C H A P T E R 1 4
Antineoplastic agents
195
drugs. These agents also jeopardise the immune system
by causing
bone marrow suppression
, inhibiting the
blood-forming components of the bone marrow and
interfering with the body’s normal protective actions
against abnormal cells. The person’s haematological
profile must always be assessed for toxic effects. People
also need to understand the importance of returning
every few weeks to go through the chemotherapy, with
its adverse effects, over and over again.
Many antineoplastic drugs often result in another
adverse effect: cancer itself. Cell death due to these
agents increases the need for cellular growth, placing the
person at increased risk for mutant cell development.
Most cancer sufferers are not considered to be
“cured” until they have been cancer-free for a period of
5 years due to the possibility that cancer cells will emerge
from dormancy to cause new tumours or problems. No
cells have yet been identified that can remain dormant
for longer than 5 years, so the chance of the emergence
of one after that time is very slim.
A cancerous mass may be so large that no therapy
can arrest its growth without killing the host. In such
cases, antineoplastic agents are used as palliative therapy
to shrink the size of the tumour and alleviate some of
the signs and symptoms of the cancer, decreasing pain
and increasing function. Here the goal of drug therapy is
not to cure the disease but to try to improve the person’s
quality of life in a situation in which there is no cure.
Some emerging antineoplastic agents are discussed in
Box 14.2.
ALKYLATING AGENTS
Because alkylating agents can affect cells even in
the resting phase, these drugs are said to be non–cell
cycle-specific (see Figure 14.4). They are most useful
in the treatment of slow growing cancers, which have
many cells in the resting phase. Alkylating agents
(see Table 14.1) include the following drugs: busulfan
(
Busulfex
,
Myleran
), carboplatin (
Carbaccord
), car
mustine (
BiCNU
,
Gliadel
), chlorambucil (
Leukeran
),
cisplatin (generic), cyclophosphamide (
Cytoxan,
Endoxan)
,
dacarbazine
(generic),
fotemustine
(
Muphoran
), ifosfamide (
Holoxan
), lomustine (
CeeNU
),
melphalan (
Alkeran
), oxaliplatin (
Oxalatin, Xalox
),
procarbazine (
Natulan
), temozolomide (
Astromide,
Temizole, Temodal
) and thiotepa (generic).
Therapeutic actions and indications
Alkylating agents produce their cytotoxic effects by
reacting chemically with portions of the RNA, DNA
or other cellular proteins, being most potent when they
bind with cellular DNA. The oldest drugs in this class
are the nitrogen mustards, and modifications of the
structure of these drugs have led to the development of
the nitrosoureas.
These drugs are most useful in the treatment of
slow growing cancers such as various lymphomas, leu
kaemias, myelomas, some ovarian, testicular and breast
cancers, and some pancreatic cancers. See Table 14.1
for usual indications for each of the alkylating agents.
These agents are not used interchangeably.
Pharmacokinetics
The alkylating agents vary in their degree of absorption,
and little is known about their distribution in the tissues.
They are metabolised and sometimes activated in the
liver, with many of these agents using the cytochrome
P450 systems. They are excreted in the urine.
Contraindications and cautions
Alkylating agents are contraindicated during pregnancy
and breastfeeding due to their potential for severe effects
on the fetus and neonate. Caution is necessary when
giving alkylating agents to any individual with a known
allergy to any of them; with bone marrow suppression,
which is often the index for redosing and dosing levels
;
New drugs for the battle against cancer
Arsenic trioxide (Phenasen), known as a poison in
forensic medicine, has been approved for the induction
and remission of promyelocytic leukemia (PML) in
people whose disease is refractory to conventional
therapy and whose leukemia is characterised by t(15;17)
translocation of PML/RAR-alpha gene expression. It is
given intravenously at a rate of 0.15 mg/kg per day until
bone marrow remission occurs and then 0.15 mg/kg per
day starting 3 to 6 weeks after induction.The person needs
to be screened carefully for toxic reactions.
Other drugs are under development that target specific
areas of the human genome. In the future, antineoplastic
drugs may be able to target abnormal cells and not affect
the healthy cells.This could relieve the suffering of many
people undergoing cancer chemotherapy.
Several familiar drugs are being studied for their ability
to block angiogenesis. By blocking the development of
new blood vessels to feed the tumour, the growing cells in
the tumour will lack nutrition and oxygen and will not be
able to survive. Celecoxib (Celebrex), an anti-inflammatory
drug, is being studied in various cancer combination-drug
trials for this effect. Some low-molecular-weight heparins,
such as dalteparin (Fragmin), are also being studied for
this effect.
The evidence
BOX 14.2
