1/9 Chemotherapy - Weber

Question 1

overview of cell cycle and agents

3 important points for intervention/mechanisms

Answer 1

agents acting during DNA synth

• antimetabolites
• antifolates
• topotecan

agents disrupting mitotic spindle

• paclitaxel

agents causing DNA damage

• alkylating agents
• DNA intercalating agents

Question 2

alkylating agents: tox

sites

effects

Answer 2

dose related tox in areas with rapidly growing cells

1. GI tract (nausea, vomiting, mucositis)
2. bone marrow (neutropenia, thrombocytopenia)
3. reproductive systems

vesicant effects

carcinogenic: risk of secondary malig, AML

Question 3

alkylating agents x5

Answer 3

nitrogen mustards: bis-chroloethyl amine

CYCLOPHOSPHAMIDE

alkylsulfonate

BUSULFAN

nitosureas

carmustin

non-classic alkylating agents

procarbazine

platinum compounds

cisplatin

carboplatin

oxaliplatin

Question 4

cyclophosphamide

Answer 4

nitrogen mustard

mech: forms DNA crosslinks → inhibition of DNA synth/fx

tox:

• acute: GI n/v
• delayed: depressed periph blood count
  
  • v high doses: hemorrhagic cystitis

Question 5

busulfan

Answer 5

alkyl sulfonate

mech: forms DNA crosslinks → inhibition of DNA synth/fx

tox:

• acute: GI n/v
• delayed: pulm fibrosis

applications: CML, bone marrow ablation

Question 6

carmustine

Answer 6

nitrosurea

mech: forms DNA crosslinks → GC crosslinks

• highly lipid soluble
• crosses bbb (so brain tumors!)

tox:

• acute: GI n/v
• delayed: myelosuppression (except streptozocin)

applications: brain tumors

Question 7

procarbazine

Answer 7

non-classic

mech: inhibits DNA/RNA/protein synthesis

metabolism: oral

• cytotoxic drug metabolite acts as MAOI
• adverse interactions with: sympathomimetic amines, TCAs, antihistamines, CNS depressants, alcohol

tox:

• acute: GI n/v
• delayed: myelosuppression, CNS tox (when used with MAOIs)
• high risk of secondary malignancy

applications:

• HL
• NHL
• brain tumors
• components of MOPP (mechlorethamie, vincristine, procarbazine, prednisone for Hodgkin’s disease)

Question 8

cisplatin

Answer 8

alkylating agent: platinum based

mechanism: “stick” to DNA strands

• intra/inter strand DNA crosslinksbind cytoplasmic and nuclear proteins too
• cytotoxic in all stages of cell cycle

metabolism: renal excretion

synergize with: other alkylating agents, fluropyrimidines, taxanes

toxicity:

• acute: n/v (highly emetogenic)
• delayed: nephrotoxicity, peripheral sensory neuropathy, ototoxicity
  
  • irrev nerve dysfx

clinical applications: nonsmall cell and small cell lung cancer, head/neck cancer, breast/ovarian/bladder/GE jx cancers

Question 9

carboplatin*

oxaliplatin*

Answer 9

carboplatin: less renal/GI tox than cisplatin

oxaliplatin: effective in cells with DNA mismatch repair defects

• reversible, dose dependent neruopathy

Question 10

drugs affecting DNA nt synthesis in context

Answer 10

Question 11

methotrexate (MTX)

Answer 11

folic acid analog → disrupts fulate metabolic pathway

mech: binds/inhibits DHFR and TS (thymidylate synthase)

• IV or intrathecal

metabolism: in cell

• renal excretion (adjust dose with renal insuff)
• ASA, penicillin, NSAIDS inhibit renal excretion

toxicity: mucositis, diarrhea, myelosuppression (neutropenia, thrombocytopenia)

reverse effects with LEUCOVORIN

Question 12

5FU/DPD

Answer 12

fluoropyrimidine

(5-fluorouracil)

mech:

• parent form is inactive
• activated metabolites include:
  
  • FdUMP (DNAi) inhibits TS: inhibits DNA synth and induces thymineless death
  • FdUTP: inhibits DNA synth and fx
  • FUTP: interferes with RNA processing and translation

metabolism

• IV admin (not orally available)
• short halflife → 85% of dose catabolized by DPD (dihydropyridine dehydrogenase)
  
  • if DPD low/absent, tox is severe/lifethreatening!

toxicity

• myelosuppression
• GI: n/v, diarrhea, mucositis
• neurotixicity
• derm: hand-foot syndrome with cont infusion

Question 13

capecitabine

Answer 13

pro-prodrug of 5FU

• orally available
  
  • active metabolites generated into liver
  • metabolites converted to 5FU in TUMOR!!! by thymidine phosphorylase

toxicity:

• profile reflects continuous infusion, esp: hand-foot syndrome, diarrhea

Question 14

cytarabine (Ara-C)

Answer 14

S phase specific antimetabolite

mech:

• competitively inhibits DNA polymerases → blocks DNA synthesis and repair
• is incorporated into DNA → blocks chain elongation and DNA ligation

metabolism: IV admin bc cleared v v rapidly (almost continuous infusion)

good for hematologic malignancies (exclusively)

toxicity:

• acute: GI
• chronic: myelosuppression

Question 15

6-mercaptopurine/TPMT/allopurinol

Answer 15

• inactive parent molecule that is metabolized by HGPRT
• inhibits enzymes of purine nt synthesis
• 3P forms can be incorporated into RNA and DNA

deactivation of 6MP catalyzed by xanthine oxidase

• how do you get around this? allopurinol!!! (XO inhibitor)
  
  • have to be careful, bc can lead to toxicity when used with 6MP (need to reduce the 6MP dose)

pharmacogenetics: TPMT deficiency can result in severe toxicity (myelosuppression, diarrhea)

Question 16

cladribine

Answer 16

mech:

• inhibits DNA synthesis/repair via inhibition of ribonucleotide reductase
• cladripineTP is incorporated into DNA → induces apoptosis

toxicity:

• myelosuppression
• n/v
• imunosuppression: CD4/CD8 T cells

Question 17

vincristine

Answer 17

vinca alkaloid

• induce microtubule dysfx: inhibit mt polymerization by binding to beta tubulin → mitotic arrest in metaphase
  metabolism: CYP450
  toxicity: n/v, bone marrow suppression, alopecia, potent vesicant (blistering agent)

Question 18

paclitaxel

toxicity

role of abraxane

Answer 18

toxicity:

• acute: n/v/hypotension, hypersensitivity in 5% (prevent with premedication: dexamethasone, diphenhydramine)
• delayed: myelosuppression, neurotoxicity, peripheral sensory neuropathy

abraxane: paclitaxel formulated with near-nanoparticle size albumin carrier

• no paclitaxel related hypersensitivity!!
• decr toxicity overall compared to paclitaxel

Question 19

irinotecan

Answer 19

prodrug converted to SN38 metabolite in liver (1000x more potent than SN38)

excreted in bile/feces

toxicity:

• diarrhea
  
  • early: cholinergic event
  • late: 2-10d post tx, can be severe
• bone marrow suppression

Question 20

doxorubicin/dexrazoxane

Answer 20

DOXORUBICIN: anthracycline: topo II inhibitor

• isolated from strep peucitius (soil microbe)
• high affinity for DNA intercalation (blocks DNA/RNA synth)
• generates semi-quinone free radicals (major mech of cardiotox)
• binds to cell embranes → alters fluidity/ion transport

metabolism:

• IV admin
• metabolized to active metabolite in liver

toxicity:

• myelosuppression with neutropenia
• mucositis
• cardiotox:
  
  • ​acute: arrhythmias and conduction abnormality
  • chronic: dose dependent dilated cardiomyopathy
  • tx? Fe chelator can reduce events in hi risk : DEXRAZOXANE

Question 21

mitomycin C

Answer 21

antibiotic (Streptomyces casepitosus)

• requires activation via reduction → acts on tumor cells which exist in hypoxic environment (favors reduction)
• potent DNA crosslinker via alkylation
• active in all phases of cell cycle

toxicity:

• n/v
• hemolytic uremic syndrome

Question 22

bleomycin

Answer 22

clygopeptide antibiotic from Streptomyces verticillus

metal binding

binds to DNA → ss/ds breaks, inhibits DNA synth, lipid peroxidation

G2 phase arrest!!!

IV, IM, SQ infusion

renal excretion

toxicity: PULMONARY

Question 23

CHEMO MAN

Answer 23