Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

IMPORTANT PRINCIPLES OF TREATMENT IN CANCER CHEMOTHERAPY
clinical development in human medicine. Some agents
which target cell signaling pathways are already licensed
for use in human medicine and many more are in
development.
Cell cycle
Most cytotoxic drugs act on the processes of cell growth
and division and thus it is important to understand these
processes.
Both normal and neoplastic cells progress through
the cell cycle which consists of five major stages
(Fig. 15.1).
● M, the mitotic phase
● G 0 , the resting phase
● G 1 , the intermitotic phase (synthesis of cellular
components for DNA synthesis)
● S, the DNA synthesis phase
● G 2 , the premitotic interval (synthesis of cellular
components for mitosis)
Synthesis of
cellular
components
for mitosis
(19%)
Fig. 15.1 The cell cycle.
Growth fraction
Mitosis (2%)
M
Differentiation
G 0 (resting)
Synthesis of
G 2 G 1 cellular
components
for DNA
synthesis
S
(40%)
Replication of DNA
genome (39%)
The growth fraction of a tumor is the proportion of
tumor cells which are actively replicating, i.e. are within
the cell replication cycle. The majority of chemotherapy
drugs are most active against cells in the cell cycle as
opposed to the G 0 , resting cells (i.e. cell cycle dependent).
These drugs will be most effective against tumors
with a high growth fraction.
Most tumors initially grow in an exponential manner
but reach a plateau by the time the mass(es) become
clinically detectable. Thus the growth fraction is highest
when the tumor first develops at a microscopic level.
Once most tumors become macroscopic, greater than
1 cm 3 , the growth fraction is relatively low. In practice,
the smaller the tumor, the better chance of a favorable
response to chemotherapy.
Some drugs are most active against cells in a specific
phase of the cell cycle (cell cycle-dependent, phasespecific).
These drugs only kill a limited number of cells
with any single drug administration because at the
time of administration only a limited number of tumor
cells will be in the phase of the cell cycle in which the
drug acts. The number of cancer cells killed depends on
the amount of time the tumor cells are exposed to the
drug, which is related to the area under the curve for
the drug being administered. The area under the curve
may be increased by prolonging exposure of the cells
to the drug by administering the drug multiple times
or as a constant rate infusion. Normal cell toxicity
also increases when cell cycle-dependent, phase-specific
drugs are administered more frequently or via a constant
rate infusion because a greater number of normal
cells also enter the phase of the cell cycle in which
the drug acts. Drugs that work in this fashion are
also termed ‘schedule-dependent’ because changing the
schedule of administration profoundly alters the drug’s
effect. This group of drugs is most active in tumors
where many cells are actively dividing. Classic examples
of cell cycle-dependent, phase-specific drugs are the
antimetabolites.
‘Cell cycle-phase nonspecific’ drugs do not require
tumor cells to be actively dividing in order to cause
lethal cell damage (so theoretically are active against
resting cells). However, ultimately, the damaged cell
must undergo division for the lethal effect to be expressed
(so the drugs do not actually kill cells in the resting
phase unless they start multiplying again). Because the
degree of cell kill is dependent on the number of cells
damaged, which in turn is dependent on the maximum
drug concentration achieved (C max ), these drugs are also
called ‘dose-dependent’. Drugs in this category include
the alkylating agents, antitumor antibiotics and platinum
analogs.
A third classification of drugs based on the cell cycle
is sometimes separated from the cell cycle-phase
nonspecific group. Named the nonselective, phasenonspecific
group, it is small, consisting of nitrogen
mustard and the nitrosoureas which are known to
damage both normal and tumor stem cells.
IMPORTANT PRINCIPLES OF TREATMENT
IN CANCER CHEMOTHERAPY
Dosing principles
The objective of anticancer chemotherapy is to use a
dose regimen that combines maximum antitumor effect
with minimal normal tissue toxicity. Unfortunately,
because their actions on dividing cells are not specific
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