Antineoplastic drugs

Learning Outcome:

After completing this chapter, the reader should be able to:

1. Identify the primary causes of cancer.
2. Explain the terms benign, malignant, and neoplasm.
3. Describe chemotherapy and the types of antineoplastic drugs.
4. Explain hormone therapy as antineoplastic drugs.
5. Describe the first group of antineoplastic agents.
6. List the classes of mitotic inhibitors (plant alkaloids).
7. Explain the mechanism of drug action of antimetabolites and antitumor
antibiotics.
8. Explain toxicity of antineoplastic agents.
9. List specific side effects of certain antineoplastic agents on particular organs or systems
in the body.
10. Explain different phases of the cell cycle.
Characteristics of Cancer
A tumor, or neoplasm, arises from a single abnormal cell, which continues to divide
indefinitely. The lack of growth controls, the ability to invade local tissue, and the ability to
spread, or metastasize, are characteristics of cancer cells. These properties are not present
in normal cells. Tumors are either benign (nonprogressive) or malignant (spreading). More
than 100 different types of malignant neoplasms occur in man. Malignant tumors are also
referred to as cancer, which is second only to heart disease as a cause of death in the U.S.
Common sites for the development of malignant tumors are the skin, lungs, prostate,
breasts, and large intestine (colon).
Cancer can be treated surgically or chemically. There are a variety of chemical
treatments to consider in the treatment of cancers. The decisions for treatments may be
made based upon the type of cancer being treated or the stage of the cancer when
diagnosed. This chapter discusses many of the chemotherapeutic treatments used in the
treatment of cancer.

Key Concept
Chromosomal changes are common in cancer cells. The Philadelphia chromosome, the first chromosomal abnormality linked to
a malignant
disease in humans, was found in patients with chronic myelogenous leukemia.
Causes of cancer development in humans may include exposure to chemicals, radiation, and viruses.
Cancer is the second-most common cause of death in the United States, eclipsed only by cardiovascular disease.
 The proliferation of neoplastic cells leads to the formation of masses called tumors. The
terms neoplasm and tumor are used synonymously. However, it is very important to note
that not all neoplasms form tumors. For example, leukemia is a malignant disease of the
bone marrow, but the malignant cells are in the blood circulation and thus do not form
distinct masses.
Most tumors can be classified clinically as either benign or malignant. Benign tumors
have a limited growth potential and a good outcome, whereas malignant tumors grow
uncontrollably and eventually kill the host.
Only malignant tumor cells have the capacity to metastasize. Benign tumors never
metastasize and always remain localized. Metastasis involves a spread of tumor cells from a
primary location to some other site in the body. The spread can occur through three main
pathways:
• Through the lymphatics
• Via blood
• By seeding of the surface of body cavities

The Cell Cycle

To understand cancer treatments, normal and malignant cell replication processes should
be reviewed. This cell cycle may last between 24 hours to many days. The phases of the cell
cycle consist of a first growth phase (G1), synthesis (S1), a second growth phase (G2), mitosis
(M), and a resting phase (G0). See Figure Cancer-1.
 i dv

t o

Anaphase
o

ph
s
p

p
Figure Cancer-1 Stages of the cell cycle.

Causes of Cancer
The cause of most human cancers is unknown. Nevertheless, many
potential agents (carcinogens) that result in the development of cancer
have been identified, and the sources of many tumors have been explained
(see Table 1).

TABLE 1 Exposure to Carcinogens

Causes Cancer
Sunlight (UV radiation) Sites
Skin cancer
Human papilloma viruses Genital
Inhalation carcinogens (3,4- Lung
Radiation Thyroid and
Metabolic liver carcinogens Liver
Metabolic excretory carcinogens Bladder
Metabolic carcinogens; nitrites Intestinal
 Treatment of Cancer
C ancer may b e treated by using surger y, radiation therapy, and chemotherapy (drugs).
Surgery is performed for the removal of a tumor that is localized in one area, or when the tumor is
pressing on the airway, nerves, or other vital tissues. It remains the major form of treatment;
however, irradiation is widely used as preoperative, postoperative, or primary therapy. Many
malignant lesions are curable if detected in the early stage.
Radiation therapy is very effective in destroying tumor cells through non-surgical means.
Radiation therapy may follow surgery to kill any cancer cells that remain following the operation.
Anticancer drugs may be given to attempt a cure, for palliation (treatment to relieve or
reduce intensity of uncomfortable symptoms, but not to produce a cure), or occasionally, as
prophylaxis to prevent cancer from occurring. Chemotherapy is often combined with surgery and
radiation to increase the probability of a cure. In this chapter, the focus will be on drug therapy for
cancers.

Antineopl astic Agents

Antineoplastic agents are used to treat cancers or malignant neoplasms. There are many types
of drug therapies for the treatment of cancer. Antineoplastic agents are also called
chemotherapeutic agents. They interrupt the development, growth, or spread of cancer cells.
Antineoplastic agents are used for malignant tumors. Antineoplastic agents do not kill tumor cells
directly, but interfere with cell replication (Figure Cancer-2). Each antineoplastic agent is effective at
a specific stage in cell replication. It may inhibit DNA, RNA, and protein synthesis of cancer cells.
Agents are most commonly given in combinations of two or more at a time. Many antineoplastic
medications also have immunosuppressive properties that decrease the patient’s ability to
produce antibodies to attack infecting organisms. These medications are toxic to the body as a
whole because they also destroy normal cells and decrease immunity.
The most common typ es of antineoplastic agents include: antimetabolites,
hormonal agents, special antibiotics, alkylating agents, and mitotic inhibitors (plant alkaloids).
Antineoplastic agents require the following special care and handling:
• Preparation only in restricted-access areas under biological safety cabinets
• Syringes and needles must have specialized fittings that are designed for use with these agents (for
example, Luer-Lok™ fittings)
• Protective gowns must be worn during preparation
 G0 Antibiotics Prophase
Resting phase Bleomycin
Actinomycin
Doxorubicin

Alkylating Agents
Nitrogen mustard
Cyclophosphamide
G1 Metaphase
Chlorambucil
Early protein synthesis

Plant Alkaloids
Vinblastine
Vincristine

S1 Anaphase
DNA synthesis
Antimetabolites
Methotrexate
Fluorouracil
Mercaptopurine
ytosine arabinoside
C

G2 Telophase
RNA synthesis

Figure Cancer-2 The effects of antineoplastic agents on various cell phases.

Medical Terminology Review

alkylating
alky(l) = free radical
lating = transfer
the transfer of free radicals
• Two pairs of protective gloves should be worn, and periodically changed
• A plastic face shield or splash goggles should be worn
• Training classes must be attended by all workers who will be handling antineoplastic
agents

Antimetabolites
Antimetabolites prevent cancer cell growth by affecting its DNA production.
They are only effective against cells that are actively participating in cell metabolism. The
antimetabolite drugs are listed in Table Cancer-2.
The classes of antimetabolites include:
1. Folic acid antagonists: methotrexate
2. Purine analogs: mercaptopurine
3. Pyrimidine analogs: fluorouracil
 TABLE Cancer-2 Antimetabolites
Mechanism of Action
Antimetabolites disrupt the metabolic functions of normal cells in the body. They
interfere with the activity of enzymes and alter the DNA structure.

Indications
Antimetabolites are used in the treatment of a variety of neoplasms. Methotrexate is
effective in the treatment of gestational choriocarcinoma a n d hy datidif or m mo le , as w e ll
as b ein g immunosuppress a nt in
kidney transplantation. Methotrexate is also used for acute and subacute leukemias
and leukemic meningitis, especially in children. This drug is often indicated to
treat severe psoriasis that is non-responsive to other forms of therapy.
Mercaptopurine (6-MP) is used primarily for acute lymphocytic and
myelogenous leukemia. Fluorouracil (5-FU) is used systemically as a single agent and in
combination with other antineoplastics for palliative treatment of carefully selected
patients with inoperable neoplasms of the breast, colon or rectum, stomach, pancreas,
urinary bladder, ovary, cervix, and liver.

Medical Terminology Review

leukopenia
leuko = white
penia = (blood cell) decrease
decrease in white blood cells

Key Concept
Antimetabolite and other antineoplastic drugs in older adults may increase the risk of adverse effects. Therefore, a lower dosage is
recommended for patients
with renal impairment.
Adverse Effects
Antimetabolite agents may cause a wide variety of adverse effects. Common adverse
effects include anorexia, nausea, vomiting, diarrhea, leukopenia, anemia, and
thrombocytopenia. Some adverse effects of antimetabolites are dose-dependent, and
may produce impaired liver function, hepatic necrosis, blurred vision, aphasia, and
convulsions.

Contraindications and Precautions

Antimetabolite drugs are contraindicated in patients with anemia,
thrombocytopenia, and poor nutrition. These agents are also contraindicated in
patients with known hypersensitivity to these drugs, renal insufficiency, and during
pregnancy (category D) or lactation.
Antimetabolite agents should be used with caution in patients with hepatic or
renal impairment, active infection, or other debilitating disorders. These drugs should
be avoided in patients with peptic ulcer, ulcerative colitis, and elderly patients.

Drug Interactions
Alcohol and other CNS depressants may enhance CNS depression if taken with
antimetabolites. Allopurinol may inhibit metabolism and increase toxicity of
mercaptopurine.

Hormonal Agents
Hormonal agents are a class of heterogeneous compounds that have various
effects on cells. These agents either block hormone production or block hormone
action. Their action on malignant cells is highly selective. They are the least toxic of
the anticancer medications. The most commonly used hormonal agents in cancer
therapy are seen in Table Cancer-3.

Mechanism of Action
The precise action of hormones on malignant neoplasms is not known. However,
these agents are able to counteract the effect of male or female hormones in
hormone-dependent tumors.
TABLE Cancer-3 Commonly Used Hormonal Agents

Indications
Hormones and their antagonists have various uses in the treatment of malignant diseases.
Steroids are especially useful in treating lymphomas, leukemias, and Hodgkin’s disease. They are
also used in conjunction with radiation therapy to reduce nausea, weight loss, and tissue
inflammation
caused by other antitumor drugs. Gonadal hormones are used in carcinomas of
the reproductive tract and advanced breast cancer. For example, estrogen is
given to a patient with testicular cancer or carcinoma of the prostate.
Estrogen may also be administered to postmenopausal women with breast
cancer. Androgens (male hormones) are prescribed in premenopausal
women with breast cancer. Antiestrogens, such as tamoxifen, and anti-
androgens are used to inhibit hormone production in advanced stages of
breast cancer.

Adverse Effects
Major adverse effects include masculization in female patients and
feminization in male patient. Estrogen therapy may cause blood clots.

Contraindications and Precautions

Hormonal agents have a wide array of contraindications, including
hypersensitivity to the agents. The use of hormonal agents must be avoided in
patients with fungal infections, endometrial hyperplasia, thromboembolic
disease, and in children. They are ranked in a variety of categories if used
during pregnancy and lactation (including categories C, D, and X).
Precautions for the use of hormonal agents include patients with
hypertension, gallbladder disease, diabetes mellitus, heart failure, liver or
kidney dysfunction, infections, nonspecific ulcerative colitis, diverticulitis,
peptic ulcer, osteoporosis, and myasthenia gravis. Hormonal agents must be
used with great caution in many other conditions.

Drug Interactions
Hormonal agents may cause drug interactions with many agents, including
but not limited to: carbamazepine, phenytoin, rifampin, corticosteroids, oral
anticoagulants, barbiturates, amphotericin B, diuretics, ambenonium,
neostigmine, and pyridostigmine. Hormonal agents may inhibit antibody
response to vaccines and toxoids.

Antitumor Antibiotics
Several antibiotics of microbial origin are very effective in the treatment of
certain tumors. They are used only to treat cancer, and are not used to treat
infections. These antibiotics include bleomycin, doxorubicin, daunorubicin,
idarubicin, mitomycin, and plicamycin (Table Cancer-4).

Mechanism of Action
The mechanism of action of antitumor antibiotics is the inhibition of DNA
and RNA synthesis. Antitumor antibiotics attach to DNA, distorting its
structure and preventing normal DNA-to-RNA synthesis.
TABLE Cancer-4 Antitumor Antibiotics

R
G T Averag
o
en r e Adult
bl B S 10–
eo l C Cancer
da A I 50
cti c V 0
ti
d C I 30–60
a e V mg/m2/
d D I 40
a a V mg/m2
d A I 6
o d V 0
ri
d D I Cancer
o o V mg/m2
e E I 1
p ll V 0
id I I 8–12
ar
mi dM V
I mg/m2/
10–
to u V Cancer
m N I 12–14
i o V mg/m2
pli M I 25–30
ca i V mcg/kg/
h
va V I 800 mg
lr a n q week

Indications
Antitumor antibiotics are used for treating a few specific types of cancer. For example,
plicamycin is used only for treatment of testicular cancer. The only indication for idarubicin is acute
leukemia (cancer of the blood).

Adverse Effects
The most serious adverse effects of antitumor antibiotics are low blood cell counts and congestive
heart failure. Their common adverse effects include nausea, vomiting, diarrhea, fatigue,
headache, and alopecia (hair loss). Bleomycin may cause pneumonitis, pulmonary fibrosis, and
rash.

Contraindications and Precautions

Antitumor antibiotics are contraindicated in patients with known hypersensitivity,
bleeding disorders, coagulation disorders, suppression of bone marrow, electrolyte imbalance,
and chickenpox, herpes zoster, and other viral infections; in women of childbearing age; during
pregnancy
(various categories, including C and D) and lactation; and in infants less than
six months of age.
Precautions for use of antitumor antibiotics include patients with
compromised hepatic, renal, or pulmonary function, previous cytotoxic drug
or radiation therapy, bone marrow depression, infections, gout, and obesity.
There are many other precautions for these agents as well.

Drug Interactions
When bleomycin is given with cisplatin, there is an increased risk of
bleomycin toxicity. Mitoxantrone, dactinomycin, mitomycin, and plicamycin
increase bone marrow depression. There may be an increased risk of bleeding
when plicamycin is used with aspirin, warfarin, heparin, or a nonsteroidal anti-
inflammatory drug.

Alkylating Agents
Alkylating agents were the first group of antineoplastic agents. During
World War I, chemical warfare was introduced using nitrogen mustard.
Alkylating agents came to be used for cancer therapy as a result of observation
of the effects of the mustard war gases on cell growth (Table Cancer-5).

TABLE Cancer-5 Alkylating Agents

R A
Ge T
o ve
ner r
Nitrogen Mustards
chl L P Initial:
ora e O 0.1–
cyc C P Ini
lop y O tia
hos t l:
e E P 14
s m O mg/kg
ifos I I 1.2
fa
m eM V
I 6g/m2/
e u V mg/m
me A P 6
lph
Nitrosoureas l O mg/da
car G I 150–
mu
lo liC V
P Cance
1
mu e O 3
str Z I 500
ept a V mg/m
(continues)
TABLE Cancer-5 Alkylating Agents—continued

R Av
G T
o era
en r
Miscellaneous Agents
bu M P 4–8
sul
ca yP O
I mg/day
360
rb
cis aP V
I Cancer2
mg/m
pl
da lD V
I mg/m2/
2–4.5
ca
ox TE V
I mg/kg/d
85
ali l V mg/m2
te T P 150
m e O mg/m2/
th T I 0.3–0.4
io h V mg/kg
Mechanism of Action
Most alkylating agents interact with the process of cell division of cancer cells. Antineoplastic or
cytotoxic action is primarily due to cross-linking of strands of DNA and RNA as well as inhibition of
protein synthesis. These drugs bind with DNA, causing breaks and preventing DNA replication.

Indications
Alkylating agents are used to treat metastatic ovarian, testicular, and bladder cancers. They are
also used for the palliative treatment of other cancers. The newer drugs in this category are
nitrosoureas, lipid-soluble drugs used in treating brain tumors and testicular or ovarian cancers.

Adverse Effects
Major adverse effects of the alkylating agents include nausea, vomiting, anorexia, diarrhea,
bone marrow suppression, hepatic and renal toxicity, and dermatitis. Other adverse effects of
alkylating drugs include cataracts, anxiety, fever, skin rash, hypertension, tachycardia, dizziness, and
insomnia.

Medical Terminology Review

myelosuppression myelo = bone marrow suppression = slowing of function
slowing of the production and function of the bone marrow
Contraindications and Precautions
Alkylating agents are contraindicated in patients with known hypersensitivity, impaired renal
function, myelosuppression, impaired hearing, history of gout and urate renal stones,
hypomagnesia, concurrent administration with loop diuretics, Raynaud syndrome, and many more
conditions, and during pregnancy (various categories) and lactation. Safe use in children is not
established for many of these agents.
Precautions include use in patients with previous cytotoxic drug or radiation therapy with
other ototoxic and nephrotoxic drugs, hyperuricemia,
Medical Terminology Review
hyperuricemia
hyper = more; excessive
uric = uric acid
emia = blood condition
excessive uric acid in the blood
electrolyte imbalances, hepatic impairment, and history of circulatory disorders.
There are many other precautions for these agents as well.

Drug Interactions
Drug interactions with alkylating agents include aminoglycosides,
amphotericin B, vancomycin, other nephrotoxic drugs, furosemide,
barbiturates, phenytoin, chloral hydrate, and corticosteroids. There are other drug
interactions with these various agents as well.

Mitotic Inhibitors
Mitotic inhibitors (plant alkaloids) are derived from plants. The primary plant
alkaloids are vincristine and vinblastine. Teniposide is a close analog of etoposide and
is active against acute leukemias in children. Topotecan is a semisynthetic plant
alkaloid used for refractory ovarian cancer that may have activity against small-cell
lung cancer. Examples of plant alkaloids are seen in Table Cancer-6.

Mechanism of Action
Mitotic inhibitors may interfere with cell division, but the antineoplastic mechanism
of these agents is unclear.

TABLE Cancer-6 Mitotic Inhibitors and Other Plant Products

R
Generic T Averag
o
Name Name e Adult
Mitotic Inhibitors
vinblastine V I 3.7–
sulfate
vincristine Onc V
I 18.5
1.4
sulfate V mg/m2
vinorelbine N I 30
tartrate
Taxoids V mg/m2
docetaxel T I 60–100
paclitaxel T V
I mg/m2
135–
Topoisomerase Inhibitors V 175
etoposide V I 5
V 0
irino C I 125
teca ® V mg/m2
teniposide V I 165
V mg/m2
topo H I 1.5
teca V mg/m2/
 Indications
Mitotic inhibitor drugs are used in various cancers. For example, docetaxel is prescribed for
breast cancer and non–small-cell lung cancer. Vinblastine is indicated for the treatment of
Hodgkin’s disease, lymphocytic lymphoma, testicular cancer, Kaposi’s sarcoma, and breast cancer.
Vincristine is used in acute leukemia and combination therapy for various cancers.
Paclitaxel is given to patients for treating ovarian and breast cancers, or for AIDS-related Kaposi’s
sarcoma.

Adverse Effects
Common adverse effects of mitotic inhibitors include nausea, vomiting, diarrhea, fatigue,
mental depression, and alopecia. Infection and peripheral neuropathy are also considered to be
unwanted effects of mitotic inhibitors.

Contraindications and Precautions

Mitotic inhibitors are cont raindicated in patients wit h know n hypersensitivity to
these drugs. Mitotic inhibitors should be avoided in patients with leukopenia or bacterial infection,
and during pregnancy (category D) or lactation.
Etoposide is also contraindicated in patients with severe bone marrow depression, and in
severe hepatic or renal impairment. Mitotic inhibitors should be used with caution in patients
who have impaired kidney or liver function, gout, obstructive jaundice, and idiopathic
thrombocytopenic purpura.

Drug Interactions
Mitotic inhibitors may interact with many drugs. For example, vincristine used with asparaginase
may cause increased neurotoxicity secondary to decreased liver clearance of vincristine. When
mitotic inhibitors are used with calcium channel blockers, they may increase accumulation of
these agents in cells.
CHAPTER Cancer • Antineoplastic Agents 391

Summary

A neoplasm is an abnormal cell division of the body. It may be benign or malignant.

Only malignant tumors are capable of spreading to other organs or systems of the
body. Treatment of the neoplasm depends on the progression of the tumor. Surgery,
radiation therapy, chemotherapy, and immunotherapy may be indicated. There are
many agents used for this purpose. Many antineoplastic medications also have
immunosuppressive properties that decrease the patient’s ability to produce antibodies
to attack infecting organisms.
Common antineoplastic agents include antimetabolites, hormonal agents,
specific antibiotics, alkylating agents, and mitotic inhibitors or plant alkaloids. In some
cases, surgery and radiation therapy are also necessary. Toxicity and side effects of
chemotherapy and radiation therapy are the major concerns regarding treatment of
malignant tumors.

E xpl oring the Web

Visit the following websites for additional information on drug therapies used to treat
cancer:
www.biochemweb.org
www.cancer.org www.cancer-
info.com www.cdc.gov/niosh
www.mayoclinic.com

Review Q uestions

Multiple Choice
1. The cell cycle consists of several phases, such as G0, G1, S1, G2, and M.
Which of the following explains the G0 phase?
A. resting
B. synthesis C. mitosis D.
growth
2. Which of the following agents is an antimetabolite?
A. cyclophosphamide
B. fluorouracil
C. mitomycin
D. nitrogen mustard
392
SECTION III • Pharmacology for Disorders Affecting Multi-body Systems

3. Which of the following is an example of an antitumor antibiotic?

A. vinorelbine B. topotecan C.
bleomycin
D. mercaptopurine
4. Mitotic inhibitors (plant alkaloids) include:
A. mercaptopurine
B. testolactone C. tamoxifen D.
vincristine
5. Mercaptopurine may have drug interactions with which of the following agents?
A. amoxicillin
B. alcohol
C. allopurinol
D. estrogen
6. An adverse effect of methotrexate includes:
A. bone marrow aplasia
B. arthritis
C. hypertension
D. hyperthyroidism
7. Busulfan has some unusual side effects in addition to its bone marrow suppressive activity.
Which of the following side effects are caused by busulfan?
A. peptic ulcer
B. testicular cancer
C. gynecomastia
D. gastrointestinal bleeding
8. Which of the following is the trade name of doxorubicin?
A. Mutamycin B. Adriamycin C.
Cosmegan D. Blenoxane
9. The route of administration for goserelin is:
A. oral
B. intramuscular
C. intravenous
D. implant
10. Most plant alkaloids may produce:
A. nausea and vomiting
B. internal bleeding
C. hypertension
D. gout
 CHAPTER Cancer • Antineoplastic Agents 393

11. Which of the following antimetabolic is useful in maintenance therapy of

children with acute leukemia?
A. fluorouracil (5-FU)
B. methotrexate (MTX)
C. mercaptopurine (6-MP)
D. vincristine
12. Which of the following is the best drug that may be given to a patient with
testicular cancer?
A. tamoxifen
B. estrogen
C. progesterone
D. megestrol
13. The term metastasize means to:
A. arise B. divide C.
spread D. occur

14. Hycamtin® is the trade name of which of the following agents?

A. vincristine B. vinblastine
C. vinorelbine D.
topotecan
15. The single most active agent against breast cancer is:
A. dactinomycin
B. mitomycin C.
doxorubicin D. bleomycin

Matching
1. Resting phase A. G1
2. Cell division B. S1
3. Synthesis C. G2
4. Second growth phase D. M
5. First growth phase E. G0

Generic Name Trade Name

1. vincristine A. VePesid
2. vinblastine B. Navelbine
3. vinorelbine C. Oncovin
4. paclitaxel D. Velban
5. etoposide E. Taxol
394
SECTION III • Pharmacology for Disorders Affecting Multi-body Systems

Critical Thinking
A biopsy revealed that a 45-year-old woman had breast cancer. She underwent surgery
and her left breast was removed. Her physician ordered radiation therapy and chemotherapy
as adjuvant therapies to the surgery.
1. If she were to refuse radiation or chemotherapy, what would be the likely consequence?
2. List the most common adverse effects of chemotherapy.
3. If the physician diagnosed that this patient had metastasis to her bones, which types of
treatment should he recommend?