150
U N I T 1
Cell and Tissue Function
can be tolerated when they are divided into multiple
smaller, fractionated doses. Normal tissue is usually able
to recover from radiation damage more readily than is
cancerous tissue.
Therapeutic radiation can be delivered in one of three
ways: external beam or teletherapy, with beams gener-
ated by a linear accelerator or cobalt-60 machine at a
distance and aimed at the patient’s tumor; brachyther-
apy, in which a sealed radioactive source is placed close
to or directly in the tumor site; and systemic therapy, in
which radioisotopes with a short half-life are given by
mouth or injected into the tumor site.
Chemotherapy
Cancer chemotherapy has evolved as one of the major
systemic treatment modalities.
58,59
Unlike surgery and
radiation, cancer chemotherapy is a systemic treatment
that enables drugs to reach the site of the tumor as well
as distant sites. Chemotherapeutic drugs may be used as
the primary form of treatment, or they may be used as
part of a multimodal treatment plan. Chemotherapy is
the primary treatment for most hematologic and some
solid tumors, including choriocarcinoma, testicular can-
cer, acute and chronic leukemia, Burkitt lymphoma,
Hodgkin disease, and multiple myeloma.
Most cancer drugs are more toxic to rapidly prolif-
erating cells than to those incapable of replication or in
phase G
0
of the cell cycle. Because of their mechanism
of action, they are more effective against tumors with a
high growth fraction. By the time many cancers reach a
size that is clinically detectable, the growth fraction has
decreased considerably. In this case, reduction in tumor
size through the use of surgical debulking procedures or
radiation therapy often causes tumor cells residing in G
0
to reenter the cell cycle. Thus, surgery or radiation ther-
apy may be used to increase the effectiveness of chemo-
therapy, or chemotherapy may be given to patients with
no overt evidence of residual disease after local treat-
ment (e.g., surgical resection of a primary breast cancer).
For most chemotherapy drugs, the relationship
between tumor cell survival and drug dose is exponen-
tial, with the number of cells surviving being propor-
tional to drug dose, and the number of cells at risk for
exposure being proportional to the destructive action
of the drug. Exponential killing implies that a propor-
tion or percentage of tumor cells is killed, rather than an
absolute number (Fig. 7-10). This proportion is a con-
stant percentage of the total number of cells. For this
reason, multiple courses of treatment are needed if the
tumor is to be eradicated.
A major problem in cancer chemotherapy is the
development of cellular resistance. Acquired resistance
develops in a number of drug-sensitive tumor types.
59
Experimentally, drug resistance can be highly specific to
a single agent and is usually based on genetic changes in
a given tumor cell type. In other instances, a multidrug-
resistant phenomenon affecting anticancer drugs with
differing structures occurs. This type of resistance often
involves the increased expression of transmembrane
transporter genes involved in drug efflux.
Cancer chemotherapy drugs may be classified as
either cell cycle specific or cell cycle nonspecific (see
Understanding—The Cell Cycle, Chapter 4).
58
Drugs are
cell cycle specific
if they exert their action during a spe-
cific phase of the cell cycle. For example, methotrexate,
an antimetabolite, acts by interfering with DNA synthe-
sis and thereby interrupts the S phase of the cell cycle.
Cell cycle–nonspecific
drugs exert their effects through-
out all phases of the cell cycle. The alkylating agents,
which are cell cycle nonspecific, act by disrupting DNA
when cells are in the resting state as well as when they are
dividing. The site of action of chemotherapeutic drugs
varies. Chemotherapy drugs that have similar structures
and effects on cell function usually are grouped together,
and these drugs usually have similar side effect profiles.
Because chemotherapy drugs differ in their mechanisms
of action, cell cycle–specific and cell cycle–nonspecific
agents are often combined to treat cancer.
Combination chemotherapy has been found to be
more effective than treatment with a single drug. With
this method, several drugs with different mechanisms
of action, metabolic pathways, times of onset of action
and recovery, side effects, and onset of side effects are
10
12
10
11
10
10
10
9
10
8
10
7
10
6
10
5
10
4
10
3
10
2
10
1
10
0
Cell Number
Time
Cycles of chemotherapy
1 2 3 4 5
Tumor regrowth
following premature
cessation of therapy
Disease in clinical
remission
1 log cell regrowth
3 log cell kill
Clinically overt disease
FIGURE 7-10.
Relationship between tumor cell survival and
administration of chemotherapy.The exponential relationship
between drug dose and tumor cell survival dictates that a
constant proportion, not number, of tumor cells is killed with
each treatment cycle. In this example, each cycle of drug
administration results in a 99.9% (3 log) cell kill, and 1 log of
cell growth occurs between cycles.The broken line indicates
what would occur if the last cycle of therapy were omitted:
despite complete clinical remission of disease, the tumor
ultimately would recur. (Reprinted by the permission from
Raymond E. Lenhard Jr., et al. The American Cancer Society’s
Clinical Oncology. Atlanta, GA: American Cancer Society; 2001:
181. © American Cancer Society.)
