chemotherapy- alkylating agents
TRANSCRIPT
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Chemotherapy Rotations:
Alkylating Agents and PlatinumCompounds
Nicole Shilkofski, M.D.
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Learning Objectives
Explain mechanisms of alkylating agents,
discriminating key differences between bifunctional
and monofunctional agents in creating inter-strand
cross-links in cancer cell DNA.
Understand the likely mechanisms of action of
platinum compounds and the association of anti-
neoplastic platinum compounds and kidney damage.
Gain familiarity with common side effects associated
with anti-neoplastic drug administration, including
neutropenia, anemia, thrombocytopenia, hair loss, and
gonadal dysfunction
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Alkylating Antineoplastic Agents
Chemical assault on DNA of cancer cells
Modify functional groups on genomic DNA
and protein of cells (attaches alkyl group to
DNA- usually guanine base of DNA, mostcommonly number 7 nitrogen atom of
purine ring)
Explains both ability to kill cancer cells viaDNA damage but also cytotoxic effects on
cells that divide frequently (GIT, bone
marrow, testicles, ovaries)
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History of Chemical Warfare:
Exposure to Alkylating Agents in Wartime:World War II- December 1943
An estimated 9,000,000 shells filled with sulfur
mustard were fired in World War I with some1,205,655 nonfatal casualties and 91,198 deaths-
skin burns, alkylation of nerve endings in
diaphragm= major cause of death
Side effects post gas experienced similar to
antineoplastic agents (hair loss, alterations in
blood counts etc.)
Sulfur mustard gas is generated when sulfur
chloride is added to ethylene
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WWII: Bombing in Italy-
US Liberty ship, which
had been carrying a
secret cargo of 2,000
M47A1 World War I
type mustard gas bombs,
each of which held 60-70
lbs of sulfur mustard
Within a day, symptoms of mustard poisoning began appearing
in rescued casualties, in medical personnel, and in local residents
(among military personnel, 628 became blind and developed
chemical burns; 83 ultimately died); medical personnel described a
garlic-like odor
A young medical officer described the striking reduction in
white blood cell counts, particularly in lymphocyte counts,
in addition to the expected chemical burns
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Reactive Nucleophilesin DNA
Drugs are electophiles- modify nucleophiles in DNA: N7
position of Guanine is most commonly modified
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Bifunctional vs monofunctional
Alkylating Agents Bifunctional (dialkylating)- can react with
2 different residues resulting in cross
linkage (antineoplastic drugs)
Monofunctional (monoalkylating)- can
react with only one N7 of guanine so do not
prevent separation of DNA strands of helixbut prevent DNA processing enzymes from
accessing DNA (mutagens and carcinogens)
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CH2
CH2 CH2
CH2
NR
Cl
Cl
:
CH2
CH2 CH2
CH2
NR
Cl
+
CH2
CH2 CH2
CH2
NR
Cl
+N
CH
N
immonium ion
carbonium ionguanine (or other
intracellular nucleophile)
alkylating agent
Chemistry of Bifunctional Alkylating AgentDamage
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immonium ion carbonium ion
adducted guanine
Chemistry of Bifunctional Alkylating AgentDamage
(continued)
:CH2
CH2 CH2
CH2
N
R
Cl
+N
CH
N
CH2 CH2
+
N
R
CH2 CH2guanine
CH2 CH2
N
R
+CH2 CH2guanine
guanine
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Interstrand DNA Cross-linkCaused by
Bifunctional Alkylating Agent
Stop tumor growth by crosslinking guanine nucleobases in DNA
double helix strands so strands cannot uncoil and separate andcells can no longer divide
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N
R
N
R
bifunctional
alkylating agent
cross-link
bifunctional
alkylating agent
cross-link
DNA Cross-linksInterfere with Replication
DNA replication
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mechlorethamine
(nitrogen mustard)
Nitrogen Mustards in Clinical Use
CH3
melphalan (L-phenylalanine
mustard; (L-PAM)
HOOC CH CH2
NH2
HOOC CH2CH2CH2
chlorambucil
P
O
O
NH
cyclophosphamide
PO
O
N CH2 CH2 Cl
NH CH2 CH2 Cl
ifosfamide
CH2
CH2
CH2
CH2
NRCl
Cl
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Pharmacology of the Nitrogen Mustards
DrugPrincipal Route
of AdministrationPlasma t1/2 Characteristics
mechlorethamine
chlorambucil
melphalan
cyclophosphamide
ifosfamide
intravenous
oral
oral
oral/intravenous
intravenous
very short
(1 minute)
1.5 hours
1.5 hours
7 hours
7 hours
rapid action
potent vessicant
slow rate of
conversion to
carbonium ion
***must be
act ivated b y
l iver metabol ism
(prodrugs)
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Toxicities of the Nitrogen Mustards
Drug Acute Delayed (Dose-Limiting)
mechlorethamine
chlorambucil
melphalan
cyclophosphamide
ifosfamide
severe nausea/vomiting,
phlebitis/skin irritation
nausea/vomiting
mild nausea
nausea/vomiting
nausea/vomiting
bone marrow suppression,
amenorrhea
bone marrow suppression
bone marrow suppression
bone marrow suppression,
hemorrhagic cystitis,
alopecia, amenorrhea,
sterility, water retention
bone marrow suppression,
hemorrhagic cystitis,
alopecia, neurotoxicity,
water retention
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Platinum based chemotherapy
drugs Often called Alkylating like drugs
Do not have an alkyl group but still damage
DNA by interfering with DNA repair
Also bind at N7 of guanine
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Platinum Compounds: Cisplatin
Cross-Links to DNA and Protein
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Pt
Cl Cl
NH2 NH2
Pt
O
O
O
O
NH2
NH2
Pt
O
O
O
O
NH2
NH2
cisplatincarboplatin
oxaliplatin
Platinum Compoundsin Clinical Use
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Pharmacology of the Platinum Compounds
DrugPrincipal Route
of AdministrationPlasma t1/2
Characteristics
cisplatin
carboplatin
oxaliplatin
intravenous
intraperitoneal
intravenous
intravenous
20-40 minutes
2-3 hours
2-3 hours
Rapid reaction; 30-50%
of drug excreted in urine
within 24 hours (thereforehas side effect of kidneydamage)
Slow reaction
Slow reaction
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Toxicities of the Platinum Compounds
Drug Acute Delayed (Dose-Limiting)
cisplatin
carboplatin
oxaliplatin
severe nausea/vomiting,
anaphylactic reactions
moderate nausea/
vomiting
nausea/vomiting
***nephrotoxicity, ototoxicity,
peripheral neuropathy,
bone marrow suppression
bone marrow suppression
bone marrow suppression,
neurotoxicity, diarrhea
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vomiting center(neural networks in the
nucleus tractus solitarius)
chemoreceptortrigger zone
(area postrema)
peripheral receptors
(vagal and splanchnic nerves)
vestibular
center
cerebral cortex
Chemotherapy-Induced Nausea and Vomiting
drugs:opiates, anesthetic
agents, cardiac glycosides,chemotherapy (immediate)
metabolic disorders:
Uremia, ketoacidosis,
hypoxia
anticipitory emesis:elicited by chemotherapy
(before administration)
motion sickness
inner ear disorders
intestinal injury
toxinschemotherapy (late)
radiation therapy
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Treatment and Prophylaxis of Chemotherapy-
Induced Nausea and Vomiting
5-HT3receptorblockadeselective serotonin type 3(5-HT3) receptor antagonistsondansetron, granisetron
dolasetron
benzamides
metoclopramide
corticosteroids
dexamethasone, methylprednisolone
phenothiazines
prochlorperazine
promethazine, thiethylperazine
benzodiazepineslorazepam
butyrophenones
haloperidol, droperidol
cannabinoids
dronabinol, nabilone
anti-emetic mechanism of action
dopamine and 5-HT3
receptor blockade
unknown
dopamine receptor
blockade
anxiolytic, amnesic
dopamine receptor
blockade
general psychotropic
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Other Toxicities: Effects on Rapidly Replicating Cell Populations
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Timing of Chemotherapy-Induced Neutropenia
Dose affects severity but not timing of decrease in ANC
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Treatment ofChemotherapy-Induced
Bone Marrow Dysfunction
Transfusion of blood components
red blood cells
platelets
granulocytes (rare- cells dont live long)
Hematopoietic cytokines
erythropoietin
G-CSF (filgrastim)
GM-CSF (sargramostim)
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chemotherapy
daily G-CSF
Effect of G-CSFTreatment on Chemotherapy-
Induced Neutropenia
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Age/Gender
pubertal (non-proliferating) gonads remarkably resistant
to cytotoxic effects of anti-neoplastic drugs
Chemotherapy agent(s) and dose, other cancer therapy
70% versus 10% recovery of spermatogenesis in boys
after treatment with cyclophosphamide at lower vs higher doses
ChemotherapyEffects on Gonadal Function
alkylating agents/platinum compounds particularly bad
Hodgkins disease treatment: MOPP (alkylating agents) with
97% azoospermia (13% recovery)
breast cancer treatment: AC (doxorubicin/cyclophosphamide)
amenorrhea 96% women age 40-49 versus 0% women age
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oxidants
electrophiles
genomedamage
cell death
mutation
repair
proliferation
exogenouschemotherapy
carcinogensother toxins/irritants
endogenousmetabolisminflammationcell signaling
many enzymes
cytochrome P450's
detoxification(GSTP1, GSTs, GPx, etc.)
inactivated
transformation
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Chemotherapy-Associated Acute Myeloid Leukemia
(AML)After Treatment for Hodgkins Disease*
RT alone
chemotherapy alone
RT + MOPP (alkylators)
RT + other alkylators
0%
1.4% +/- 2.3%
10.2% +/- 5.2%
4.8% +/- 1.6%
n = 1329 Hodgkins disease survivors
treatment actuarial risk of AML________________________________
*Valagussa et al. J Clin Oncol 4: 830 (1986)
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Important Take Home Points
Bifunctional vs monofunctional alkylating
agents
Pharmacologic mechanism of action ofalkylators on DNA
Side effects of alkylating and platinum
agents
Chemotherapy induced nausea mechanisms
Effects of antineoplastic drugs on gonad
f ti