+

Alkylating Agents
Michelle Anne P. Cruz

+Largest class of antineoplastics

General Properties/Mechanism:
All

are electrophilic molecules that covalently modify nucleophilic

molecules in cells
DNA

most important adduct (N7 and O6 of Guanine) for anticancer

properties.

General

Types of Alkylating Agents:

Monofunctional:

cause single strand DNA

breaks
Bifunctional: inhibit DNA replication and
transcription by

cross-linking DNA

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Side Effects

Gastrointestinal distress

Bone marrow supression

Alopecia

Secondary Leukemias

Sterility

Veno-occlusive disease of liver (high dose)

Subtypes:
Nitrogen

mustards

Organoplatinum
Nitrosoureas

+
Nitrogen Mustards
Compound

Agents that replace hydrogen with an alkyl group (by

substitution). Forms adducts causing DNA strand
breakage.

The nitrogen mustards are cytotoxic chemotherapeutic

agents similar to mustard gas which was used in World
War I.
Thiotepa
Mechlorethamine
Ifosfamide
Busulfan

Cyclophosphamide
Melphalan
Chlorambucil
Bendamustine

+
Thiotepa
Mainstay

therapy for solid tumors when

followed by autologous bone marrow
transplantation

Treatment

of breast and ovarian cancer, and

Hodgkins and non-Hodgkins lymphomas

Treatment
To

of superficial tumors of the bladder.

help control the accumulation of fluid in

body cavities that may result from certain
cancers

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Side effects of Thiotepa:
Common

Side Effects

Low

blood counts.

Hair

loss

Less Common Side Effects

Nausea and vomiting

Mouth

sores

Allergic

reaction

Bladder

irritation

+
THIOTEPA

+
Mechlorethamine
(2-chloro-N-(2-chloroethyl)-N-methyl-ethanamine)

+
Methclorthamine

Strong vesicant and is taken by IV infusion and is used

to treat prostate cancer.

Dialkylating agent

DOC: Hodgkins disease

Disadvantage: It has mutagenic and carcinogenic effect

on bone marrow stem cells.

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Methclorethamine (Mustargen)

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Ifosfamide
Treatment for:

recurrent testicular cancer and germ cell tumors,

sarcoma, Non-Hodgkins Lymphoma, Hodgkins disease,
bladder cancer

Produce dose limiting toxicity haemorrhagic cystitis.

Toxicity can be reduced by administering mesna (-SH

compound).

+
Side effects

Low white blood cell count.

Low

platelet count.

Nausea
Poor

and vomiting.

appetite

Blood

in the urine.

+
Ifosfamide

+
Busulfan
Mechanism

of Action:

Following

systemic absorption, carbonium

ions are rapidly formed, resulting in alkylation
of DNA.

Treatment

for:

Chronic Myelogenous Leukemia (CML)

+
Busulfan
Side

Effects:

causes sulfur stripping

Low blood counts.

Nausea and vomiting

Diarrhea

Loss of fertility.

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Busulfan

+
Cyclophosphamide
TREATMENT FOR:

Prophylaxis of nephrotic syndrome

Wegeners granulomatosis

Idiopathic pulmonary hemosideroses

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Mechanism of Action

Main effect of cyclophosphamide is due to its metabolite

Phosphoramide mustard.

Side Effects

Cough

Fever or chills

Lower back or side pain

Missing mestrual periods

Painful or difficult urination

Nausea or vomiting

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Cyclophosphamide

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Melphalan
TREATMENT FOR:

Multiple Myeloma

Mechanism of Action

Attachment of alkyl groups to DNA bases, forming

monoadducts and resulting in the DNA being
fragmented by repair enzymes in their attempts to
replace the alkylated bases, preventing Dna synthesis
and RNA transcription from the affected DNA

+
Mechanism of Action

DNA damage via the formation of cross-links

Induction of mispairing of the nucleotides leading to

mutations.

TOXICITY

Toxic to bone marrow

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Melphalan

+
Chlorambucil
TREATMENT FOR:

Chronic lympocytic leukemia and macroglobulinemia

SIDE EFFECTS

Drop in white blood cells

Drop in red blood cells

Drop in platelets

Amenorrhoea

Loss of fertility

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Chlorambucil

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Bendamustine
TREATMENT FOR:

Chronic Lymphocyctic leukemia

Non Hodgkins Lymphoma

Myeloma

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Side Effects

Skin rash

Fatigue

Loss of fertility

Drop in platelet

Drop in red blood cells

Sore mouth

Drop in white blood cells

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Bendamustine

+
Organoplatinum
Mechanism

of Action

Establishes cross-links within and between DNA strands

Cosplatin

Carboplatin

Oxaliplatin

+
Cisplatin
- Most reactive and most effective in platinating DNA
Route of administration: IV
TREATMENT FOR:

Testicular cancer

Germ cell cancer

Bladder cancer

Head and neck cancer

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Side Effects

Fatigue

Anemia

Bruising

Kidney Damage

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Cisplatin

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Carboplatin

Fromed by replacing the chloride leaving groups of

cisplatin with 1, 1 cyclobutanedicarboxylato ligand.

Side Effects

Hypokalemia

Hypomagnesium

Hyponatremia

Hypophosphatemia

Hypocalcemia

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Carboplatin

+
Oxaliplatin
TREATMENT FOR:

Colorectal cancer,

food pipe cancer

Side Effects

Diarrhea

Taste changes

Back pain

Numbness or tinglin

+
Oxaliplatin

Typically administered in combination with fluororacil

and leucovorin in a combination known as Folfox for the
rx of colorectal.

Mechanism of Action

Undergoes nonenzymatic conversion to active

derivatives

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Oxaliplatin

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Nitrosoureas

Alkylates DNA with restricted uncoiling and replicatino of

stands

Lomustine

Carmustine

Procabazine

Decarbazine amd Temozp;p,ode

Altretamine

Stretozocin

+
Lomustine
TREATMENT FOR:

Metastatic brain tumor

Recurring Hodgkins disease

Side Effects

Hair loss

Loss of appetite

Nausea and vomiting

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Lomustine

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Carmustine

It is 1,3 bis(2-chloroethyl)-1-nitrosourea. Administered

by intravenous infusion after reconstitution.

TREATMENT FOR:

Brain tumors

Side Effects

Facial flushing

Pain and burning at the injection site.

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Carmustine

+
Procarbazine
Taken capsule form by mouth.
TREATMENT FOR:

Hodgkins lymphoma

Side

Effects

Low white blood cell count

Low platelet count

Nausea and vomiting

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Procarbazine

+
Dacarbazine and Temozolomide
TREATMENT FOR:

Melanomas

Malignant Melanoma (combined with Oblimersan)

Side

Effects

Nausea

Vomiting

Diarrhea

Blurred vision

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Dacarbazine and Temozolomide

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Altretamine

Involves in hydroxylation of methyl group

Side

Effects

Nausea and vomiting

Peripheral neuropathy

Vertigo

Dizznies

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Altretamine

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Streptozocin

Useful in inducing hyperglycemia on animal model

From Strepzoticus achromogenes

Streptozocin

Decrease bone marrow function

Black stool

Fever or chills

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Streptozocin