Chemotherapy- Alkylating Agents

7/25/2019 Chemotherapy- Alkylating Agents

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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



hemorrhagic cystitis,

alopecia, amenorrhea,

sterility, water retention


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,




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

Documents

Chemotherapy- Alkylating Agents