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Onco boards 2024 > Chemo flash cards - SS/LC > Flashcards

Chemo flash cards - SS/LC

1
Q

what is the role of RAD51

A

associates with BRCA2
ATPase that forms a nucleoprotein filament on single-stranded DNA

RAD51 binds ssDNA leading to invasion of homologous dsDNA for homologous DNA repair

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2
Q

Describe the process of nucleotide excision repair (NER)

A

Large complex of > 24 subunits
requires:
- sig chang of Watson crick structure
- chemically change base
1. recognition of problem
2. cleavage on both sides ( dual incision 5’ and 3’ ) of the DNA lesion ~25 - 30 nucleotides
3. damaged sequence dissociate in an ATP-dependent manner and become bound to replication protein A (RPA). Proliferating Cell Nuclear Antigen (PCNA) binds DNA and gap is filled in by DNA polymerase (y or E or k)
4. ligases seal the nicks and complete NER

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3
Q

Formula for clearance

A

dose = auc x Cl

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4
Q

why are heterocyclic amines carcinogenic

A
  • A chemical that is formed when meat, poultry, or fish is cooked at high temperatures, such as frying, broiling, and barbecuing
  • (CYP) cytochrome P450 oxidation
  • ring oxidation -> detox amino oxidation -> followed by acetylation or sulfation to form direct-acting reactive mutagens that attack key elements in DNA
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5
Q

topotecan generase pk
and what is it

A

Topotecan (Hycamtin), a semisynthetic water-soluble derivative of camptothecin, is a potent inhibitor of DNA topoisomerase I in vitro and has demonstrated encouraging antitumour activity in a wide variety of tumours, including ovarian cancer and small cell lung cancer.

  • given IV admin
  • lactone ring -> rapid hydrolysis to carboxylate (undergo renal excretion) - non enzymatic and less active
  • minor metabolite - n- desmonyl
  • further metabolism into UGT mediated glucuronide product (reversible)
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6
Q

anthracyclines and apoptosis

A
  • increased interaction of FAS Rw/FASL cascade activation
  • anthracyclines increase cytochrome c release independent of DNA damage
  • increase p53 -> p21 (G1 arrest), increase Cyclin G (G2/m arrest), increase BAX
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7
Q

Doxo and NfkB

A

key to response to cell damage and stress and DNA
increase in resistance in cells - associated with superoxide dismutase increase

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8
Q

Why is gemcitabine not given as a prolonged infusion?

A

Myelosuppression increases with length of infusion

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9
Q

describe BER

A
  1. glycosylases recognize abnormal base and cleave covalent bond to deoxyribose
  2. sugar cleavage endonuclease ape on 5’
  3. APlyase cleaves on 3’ - liberation of sugar
  4. dna polymerase base repair
  5. ligase
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10
Q

what are major proteins that localize for dsb repair

A

MRE, RAD50, NBS1 -> ATM
Ku70, Ku80 -> DNA pk

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11
Q

s phase dna check point

A

ATM -> NBS1 -> SMC1 -> S phase

ATM/ATR -> CHK2 CHk1 blocks CBC25A from phosphorylating cyclin A CDK2 -> stops s phase

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12
Q

BER action - what occurs/

A

cleavage og bond linking a modified base to deoxyribose sugar

endogenous DNA damage - ROS, depurination

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13
Q

what occurs during ner

A

excision of entire nucleotide including base and sugar

exogenous damage - chemicals, UV

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14
Q

what abnormality is most commonly cause by UV damage

A

pyrimidine dimers - intrastrand

60% are TT - weak mutagen
30 % are CT
10% CC - most significant mutagenic potential

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15
Q

what drug should vincas not be given with due to increase toxicity

A

erythromycin
itraconazole
other cyp3A inhibitors

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16
Q

MTD doxo in horse

A

75 mg/m2

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17
Q

mechanism of chemo resistance; dec affinity of a drug

A
  • tubule - taxanes, vincas
  • topo i - topotecan, Irinotecan
  • topo ii - anthracyclines, Epipodophyllotoxin -etoposides
  • DHFR - mitoxantron
  • thymidylate synthase - 5fu
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18
Q

what drug can increase microtubule formation and thus dec neurotoxicity

A

glutamine - anecdotal

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19
Q

what drug does vincas increase the efficacy of

A

methotrexate - inc accumulation in cells due to vInca blocking drug efflux

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20
Q

BSA formula

A

10.1 x Wt(kg) ^ 2/3 / 1000 - dog
10 x wt (kg) ^ 2/3 / 1000

27 kg = 1 m2 ( same dose)

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21
Q

how to vinca interact with lspar

A

decrease hepatic clearance of vincas

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22
Q

vinblastine metabolism

A

binds to proteins extensively
so more sequestration in tissues

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23
Q

vincristine metabolism

A

bind proteins extensively
cyp450 and cyp 3A

increased clearance with phenytoin and carbamazepine due to increase cyp3A

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24
Q

why does vincristine target platelets

A

high tubular concentration

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25
Q

what tissue accumulates vcristine

A

spleen

also liver heart kidney muscle

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26
Q

where is pGp normally over expressed

A

renal tubules, colonic mucosa, adrenal medullar, other epithelium

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27
Q

other than MDR1 what protein can results in vinca resistance

A

MRP1

also methotrexate resistance

increased MAP Microtubule-associated proteins expression which stabilize MT

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28
Q

MAP Microtubule-associated proteins (MAPs)

A

promote microtubule assembly and stability in neuronal axonal chambers

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29
Q

how do vincas enter the cell

A

simple diffusion

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30
Q

how to vincas produce neurotoxicity

A

major proposed mech - MT loss, MAP hindrances, change in MT dynamics in axons

neurons are enriched in a = b tubular

** axonal degeneration and dec transport due to dec MT function**

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31
Q

randing vinca tubulin binding affinity

A

vincristine>vinb> vinorelbine > vinflunine

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32
Q

aside from microtubule effect what 2 other mechanisms contribute to vinca function

A
  1. change in angiogenesis
  2. radio sensitization due to G2/m phase blocking
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33
Q

actinomycin d resistance

A

P170 glycoprotein transporter

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34
Q

what’s the difference between dynein and kinesin

A

dynein -> gtpases, retrograde motor protein but can be bidirectional
kinesis -> atpases , unidirectional motor protein anterograde> retrograde

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35
Q

how are tubulin subunits organized

A
  • a -b end in helix
  • a at slow growing - end -> MTOC = deployment
  • b at + end with net elongation = polymerization
  • y tubular - scaffold for association into microtubules - caps the - end
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36
Q

explain process of microtubule elongation

A

each tubulin has 2 GTP
- a = non exchangable
- b can be exchanged fro gdp
when tubulin - gtp binds microtubule -> undergoes b subunit hydrolysis

the gtp is non exchange able until the b subunit dissociates from the microtubule

gtp hydrolysis lags behind polymerase - > GTP cap => stabilizes and promotes further assembly
required for growth

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37
Q

ifosphamide metabolism

A

ifosfamide x cyp3A -> 4 hydroxyifosphamide -> aldophosphamide
-> isophosphoramide mustard = acrolein
-> chloroacetaldehyde

hydroxylation is slower than cytoxan - longer t1/2

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38
Q

facts about cytoxan/ifosphamide met/pk

A

dose dependent, non linear
* induces its own metabolism = decreases the t1/2 if given on consecutive days

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39
Q

what does acrolein cause

A

SHC
06G adducts

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40
Q

what product of chlorambucil metabolism has alkylating activity

A

phenyl acetic acid mustard

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41
Q

why is there an increased the risk of SHC with ifosfamide

A

slower activation rate = prolonged exposure to acrolein

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42
Q

what are special consideration with high dose ifosfamide or cytoxan

A

ifosfamide: tubular damage, falcon acidosis, metabolic encephalopathy
cytoxan: SIADH -> water retention

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43
Q

what is the shared structure feature of non classical alkylating agents

A

** N-methyl group**
no bifunctional activity
progress metabolize to active intermediates

  • procure, DTIC, temozolamide
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44
Q

major metabolite of DTIC

A

5-aminoimidazole-4-carboxamide (AIC)

formed int he liver by cap enzymes and some tumor cells

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45
Q

TMZ metabolism

A
  • pH dependent
  • stable when acidic -> MTIC if pH >7
  • MTIC stable in basic -> degrade at pH <7
  • spontaneous conversion by effect of h20 and electro + C4 of TMZ -> ring opening
    -> C)2 released -> MTIC (methylating agent)
    -> degrades methyldiazonium cation -> DNA methylation via methyl group donation

methydiazonium -> RNA or AIC (final degradation product) -> renal excretion

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46
Q

lesions produced by TMZ
most common
most critical

A
  1. N7 methylation of guanine
    - 03 position
    - 06 position
  2. 06 most impt = dec AGT = sensitive to cell death

O6-Alklyguanine-DNA alkyltransferase (AGT) is an important DNA repair protein that protects cells from mutagenesis and toxicity arising from alkylating agents

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47
Q

Tmax

A

time to reach Cmax

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48
Q

cytoxan in the dog vs cat

A

dog - P450 enzyme - best cytoxan
cats - 4OHCP doesnt metabolize as rapidly -> can tolerate higher doses

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49
Q

what clearance parameters coorelate with BSA

A
  • CO
  • liver volumes

NOT GFR

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50
Q

what are lymph prevalence in blood? LN?

A

CD4
- Blood 50-60%
- LN 50-60%
CD8
- Blood 20 - 25%
- LN 15-20%
B
- Blood 10 - 15 %
- LN 20 - 25%
NK
- Blood 10%
- LN rare

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51
Q

what enzyme is responsible for cytoxan activation

A

CYP450
CYP2B**

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52
Q

liposome encapsulation

A

enhanced tissue distribution
pegylated (polyethylene glycol) -> extends plasma t1/2 of the drug and restricts distribution

unknown idi it improved cardiotoxicity

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53
Q

mitoxantrone moa

A

binds nucleic acids and inhibits DNA/RNA

intercalation GC preference

dec ability to undergo electron reduction

topoisomerase II inhibition - ssbreaks

dec cardiotoxicity (poss d/t dec ROS)

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54
Q

paciltaxel disposition

A

cyp450 in liver

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55
Q

taxanes - other chemo interactions

A

inc doxo cardiotoxicity

increase thymidine phosphorylase -> inc fluoropyrimidine prodrug Capecitabine activity , a precursor of 5-FU

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56
Q

what is the concern of using cimetidine with either taxanes or vincas

A

dec p450 metabolism -> increased toxicity

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57
Q

taxmen toxicity

A

paclitaxal
1. hypersensitivity
2. neurotoxicity - mild
3. cardiac rythme disturbance bradycardia
docetaxel
1. fluid retention d/t inc cap permeability - can dec by premeding with Benadryl
2. hypersensitivity
3. rash
4. neuro toxicity

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58
Q

what are Epothilones

A

Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin

** evade MDR*

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59
Q

what drug is formulated in castor oil (other than paclitaxel) and causes severe hypersensitivity

A

ixabepilone

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60
Q

what is KSP (EgS)

A

specific kinesin that establishes mitotic spindle bipolarity

drugs - Ispinesib blocks ATPase

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61
Q

what is CENP-E

A

kinesin protein that plays a role in chromosome movement early in division

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62
Q

N7meG base excision repair

A

BER

N7MeG - recognized by MPG -> PAR endonucleaosome -> PARP -> recruitment of POIb, XRCCI, DNA ligase _> survival

methoxyamine blocks PARP -> ds DNA breaks -> cytotoxic

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63
Q

what is the most common alkylation lesion

A

N3meA
N7me G

> 80%

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64
Q

how does PI3k/AKT confer resistance and inhibit apoptosis

A

Phosphorylation of BH3 Bad Bax and Bio -> dec ability to hold mitochondria open

phosphorylation of cascade 9 -> dec activity of executioner caspase 3

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65
Q

cytoxan metabolism

A

met by cyp450 -> alkylating and cytotoxic metabolites

  1. oxidation of ring adjacent to nitrogen to produce 4-hydroxycyclophosphamide + aldophosphamide
  • ALDH -> detox carboxyphsophamide ( won’t enter cells d/t anionic for
  • spontaneous elimination
    -> phsophoramide mustard -> DNA cross linking
    -> acrolein
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66
Q

alkylation of targets of:
1. bysulfan
2. mustargen
3. nitrogen mustards
4. melphelan
5. nitrosoureas
6. non classical methylators

A

N7 most electro negative -> most susceptible

  1. & 2. N7 guanine
  2. N7 guanine and N1 adenine
  3. guanine /adenine N3
  4. & 6. O6 guanine
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67
Q

what are procarb/dacarbazine

mono or bifunctional

A

mono functional

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68
Q

what are the two roles of intracellular resistance to alkylation agents

A
  1. increased sulfhydryl (glutathione)
  2. inc GST activity
  3. inc ALDH activity -> aldophosphamide -> inactive carboxyphosphamide (inactive form of cytoxan)
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69
Q

what are some mechanisms of GSH related tumor cell resistance

A
  • inc inactivation by direct conjugation to GSH
  • GSH dependent denitrosation of nitrosureas
  • scavenging for reactive organic peroxidase
  • quenching of chloroethylated - DNA mono adducts
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70
Q

what is the importance of ALDH in alkylation

A

converts activated cytoxan to inactive carboxyphosphamide

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71
Q

how does gemcitabine evade normal DNA repair

A

extra nucleotide added after dFdCTP

Incorporation of dFdCTP into DNA is most likely the major mechanism by which gemcitabine causes cell death. After incorporation of gemcitabine nucleotide on the end of the elongating DNA strand, one more deoxynucleotide is added and thereafter, the DNA polymerases are unable to proceed.

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72
Q

gemcitabine metabolism

A

dFdCTP blocks DNA polymerase and dna synthesis see diagram

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73
Q

when is gemcitabine active

A

NOT confined to S phase kills cells nor in log growth

maybe d/t
1 competition with DCTP for polymerase
2 dFDCDP blocks ribonucleatide reductase = deoxycytidine depletion
3 dFdCTP incorporation into DNA -> strand termination

74
Q

how does gemcitibine enter the cell

A

active nucleoside transporters

75
Q

busulfan MOA

A

SN2
reacts with thiol groups of AA
N7 guanine

cytotoxicity - adenine -> guanine cross linking

76
Q

BCNU alkylation reaction

A

BCNU hydrolysis -> 2 chlorophyl carbonium (electrophile) = alkylation of G,C,A
-> Cl displaced by e- ion nitrogen on complimentary DNA strand - cross linking

DNA protein cross links also possible by initiating chlorethylation and amino or sulfhydryl group

77
Q

nitrosurea MOA

A
  1. chloro ethyl groups transfers to the O-6 methyl of guanine on DNA - alkylating
  2. carbamylation of nucleophile

carmustine, temo, DTIC-> lipophilic and penetrate CNS

only cross resistance with other alkylating agent

N7 alkylation -> cross linking

BCNU hydrolysis -> 2chloroethyl groups -> inc alkylation

78
Q

what is an isocyanate and what’s the relevance

A

product of spontaneous break down of methyl and chloroethyl nitrosureas

responsible for some tox with nitrosurea tx

Carbamylation (carbamoylation) is a post-translational modification resulting from the nonenzymatic reaction between isocyanic acid and free functional groups of proteins, in particular with the free amino groups

alters structural and functional properties of proteins and results in faster aging of proteins

79
Q

nucleophile selectivity preference for nitrogen mustards

A
  1. phosphate oxygens
  2. base oxygen
  3. purine amino groups
  4. protein amino groups
  5. sulfide atoms of methionine
  6. thiol group s
80
Q

doxo resistance - most impt transporter

A
  • p170 (atp dept ABC)
  • inc MDR1 via inc FOXO3A
81
Q

doxo and TGF-B

A

inhibition of TGFB signaling
blocks HIF1a expression

82
Q

doxo and PI3K/AKT

A
  • in tumor cells and inc phosphorylation AKT
  • in the heart doxo = dec AKT/ERK phosphorylation -> inc apoptosis

inhibited by dexrazoxane

83
Q

doxo changes signal transduction

A
  • PKC inhibition @ high doses
  • @ lower doses - increased Phosphoinositides and phsophatidyl closure => accumulation of DAG & IP3 & 2x PKC activity => inc protein cross links +/- inc topo II
84
Q

doxo membrane perturbations

A
  • binds to phospholipids (cardiolymphatics)
  • change fluidity of tumor cell plasma membranes and mitochondria
  • cytotoxic w/o even entering the cell
  • inc EGFR - blocks transferrin reductase, increase iron-dependent protein oxidation in RBC
85
Q

2 e- reduction of anthracyclines

A

formation of unstable quinone methide -> loss of daunosamine sugar and formation of deoxyglycose (LESS CYTOTOXIC)

may be means to dec tissue reactions

86
Q

cardiac toxicity of anthracyclines

A
  • dec catalase activity and high mitochondrial myoglobin content -> inc activation
  • sensitivity of cardiac glutathione peroxidase to free radical attack
  • increased release of iron
    1. abstract iron from ferritin
    2. semiquinone (free radical) -> release Fe under hypoxic conditions

**doxorubicinol production by carbonyl reductase 3 ***

IRP1 is critical to iron homeostasis

87
Q

dexrazoxane moa

A

Fe2+ chelator in urinary clearance

prevents doxo induced lipid peroxidation and cardiac toxicity

prodrug -> ICRF198 -> Fe binding
enhanced in cardiac myocytes

88
Q

what is one electron reduction

A
  • @ quinone oxygen of chromophore
  • central to cardiac toxicity
  • react w/ o2 -> superoxide
  • activates reactive compounds that cause widespread damage in all intracellular components
  • catalyzed by NO synthase -> superoxide production + dec NO
89
Q

effects of anthracyclines on DNA

A
  • intercalation -> dGdC regions flanked by A:T pairs. Potentiated by methylation.
    • planar ring: intercalates
    • side chain: H+ bonding
    • sugar: minor groove binding
    • critical for BP recognition*
  • TOPO II -> cleavable complex stabilization
    • trapping intermediated and prevent resealing
    • specific regions: 3’ adenine @ break site
    • inhibition of catalysis
  • helicase - inhibition via helices stabilization
  • ROS generation -> DNA and mitochondrial damage
90
Q

what is the consensus sequence for doxo affinity and intercalation

A

5’-TCA

91
Q

what do anthracyclines do once entering the cell

A

bind 2OS proteasome -> inc ubiquitin system -> enter nucleus through ATP dependent pore system -> proteasome -> DNA (higher affinity)

92
Q

why do anthrocyclines accumulate in cells

A

rapid association with membranes
avid DNA binding
intracellular storage in compartments

93
Q

how do anthrocycluines enter the cell

A

passive diffusion of un-ionized drug
daunorubicin uptake faster (less polar)
pH dependent fxna nd uptake

94
Q

what is the basic anthracycline structure

A

4 planar rings
danosamine sugar is D ring
quinone and hydroxyquinone on B+ C rings
- redox potential and free radical generation

doxo - single OH on C14??
epirubisin epimeric 4’ subunit on danosamine sugar

95
Q

how may lspar change drug clearance

A

decrease serum albumin and dec binding
accelerated clearance

96
Q

what chemo drug is contraindicated with lspar d/t dec efficacy

A

methotrexate

lspar block protein synthesis
dec protein synthesis means block entrance into the s phase - dec cytotoxic effects

97
Q

why might lspar cause clotting abnormalities

A

dec synthesis of AT III
particularly problematic in CNS

98
Q

does lspar penetrate CNS

A

yes but concentration falls rapidly

99
Q

what is benefit of pegylated Lspar

A

dec immunogenicity
inc T1/2

100
Q

how does lspar work

A

lspar -> aspartic aci and ammonia

101
Q

how is asparagine normally synthesized

A
  • transamination of l-aspartic acid
  • amine groups donated by glutamine
    catalyzed by l-asparagine synthetase (tumor cells lack this)
102
Q

what drugs have toxicity based on BSA calculation in small dogs

A

doxo
cisplatin
carbo
melphalan

103
Q

what type of mutation results from 06 methyguanine

A

G-> A transition

104
Q

means of methylation repair

A

MGMT (O6 MG)
AlkB ( oxidizes methyl groups attached to bases _> shead as formaldehyde

105
Q

yondelis “Trabectedin”

A
  1. DNA alklyation
  2. inhibition of gene transcription

FDA approved for liposarcoma and leiomyosarcoma in people

106
Q

mitomycin c moa

A
  • crosslinks in DNA and induces mono functional alkylation
  • DNA replicaiton inhibitor

cross links = most lethal
monofxn = most common interaction

HCl -> N6 adenine
reductively activated -> N217guanine

107
Q

dactinomycin moa

A

binding ss and dsDNA -> potent inhibition of DNA and RNA + protein synthesis

108
Q

what happens with you dose obese dogs on ideal body weight

A

underdose them

109
Q

carbo dosing in cats

A

dose = auc x (GFR x 2.6) x Kg (wt)

110
Q

endocrine effects of vincas

A

SIADH

111
Q

vinorelbine dose in dogs and cats

A

dog - 15 mg/m2
cat - 11.5 mg/m2

dose limiting tox - neutropenia, v, nephrotoxicity

112
Q

with what chemo drugs is carbo synergistic

A

drugs that decrease intracellular pyrimidine precursors
5FU and Gemcitabine

113
Q

means of cisplatin resistance

A
  1. change in cellular accumulation
  2. cytosolic inactivation
  3. change in dna repair
  4. change in apoptosis - inc dna damage tolerance
114
Q

platinum renal toxicity mechanism

A

primary distal tubule damage

mg/ca loss is common and should be monitored

115
Q

what should you never use in a patient receiving carbo to potential minimize renal toxicity

A

FUROSEMIDE - dec in total h20 leads to inc drug exposure and inc toxicity

okay to use mannitol bc inc flow

116
Q

what neoplasia have platinum been causative agents

A

AML - cisplatin and carbo

117
Q

when in the cell cycle are topo I and ii inhibitors active

A

topo I - require active replication, S phase
Camptothecin

topo II - less cell cycle specific-> deplete s phase cells via g2 arrest

118
Q

what’s th most well known topo1 inhibitor class

A

Camptothecin
topotecan, irinotecan

119
Q

how does etoposide interact with radiation

A

it is a radiosensitizer

  1. change response of dna repair genes
  2. dec topo i/ii expressoin
120
Q

how ar eetoposide and teniposide eliminated

A

etoposide - renal and non renal - can cause azotemia dec dose if azotemia seen

tenoposide - non renal

121
Q

what happens with topo II sensitivity as topo enzyme increases

A

inc top2 = inc sensitivity to topo inihibition

122
Q

moa topII inihbitors

A

stabilize DNA cleavage component d/t inhibition of dna regulation
( inihibts ds break)

123
Q

when are topII concentrations highest during the cell cycle

A

end of s phase - headed to separate chromatin loops

top2a - linked to proliferative state and ki67
top2b- constant throughout the cell cycle

  • top 2a inc 2-3 x during g2/M
124
Q

what part of the alpha folate structure affords DMFR inhibition

A
  • 2,4-diamino
    + charge added to structures of folates -> N10 bridge
    change 5-8N position
125
Q

what is the general structure of folic acid and alpha folate

A

FA; pteridine ring (2,4 diamino inhibits DMFR) + p amino benzoic acid + glutamic residue (1-6)

Methotrexate: truncated glutamyl

126
Q

how does folate enter the cell

A

folate receptor (FR), reduced folate carrier (RFC1) and proton-coupled folate transporter (PCFT) , pH sensitive transporter (intestines, some tumors, most tissue)

127
Q

which folate proteins are present in membrane and share folate binding site

A

alpha
beta
less efficient (dec capacity) for reduced folates and Methotrexate

128
Q

what is the most important transporter for methotrexate

A

reduced folate carrier system RFC1

129
Q

what is different about methotrexate and piritrexim

A

piritrexim dont require transport
they are lipid soluble

130
Q

what is the effect of low folate conditions

A

increased toxicity d/t folate receptor up regulation.

131
Q

what are most important drug efflux pumps for methotrexate

A

MRP1/2/3
BCRP

132
Q

how may lspar change methotrexate

A

dec effect d/t amino acid deprivation and growth arrest

133
Q

what are the effects of polyglutamation

A
  1. inc intracellular accumulation
  2. selective intracellular retention = inc t1/2
  3. inc folate affinity for folate dependent enzymes

methotrexate also polyglutamated -> inc tox
inc retention in cells
inc inhibition of folate dept enzymes -> slower dissociation

134
Q

Tumor lysis bw

A

increased K, P, decreased Ca – metabolic acidosis low HCO3

135
Q

how do folates normaly exist within cells

A

poly glutamates form

directed by FPGS -> adds < 8 glutamic group in y linkage

figs - correlated with rate of cell growth inversely with concentration of intra cellular folates

high levels = dec max polyglut

136
Q

what is an important determinant of optimal max binding to DMFR

A

NADPH concentration

co-substrate for DMFR

NADPH does not promote mix binding

137
Q

under what condition is methotrexate INeffective

A

1 high concentration of dihydrofolate (a competitive substrate)
2. neutral pH

under these you need a higher concentration of Mtx to except effect

an excess of free unbound max is required for DMFR inhibition

138
Q

Aminopterin

A

original alpha folate

4 amino analog of folic acid

139
Q

why is FR system not as effective for methotrexate transport vs endogenous folate

A
  1. inc affinity for reduce folates and folic acid
  2. max PG 75x affinity vs mono glutamate
140
Q

other ara- c functions

A
  • inhibition of neonucleotide reductase
  • formation of are cap choline - inhibit synthesis of membrane glycoproteins
  • diff of leukemic cells
  • ceramide formation -> apoptosis
  • DAG induction -> PKC
141
Q

5FU metabolism

A
142
Q

what is a 2nd MOA in vivo of hydroxy urea

A
  • change to NO -> ribonucleotide reductase inhibitor
  • acceleration of loss of double minute chromosomes

which are extrachromosomal circular DNA fragments frequently found in brain tumors

143
Q

ribonucleotide reductase structure

A

1 subunits: m1 + m2

m1: diphosphate binding site and allosteric triphosphate reg sites
- stable throughout the cell cycle except very decreased in G0

m2: Fe2+ and free radical attached to tyrosine
- peak in s-phase

hydroxy urea target - chelates iron and inactivates m2 tyrosine
* s phase selective*

144
Q

how does hydroxyurea interact with other chemo

A
  • inc cytotoxicity of purine/pyrimidine analogs by dec dcompetitive pools of triphophates

Hydroxyurea and fluorouracil (5-FU) have shown synergistic activity in vitro in g1/s phase
Both drugs also act as radiosensitizers
dec deoxynbonucleaotide pools -> dec dna repair after alkylation/RT damage

145
Q

dog/ cat doses of
1. ara c
2. 5 aza
3. gemcitibine

A
  1. dog - 300 mg/m2/d up to 600 over 2-4 d
    cat - 10mg/m2 every 12 hours SQ
  2. 0.2mg/kg q 24h SQ on day 1-5 of 25 d or
    0.1 mg/kg every 24 hours SQ d 1-5 every 14 days
  3. dog - 350 - 400 mg/m2 weekly x 5 weeks for HCA
    800mg/m2 weekly for tcc
    original dose 675mg/m2 q 14 d
    lymphoma rescue - 400 mg/m3
    cat 0 10mg/m2/min
146
Q

sig difference between gemcitabine and ara-c

A
  1. dFDCTP biophasic elimination
  2. inc RNR inhibition
  3. dFfC (gemcitabine) - . dec dNTPS d/t RNR inhibition
147
Q

nitrogen mustard moa

A
  1. choline lost
  2. B carbon -> nitrogen nucleophile - > aziridinium moiety (reactive)
    • nucleophile -> alkylated product
  4. 2ndary fn - 2nf aziridinium 2 alkylation = cross linking
148
Q

what is unique about nitrosurea

A

no carbamoylating activity

149
Q

what is the natural cofactor of Thymidylate Synthase rxn

A

5-10-CH-2FH4 (or polyglutamases) bings fdUMp/dump

Thymidylate synthase (TS) catalyzes the conversion of deoxyuridine monophosphate (dUMP) to thymidylate (TMP), in a reductive methylation that involves the transfer of a carbon atom from the cofactor 5,10-methylenetetrahydrofolate to the 5 position of the pyrimidine ring

150
Q

why were cytoxan and ifosfamide created as prodrugs

A

hope that high concentrations of phosphamidase in epithelial tumors would selectively activate

151
Q

what is required for function of top II

A
  1. Mg2+
  2. ATP
152
Q

ccnu moa and pharacology

A
  1. spontaneous met to alkylating + carboxylating compounds
  2. chloroethyl group 06 guanine -> cross linking

only Cl group - monofuncional
metabolites have increase alkylating ability and dec carbamylating ability

153
Q

how to alkylating agent enter the cell

A

lipid soluble (passive) - ccnu bcnu chlorambucil
mustargen - via choline transport
melphalan - active transport systems show with cell line

154
Q

what favors glutathione conjugation

A

GST presence -> offer catalysis

155
Q

what is an important mech of resistance to chlorambucil

A

increased gut dept MRP1/2 efflux

156
Q
A
157
Q

alkyl guanine DNA alkyltransferase repair AGT

A

O6 -meG -> AGT -> survival (can be ubiquinated)
or

O6-meG -> MSH2/6-> DNA break/toxicity

encoded by MGMT

158
Q

what are 2 branches of DNA damage-debt S phase check point

A
  1. phosphorylation of SMC1 - cohesion + by ATM/ATR
  2. ATR (chk1)/ATM(chk2) complexes -> turnover of CDC25A removes the inhibitory phosphorylation in CDK2 and blocks replication initiation
159
Q

cytotoxic mech of TMZ

A
  • failure of mar to find complement for methyl guanine
  • g2/m arrest via chk1 kinase activation -> phosphorylation of CDC25 phosphatase -> dephosphorylation of CDK2 - blocking cell replication

*p53 independant

160
Q

what is the primary met of doxo
how is it formed

A

doxorubianol - greatest cardiotoxicity

created by carbonyl reductase 3

taxanes -> inc CR3 -> inc alcohol ( humans will have inc BAC)

161
Q

taxanes and other chemo drugs

A
162
Q

doxo excretion

A

50% biliary - parent + metabolite
<10% urinary

163
Q

what determines pK of doxo

A

tissue binding
75% protein bound in plasma

higher binding for dna vs plasma

164
Q

how is innotecan pk unique among campothecans

A

must be converted by carboxyl esterase converting enzyme -> SN-38 (metabolite thought to be responsible for activity and toxicity)

NS38 detox via UGT IAI -SN 38G

innothecan is a p450 substrate

165
Q

what determines
Cmax
Cmin
Cavg
accumulation factor
Tmax

A

Max/min/avg - t1/2, tauc, dose

accumulation factor - how high at steady state - t 1/2 and tauc

Max dept on K and t 1/2

166
Q

what neutrophil cutoff is associated with increased duration and ST in LSA

A

<3000

167
Q

what enemy form metabolite doxorubianol in dogs

A

Aldo - keto reductase

168
Q

how do you calculate dox exposure without full course sampling

A

AUC = 46.9 + 0.63 (C5min) + 1.96 (C45min) + 6.63 ( c60min)

5, 45, 60 min sampling

169
Q

what’s the relevance of protein binding for carbo

A

it inactivates it

170
Q

vinc general structure

A

asymmetric structure of dihydroindole nucleus ( vindoline) linked to indole nucleus (Catharanthine)

vcr and vbl identical except R1 of nitrogen of vindolene nucleus

171
Q

when do vincas bind

A

vinca domain of microtubules ( not soluble tubulin like colchicine)

2 sites
1. high affinity - change treadmilling, no change in microtubule mass
- enhance - end instability
- inhibit + end instability

  1. low affinity ( high concentraiton of vinca -> depolymerization
172
Q

what protein plays a critical role in vina driven destabilization

A

MAPs
1. stabilize longitudinal dimers as they splay apart
2. may help destabilize microtubules

173
Q

describe the basic structure of the platinum agents

A

divalent inorganic complexes

h20 soluble and readily activated by h2O displacement of Cl/carboxyl groups

complex leaving groups of carbo+ oxiplatin -> dec reactivity in aqueous solution, dec renal toxicity

174
Q

what proteins aim to repair platinum adducts

A

NER pathway

ERCC1, XPA, etc

175
Q

how is apoptosis altered with platinum agents

A

mmr complex and p53

176
Q

etoposide metabolism

A

main metabolite - etoposide glucuronide

177
Q

when is top2 phosphorylation the highest

A

correlates with cellular need for enzyme

  • s phase -> peak @ G2

primary enzyme - casein kinase II

178
Q

what happens to topo 2 when DNA is bound

A

closed confirmation ->
tyrosine of each monomer attacks DNA PDE bond 4 bases apart on the G duplex -> linked 5’ ends while 3’ re hydrolyzed
t sement passes through the gap

ATP hydrolysis -> open and release

179
Q

what is a prominent and general feature of top mediated DNA breaks

A

type 1 enzyme (1,3) -> ss dna breaks
type 2 enzyme (2a,b) _> ds dna breaks

  • DNA cleavage by topoisomerases is a **transesterification reaction, in which a tyrosine residue(s) of the enzymes forms a transient covalent bond with phosphates of the DNA backbone

top1 - linked to the 3’ terminus of dna
top 2 - each enzyme molecule of homodimer -> linked to 5’ terminus each on each of the cleaved dna strands

180
Q

what product of 2e- reduction - anthracycline metabolized to ?

A

7 deoxyaglycone
7 hydroxyaglycone

181
Q

treatment of SHC

A

oxybutynin (0.2–0.3 mg/kg PO q8–12 h), and/or pentosan polysulfate sodium (20 mg/kg PO twice weekly for 5 weeks, then once weekly for 12 weeks). In extreme cases, intravesicular dimethyl sulfoxide (DMSO) or dilute formalin, or surgery can be considered

182
Q
A

Onco boards 2024 (17 decks)

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