B35 Alkylating agents

Question 1

Most common alkylating agent

Answer 1

Cyclophosphamide

Question 2

Cyclophosphamide

MoA and kinetics

Answer 2

It is a Prodrug, can be given Orally or IV.

Hydroxylated intermediates are made by liver CYP enzymes, then these are broken down to the active metabolites:

• Phosphoramide mustard
• Acrolein

Phosphoramide mustard reacts with DNA to create the crosslinks.

Cyclophosphamide and all its metabolites are excreted in urine.

Question 3

Cyclophosphamide
Indications
SEs

Answer 3

Rx:

1) Broad range of solid and blood tumors.
2) For very severe autoimmune syndromes

SEs:

• Hemorrhagic cystitis from its Acrolein metabolite
• Increased risk of bladder cancer after treatment
• SIADH and hyervolemic hyponatremia
• Potentially permanent infertility in both men and women, can induce premature menopause in women
• Marrow suppression and infections, weekly blood counts needed.

Question 4

The other drug sharing its MoA with cyclophosphamide

Answer 4

Ifosfamide

Question 5

Ifosfamide

Kinetics, SEs

Answer 5

Unlike Cyclophosphamide, Ifosfamide can only be given by IV.

Its effect is the same, but generates different toxic metabolites than acrolein, still has hemorrhagic cystitis and all the same SEs.

Additionally, Has a high incidence of neurotoxicity

Question 6

List the alkylating agents

Answer 6

Mustard derivatives

• Cyclophosphamide
• Iphosphamide (Ifosfamide)

Nitrosureas

• Carmustine
• Lomustine
• Stretozocin

Others:

• Busulfan
• Dacarbazine and Temozolomide
• Thiotepa
• Chlorambucil

Question 7

What are the 2 main nitrosourea drugs and their acronyms

Answer 7

Carmustine - BCNU, bis-chloroethylnitrosourea

Lomustine - CCNU

Question 8

Streptozocin

MoA and indications

Answer 8

A nitrosourea alkylating agent with selective and very high toxicity to pancreatic beta cells.

Used for islet cell cancers and in animal diabetes models

Question 9

Carmustine and Lomustine kinetics

Answer 9

Both are very lipophilic and readily penetrate the CNS.
Wide body distribution
Excreted by kidneys

Carmusine has to be IV

Lomustine must be given orally

Question 10

Camustine and Lomustine indications and SEs

Answer 10

Rx: Tumors of the CNS.

SEs;
-CNS side effects mainly....
Dizziness
Confusion
Ataxia
Convulsions

Question 11

Busulfan
MoA
Indications

Answer 11

Alkyl Sulfonate class drug,

Forms intrastrand DNA crosslinks

Rx:
It is severely toxic to bone marrow cells, and is used as a conditioning agent prior to bone marrow transplant

Question 12

Busulfan

SEs

Answer 12

Busulfan tan, Busulfan lungs

Significant lung toxicity, that can present a range of symptoms

• Acute lung injury
• Alveolar hemorrhage
• Chronic interstitial fibrosis.

Busulfan tan - hyperpigmentation skin reaction.

marrow depletion and infections. 
secondary neoplasms (like all alkylating agents)

Question 13

What two alkylating agents generate the same active metabolite, and what is it?

What differs about their MoA?

Answer 13

Dacarbazine and Temozolomide

MTIC
which methylates DNA on O6 oxygen of guanine.

Temozolomide also inhibits the DNA repair enzyme that removes the methyl group from guanine.

Question 14

How do the kinetics of Dacarbazine and Temozolomide differ?

Answer 14

Dacarbazine is transformed to active MTIC by liver CYP enzymes

Temozolomide spontaneously generates MTIC at physiologic pH in solution.

Temozolomide also crosses into the CNS, and dacrbazine does not.

Question 15

Dacarbazine and Temozolomide
Indications
SEs

Answer 15

Dacarbazine: Melanoma, Hodgkin’s lymphoma

Temozolomide: Glioblastomas and Astrocytomas
also metastatic melanoma

SEs:
general chemo SEs, myelosuppression.

Question 16

What are the last other alkylating agents, and their use

Answer 16

Melphalan - multiple myeloma

Chlorambucil - CLL

Thiotepa - Conditioning agent prior to marrow transplant.