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medical school midcomp 5 > anti neoplastics 1 > Flashcards

anti neoplastics 1 Flashcards

1
Q

mechanism of resistance

A
  1. inc rate of DNA repair
  2. formation of trapping agent
  3. change in drug sensitivity to target enzyme
  4. decreased activation of prodrugs
    5.inactivation of anticancer drugs
    decreased drug accumulation
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2
Q

chemoherapy treatment strategies

A
  • multi drug combo
  • max individual dose
  • avoid overlap in toxicities
  • manage toxicities
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3
Q

alkylating agents mechanism of action

A
  • interfere with DNA integrity and may induce apoptosis in :
    rapidly proliferating tissues-alkylation occurs in lare G1 and S phases and express in G2
    Non dividing cells-cells blocked in G1/S interface
    cell death relies on -> activation of DNA repair system creates DNA strand breaks by repair enzymes-> triggers apoptotic response
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4
Q

resistance to alkylating agents

A
  • dec cell permeability to drug
  • inc detoxification capability
  • inc dna repair processes
  • inc rate of metabolic degradation
  • impaired apoptotic pathway
  • defective checkpoint
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5
Q

alkylating toxicities

A
  • bone marrow supression
  • mucosal toxicity
  • nausea/vomiting
  • neurotoxicity-altered mental state seizure
  • extravasation from injection site:ulcerations
  • pulmonary fibrosis
  • veno occlusive disease o fliver-obstruction of small hepatic veins
  • reproductive system toxicity
  • leukemogenesis
  • pregnancy-teratogenic
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6
Q

cyclophosphamide/ifosfamide

A
  • cytotoxic metabolite
  • metabolite activation via CYP2B6
  • hydroycyclophsphamide->aldophosphamide->phosphamide mustard->acrolein
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7
Q

cyclophosphamide/ifosfamide resistance

A
  • aldehyde dehydrogenase- inc rates of metabolic degradation to inactivate keto and carboxy metabolites
  • gluthathione transferases-detoxification of most alkylating intermediates
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8
Q

cyclophosphamide/ifosfamide therapeutic uses

A

cyclophosphamide;

  • broad use-solid tumors,hematologic cancers
  • potent immunosuppressive properties-treatment of autoimmune disorders (RA, nepritic syndrome, wegeners granulomatosis)
Ifosphamide;
testicular cancer
lymphomas
bone tissue sarcoma
bladder
cervical
ovarian
lung cancer
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9
Q

cyclophosphamide toxicity

A

-hemorrhagic cystitis(acrolein)
-IV hydration+mesna conjugates/inactivates
acrolein->dec in toxicity
-CHF; nephrotoxicity, bladder cancer
-SIADH reported

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10
Q

platinum analog

A

Cisplatin, carboplatin, oxaliplatin

IV,poor CNS penetration, renal clearence
dose adjustment in renal impairment

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11
Q

platinum analog mechanism

A
  1. passive diffusion and CU active transporter
  2. activation
  3. reacting with purine (mostly G) on same or neighboring DNA aka dna cross linking
    - cell cycle arrest
    - strand break
    - apoptosis
    - replication inhibition
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12
Q

resistance to platinum analogs

A

decreased uptake;
-CTR1 copper transporter down regulation and decreased expression= decreased uptake. predominant mechanism of resistance

efflux;
ATP7A and ATO7B transporters remove excess copper from cell

inactivation;
inc intracellular levels of
1.gluthione
2.metallothionein
3.other sulfhydryls...molecules bind and inactivate drugs
repair;
overexpression of 
1.nuceotide excision repair
2. base excision repair
3.mismatch repair

cross resistance may occur btw cisplatin and carboplatin

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13
Q

platinum analogs therapeutic effect

A

cisplatin
major anti tumor activity broad range solid tumors

carboplatin
broad spectrum activity against a wide rage of solid tumors

oxaliplatin
colorectal and gastic cancer
first line therapy in advanced colorectal cancer

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14
Q

toxicities of platinum analogs

A 
cisplatin
vomiting
myelosuppression
ototoxicity
nephrotoxicity-dose dependent- vigorous chloride dieursis with saline and diuretic (furosemide or mannitol)

carboplatin
less severe myleosuppression but similar toxicity ro cisplatin

oxiplatin
similar to cisplatin but less peripheral neuropathy(exacerbated by cold)

ALL have leukemia and pulmonary fibrosis month-years later

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15
Q

platinum drug interaction

A

platinum analog+taxane
platinum analog->dec taxane clearance=
administer taxane before platinum

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16
Q

folate antagonist methotrexate

A
  • narrow therapeutic window. drugs that displace methotrxate from albumin inc risk of severe myelosuppression
  • poor CSF distribution, distributes in body water
  • enter cell via folate transporter
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17
Q

methotrexate mode of action

A
  1. dec fh4 synthesis->dec purine nucleotides and thymidylate
  2. ultimately impair synthesis of purine nucleotides and thymidylate
  3. dec dna and RNA synthesis
  4. induces p53 and cell cyle arrest
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18
Q

mtx resistance

A
  1. impaired transport into cell
    - dec ability to synthesize methotrexate polyglutamates
    - inc conc. of DHFR
    - inc expression of drug efflux
    - production of altered DHFR with reduced affinity for mtx
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19
Q

mtx therapy

A
  • broad spectrum liquid and solid tumor
    • ALL
    • methotrexate can be curative
  • immunosuppressant
  • abortifacient
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20
Q

MTX toxicity

A 
acute:
-myleosuppression
rash
neurotoxicity-seizure,coma
pneumonitis
mucositis

delayed
nephrotoxicity
impaired fertility
oppurtunisitc infection
lymphome
encephalopathy
hepatoxicity

-leucovorin..converted to methylene FH4-> rescue from toxicity but does not reverse neurotoxicity

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21
Q

F-FU resistance

A

works by incorporating into dna

  1. decreased activation-cancer cells dont convert 5-FU to 5fdUm
  2. altered substrate-altered or increase thymidylate synthase levels
22
Q

5-Fu therapy

A

-broad spectrum solid tumors
- first line for colorectal cancer
synergy -folinic acid-5FU-thymidylate form ternary complex

23
Q

5-fu toxicity

A

-gi toxicity-nausea vomiting
-alopecia
neurotoxicity
myelosuppression
hand-foot syndrome
-palmar plantar erythema-pain, sensitivity to touch
coronary artery vasospasm
acute chest pain with EKG evidence of ischemia

24
Q

cytarabine moa

A

degraded by cytidine deaminase to inactive uracil metabolites-primarily in liver

-enters cells via nucleoside transporter->cytarabine->
1.incorporates into DNA and blocks elongation,activates checkpoint kinases and apoptosis
competitive inhibition of dna polymerase alpha(dna synthesis) and beta(dna repair)

25
resistance to deoxycytidine analogs
- dec conversion to active form-loss of deoxycytidine kinase - dec transport - inc deactivation
26
deoxycytidine analogs therapeutic use
cytarabine AML other lymphomas and leukemias has no affect on solid tumors gemcitabine broad range solid tumors non hodgkin lymphoma azacitidine aml myelodysplastic
27
deoxycytidine analogs toxicity
gemcitabine can cause radiation toxicity and should not be used with radiotherapy hemolytic uremic syndrom gemcitabine and cytarabine dyspnea, pulmonary infiltrates-can be fatal mucositis-nausea vomiting alopecia cerebellar toxicity- high dose or intrathecal -ataxia-slurred speech cerebral toxicity- high dose or intrathecal-seizures or come
28
purine analog 6MP MOA
converted to TIMP TIMP inhibits de novo purine synthesis 6-TGN incorporation into DNA creates strand breaks and mispairing
29
resistance to purine analogs
- inc alkaline phosphatase - deficiency in activating enzyme HGPRT - dec drug uptake or in drug efflux - impaired recognition of dna breaks and mismatches cross resistance btw mercaptopurine and thioguanine
30
6-MP therapeutic use and toxicity
therapeutic: acute lymphoblastic leukemia components of various regimens immunusuppressant: crohns disease potent t cell suppression ``` toxicities myelosuppression hepatotoxicity gi symptoms risk to infection ``` drug interaction-allopurinol inhibits xanthine..more toxic metabolite..decrease dose of 6mp
31
Doxorubicin MOA
-cyp inhibitor MOA topoisomerase inhibition- irreparable DNA breaks apoptosis intercalation into DNA- insert btw base pairs ->uncoiling 1. blocks dna synthesis 2. causes dna strand scission free radical formation - free radicals attacks DNA and oxidize bases - single strand dna scission
32
anthracycline resistance
multidrug resistance is common 1. inc glutathione peroxidase activity 2. dec activity of topoisomerase 3. inc repair of dna breaks 4. cellular export of drug
33
anthracycline therapeutic uses
``` doxorubicin wide range of solid tmors lymphomas myeloma (most widely used cancer drug) ``` daunorubicin AML(with cytarabine) idarbicin AML (with cytarabine) valrubicin intravesical for refractory bladder carcinoma
34
anthracycline toxicity
cardiotoxicity pericarditis-myocarditis CHRONIC- cumlative,irreversible, progress to CHF neurotoxicity peripheral and CNS injection related extravasion radiation recall severe local skin reaction in irradiated tissue malignancy leukemogenic
35
anthracycline drug interaction
doxrubicin and trastuzumab -inc risk of cardiac toxicity paclitaxel and anthracycline inc risk of anthracycline toxicity (administer anthracycline before paclitaxel) metabolic and transport related inducers /inhibitors/ substrates of p glycoprotein, cyp3a4, cyp2d6
36
vince alkaloids moa and special traits
- major substrates of cyp3a4 and p glycoprotein | - block polymerization with alpha tubulin by binding wiht beta tubulin..cells are blocked in mitosis=apoptosis
37
vince alkaloids resistance
- inc expression of mdr increase efflux - mutation in beta tubulin or dec expression of it...vince alkaloids prevented from binding to target - multiple drug resistance is common
38
vince alkaloids therapeutic use
vinblastine and vincrastine= various solid tumors | vinorelbine= non small cell lung cancer and breast cancer
39
vince alkaloids adverse effects
vinblastine myelosuppression (less neurotoxicity than vincristine) vincristine neurotoxicity-SIADH limited myelosuppression Vinorelbine -myelosuppression with neutropenia other toxicities nausea vomiting constiptaion CAUTION: fatal if given intrathecally , cyp3a4 and pgp related drug interactions
40
Taxane MOA
1. bind to beta tubulin ...enhancing polymerization 2. nonfunctional microtubules created 3. chromosome segregation does not occur 4. arrest in mitosis-apoptosis
41
taxane resistance
- inc expression of mdr - inc anti apoptotic factor - mutation in beta tubulin
42
taxane therapeutic use
paclitaxel broad spectrum tumors paclitaxel protein bound metastatic breast cancer docetaxel broad spectrum solid tumors cabazetaxel metastatic prostate cancer..hormone refractory
43
taxane adverse effects
peripheral neuropathy edema leukemogenic potential severe hypersensitivity reaction..premedicate to reduce reaction radiation recall-severe reaction in irradiated skin
44
taxane toxicities
- cyp2c8,cyp3a4,pglycoprotein - inhibitors may inc taxane levels=toxicity - inducers may dec levels-subtherapeutics
45
camptothecin analogs
requirements for activity - s-conformation of chiral center at c20 - c10 hydroxyl group irinotecan is prodrug converted SN38 topotecan is not a prodrug closed ring form is active and open ring form is inactive basic ph favor open ring...acidic ph favor lactone closed ring form does reduction recommended in patients with UGT1A1 allele dec UGT activity=inc toxicity
46
camptothesins mechanisms
1. bind to topoisomerase 2. strand resealing prevented 3. single strand break accumulates 4. replication fork collides with complex..irreversible double strand break-apoptosis
47
camptothesins resistance
1. decrease in efflux | 2. alterations in topoisomerase
48
camptothesins therapeutic use
irinotecan solid tumor metastic colorectal cancer FOLFIRI folinic acid-5FU-irinotecan ``` Tropotecan recurrant ovarians cancer small cell lung cancer cervical cancer ewings sarcoma ```
49
camptothesins toxicities
sever diarrhea=irinotecan myelosuppresion nausea vomiting
50
epipodophyllotoxins MOA
1.formation of ternary complex 2. inhibition topoisomerase..prevent resealing of double breaks 3.accumulation of dna breaks-apoptosis cell arrest in S or early G2
51
epipodophyllotoxins resistance
- dec topoisomerase - efflux amplification of mdr - mutation in p53 supressor gene (required for apoptosis)
52
epipodophyllotoxins therapeutic and toxicities
etoposide testicular cancer small cell lung cancer teniposide ALL acute lymphocytic toxicites myelosupression alopecia leukemia

medical school midcomp 5 (11 decks)

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