercalation by planar region
2) free superoxide anion radical generation plus
H2O2 Leads to OH radical formation (quinone or Fenton reaction) and breaks DNA strand scission

Hydroxyl radical oxidizes guanine to 8-oxo-dG
Pairs A and leads to G:T mutation

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20
Q

Bleomycin

A

Metal binding region- Perfect for Fenton reaction with multiple dipoles to interact with Fe to generate hydroxyradical

Cyclohexane Sugar region - causes cancer cell selectivity

Intercalation region - anchor to DNA

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21
Q

Mitomycin

A

Quinone (form superoxide radical) antibiotic and mono/di-alkylating agent (crosslink)

1) reduction
2) Michael addition (beta carbon attack) by nucleotide usually by guanine

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22
Q

Antimitotic agents

A

Placlitaxel, docetaxel - taxanes spindle poison and promoted stabilization against breaking
Taxol 4 esters, 3 benzene rings, large cyclic structure

Vinblastine, vincristine - vinca alkaloids dissolve microtubules (anti tubulin): no polymerization

Disrupt cell division and induce apoptosis

23
Q

CISplatin , carboplatin

A

Inhibits DNA polymerase by INTRAstrand crosslinking on 2 electron rich guanine
Induce apoptosis by p53

Like an alkylating agent Platinum replacing the nucleophile

HMG (repair protein) binds tightly to adduct and kinks DNA helix. HMG DNA repair enzyme gets blocked

24
Drug resistance
1) increased expression of membrane glycoproteins causing decreased active transport of mustard drugs (mechlorethamine) 2) increased levels of glutathione which can detoxify electrophilic anti cancer drugs (alkylating agents, sulfur-stripping busulfan) 3) increased deactivating enzymes that destroy anticancer drugs (cyclophosphamide and aldehyde dehydrogenase) 4) decreased prodrug activating enzymes (cyclophosphamide and CYP2B) 5) increased DNA repair enzymes (AGT:O6-benzylguanine:BCNU, GST:ethacrynic acid:alkylating agents, busulfan)
25
Tamoxifen
Anti-estrogen antihormonal therapy Inhibit breast cancer growth by 50% Estrogen receptor antagonist May increase risk of developing endometrial cancer
26
Carcinogens
Even include cytotoxic anticancer drugs All substances are poisonous depending on dose
27
Estrogen biosynthesis (CPATE)
``` Cholesterol Progesterone Aldosterone Testosterone to Aromatase Estradiol ```
28
Aromatase inhibitors
Block conversion of androgens to estrogens Anastrozole, -ozole Exemestane- irreversible Aromatase inhibition!
29
Depurination abasic site
Frequently affects guanine Busulfan A-rule replaces with adenine
30
Deamination
Can lead to mutation 5methylcytosine naturally mutates to Thymine
31
Mutation genesis
Depurination Deamination Oxidation of DNA bases
32
Higher metabolic rate in rats
More oxidation of DNA and more excretion of thymine glycol Humans have less breathing and less oxidative damage and less thymine glycol. Leads to longer life
33
Exemestane
Irreversible Aromatase inhibition
34
Chemopreventive agents
Increase phase II enzymes to detoxify carcinogen Decrease phase I (CYP oxidation) enzymes that activate carcinogen
35
Deoxythymidine glycol
Mutation product that causes oxidative damage
36
Cyclobutane Pyrimidine Dimer (CPD)
Generated by UV light (can come in the dark) Melanoma 2 thymines interacting
37
SAM
Adds methyl to bases | Leads to mutation if not repaired by AGT
38
Resveratrol
Polyphenol in grapes&wine, block PDE activity ``` Chemopreventive: Antioxidant Block phase I (CYP) Boost phase II (glutathione, quinine reductase) Arrests cell proliferation ``` Chemotherapeutic Turn off angiogenesis Suppress invasion and metastasis Induces apoptosis
39
Vitamin C
Highly effective antioxidant Controversy: can cut effectiveness of chemotherapy drugs
40
Antioxidants
Get oxidized themselves instead of cells that may get damaged Often reducing agents Prevent excessive oxidation and neutralize free radicals and reactive oxygen species SODismutase, catalase, glutathione
41
Isothiacyanate (ITC)
In broccoli, watercress N=C=S Induce phase II GST and quinone reductase Reduce phase I CYP450
42
Raloxifene
Selective estrogen receptor modulator Antiosteoporotic agent: agonist on bone Estrogen antagonist on breast
43
Coffee
Has caffeine and antioxidants One cup of green or black tea also antioxidant
44
Issue of Chemoprevention
Single molecule vs. mixture synergy Difficult to predict an optimum dose
45
Bisphenol (BPA)
Chemical Plastic, can lining Endocrine destructant
46
Vitravene
Antisense, phosphorothioate oligonucleotide Blocks translation of Bcl-protein that blocks chemotherapy induced apoptosis Replaces phosphodiester O to S More difficult for nuclease to recognize and breakdown
47
TMPyP4
Intercalated and Binds G-quadruplex to repress c-myc oncogene Stabilizes off position and decreases telomerase aka immortality enzyme (lengthens age of cancer cells) Telomeres shorten with age
48
Novel approach to chemotherapy
A) antisense (Vitravene) B) anti-telomerase (TMPyP4) C) anti-DNA repair (PARP inhibition)
49
DNA adduct in prostate cancer
Blocks DNA repair Warhead mustard Cancer cells overexpress steroid receptor and bind specific protein of drug molecule
50
PARP inhibition Lynparza (olaparib)
Target DNA repair in breast cancer Doubles strand break leading to tumor cell death due to loss of BRCA function
51
Kadcyla
Antibody-drug conjugate Antibody = precision guide to tumor antigen (HER2) Cytotoxic agent (~vincalkaloid antitubule) attached to kill tumor cells (apoptosis) when internalized Limits tissue exposure to free cytotoxic agent
52
Moore's law
Technology doubles every 2 years
53
2 defects of anticancer agents
A) poor selectivity toward cancer cells vs. normal cells B) poor efficacy against slow-growing tumors
54
Selectivity and efficacy can be influenced by
1) No selectivity for Slow-growing tumors (colon, breast, prostate) 2) Some cancer cells lack DNA repair (PARP) 3) Structure-based selectivity (Bleomycin, streptozotocin) 4) overexpression of enzymes (telomerase, AGT) telomerase lengthens cancer life AGT inhibits effectiveness of alkylating agent
55
Doxorubicin
Quinone antitumor antibiotic Potentiates superoxide anion radical formation Leads to hydroxy radical DNA strand scission

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