ALKYLATING AGENT Flashcards
classification of alkylating agents
Nitrogen mustards are also known as bischlorethylamine
A. triazenes
(dacarbazine),
B. alkyl sulfonates
(busulfan),
C. nitrogen mustards(bischlorethylamine)
(cyclophosphamide), mechlorethamine, chlorambucil, ifosfamide,Melphalan
D nitrosoureas
carmustine,
lamustine
samustine
NON CLASSIC ALKYLATING AGENTS
PROCARBAZINE
DECARBAZINE
BAMUSTINE
WHAT ARE THE bis(chloroethyl)amines,
For treating breast and ovarian cancer, chronic myeloid leukemia,
cyclophosphamide,
mechlorethamine, melphalan, and chlorambucil are the most useful
Thiotepa and busulfan
How CLASS OF alkylatign agents exert their effect
the alkylating agents exert their cytotoxic effects via
transfer of their alkyl groups to various cellular constituents.
However, these drugs
react chemically with sulfhydryl, amino, hydroxyl, carboxyl, and
phosphate groups of other cellular nucleophiles as well.
The general
mechanism of action of these drugs involves intramolecular cycliza-
tion to form an ethyleneimonium ion that may directly or through
formation of a carbonium ion transfer an alkyl group to a cellular
constituent
Major sites of alkylation
The major site of alkylation within DNA is the N7 position of
guanine; however, other bases are also alkylated albeit to lesser
degrees, including N1 and N3 of adenine, N3 of cytosine, and O6
of guanine, as well as phosphate atoms and proteins associated
with DNA. These interactions can occur on a single strand or on both strands of DNA through cross-linking, as most major alky-
lating agents are bifunctional, with two reactive groups.
How guanine is affected?
Is it cell specific or act on replicating cells?
Alkylation of guanine can result in miscoding through abnormal base pairing
with thymine or in depurination by excision of guanine residues.
The latter effect leads to DNA strand breakage through scission of
the sugar-phosphate backbone of DNA.
Cross-linking of DNA appears to be of major importance to the cytotoxic action of alkylating agents, and replicating cells are most susceptible to these
drugs. Thus, although alkylating agents are not cell cycle specific,
cells are most susceptible to alkylation in late G 1and S phases of the cell cycle.
SIDE EFFECTS OF ALKYLATING AGENTS
dose-related and occur in rapidly growing tis-
sues such as bone marrow, gastrointestinal tract, and reproductive system.
ALOPECIA
CYSTITIS
SKIN PIGMENTATION
Nausea and vomiting can be a serious issue
are potent vesicants.
alkylating agents are carcinogenic in nature, and there is an increased risk of secondary malignancies,
especially acute myelogenous leukemia.
MOST WIDELY USED ALKYLATING AGENT
How alddophosphamide in differs of action
Liver appears to be protected
through the enzymatic formation of the inactive metabolites
4-ketocyclophosphamide and carboxyphosphamide.
its high oral bioavailability.
oral and IV
inactive in parent form, activated by cytochrome p450 enzymes converts cyclophosphamide to 4 -hydroxycyclophosphamide, which is in equilibrium with aldophosphamide.
active metabolites are delivered to
both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mus-
tard and acrolein—occurs.
MOPP
CYCLOPHOSPHAMIDE
MELPHALAN
NITROSUREAS
Used for haematologic and solid cancers generally as
combination therapy. E.g MOPP
M=Mechlorethamine
O=Oncovin
P=Prednisone
P=Procarbazine
Cyclophosphamide as single or in combination used for Burkitt’s
lymphoma. Hodgkin’s lymphoma and breast cancer.
Nitrosoureas are preferred in brain tumors
Melphalan (amino acid analogue) is used in multiple myeloma,
ovarian cancer and breast cancer
where does the toxicity occur?
Why cyclophosphamide has less side effects?
Toxicities are generally dose related and particularly occur in
rapidly growing tissues such as bone marrow, gastrointestinal
tract and gonads.
Cyclophosphamide produces less GIT and
hematopoitic toxicity than other alkylating agent. This is due
to that aldehyde dehydrogenase oxidizes aldophosphoramide
into carboxyphosphamide, an inactive product that excreted
through urine.
Toxicity of alkylating agents
nausea vomiting within 30-60 min
WBC count reach their low point after 10-12 days
oral ulcer, cystitis, sepsis, cardiotoxicity
