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Antineoplastic Agents and Biologic Response Modifiers
Antineoplastic Agents
Anticancer/AntineoplasticDrugs
Introduction___________________
In the United States cancer the second
leading cause of death- second only to heart disease. It is the leading cause of
death in women. In children between ages 1 and 15 years, cancer is the leading
cause of death after accidents. The most common types of cancer in men are
prostate, lung, and colorectal cancer. In women, common types include breast,
lung, and colorectal cancer.
Cancer results from alterations in the deoxyribonucleic acid (DNA) within
the cell. DNA is the genetic substance in the body cells. In addition, DNA
transfers information necessary for the production of enzymes and protein
synthesis.
Anti-cancer drugs, also called cancer chemotherapeutic agents or
antineoplastic drugs were introduced in the treatment of cancer in the 1940s.
The first antineoplastic drugs included estrogen for prostatic cancer and the
nitrogen mustard drug mechlorethamine hydrochloride (Mustargen). Many of theearly anticancer drugs such as methotrexate, 5-flourouracil, 6-mercaptopurine,
and cyclophosphamide, are still in use. Since the early 1970s more anticancer
drugs have been marketed, and drug protocols (detailed plans) using
combinations of drugs have been proven effective in curing specific leukemias
and Hodgkins disease. Anticancer drugs are given for several reasons, including
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cure, control, and palliation. Chemotherapy may be used as the sole treatment of
cancer or in conjunction with radiation and surgery.
Cancer Chemotherapy_____________________________
It is difficult for anticancer drugs to be selective in killing tumor cells and
not normal cells. If large anticancer doses are given to kill malignant cells, normal
cells usually are also killed; thus the death of the client could result.
There are various protocols for successful chemotherapy. If the
chemotherapy is extended too long or the doses are too high, toxicity is likely to
occur. Eliminating every cancer cell can be difficult. When symptoms disappear;
it had once been thought that malignant cells were eradicated but this is
generally not true, because 1 million cells could remain when there are no
symptoms. It is still not known how long cancer therapy should be continued.
With continuous research and protocol drug therapy, an answer is anticipated
soon.
Drug Resistance__________________________________
Tumor resistance can develop against an anticancer drug because the
drug is used too infrequently or the tumors location limits the effectiveness of the
drug. Brain tumors respond poorly to anticancer drugs because most drugs do
not cross the blood brain barrier. Nitrosoureas, however, do cross the blood-brain
barrier. Intraarterial infusion of drugs at the site may be necessary.
Changes in DNA are major cause of drug resistance and mutation of
cancer cells is also a factor in drug resistance. As the tumor ages, cancer cells
mutate as they multiply; thus the cancer cells are no longer identical. The
mutated cells may differ in response to drug therapy.
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Combination Chemotherapy________________________
To achieve the best tumor kill, chemotherapy needs to target cells in all
phases of the cell cycle. Combining chemotherapy drugs makes this possible.CCS and CCNS are often combined to maximize cell death.
Classifications of Anticancer Drugs
1. Alkylating Drugs
- It belongs to CCNS category and kills cells by forming cross-links on the DNA
strands
Cyclophosphamide (Cytoxan)______________________________
Pharmacokinetics
Cyclophosphamide is well absorbed from the GI tract. Its half-life is
moderate, and it is moderately protein-bound. The drug is metabolized by the
liver, and less than 50% is excreted unchanged in the urine.
Pharmacodynamics
The onset of the action begins within hours; however, the desired effect
may take several days. It is one of the anticancer drugs that can be administered
orally.
Several drug interactions may occur with cyclophosphamide: thiazides
and allopurinol can increase bone marrow depression; the effect of digoxin
decreases; and the effect of insulin increases, causing hypoglycaemia.
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Phenobarbital and rifampin may increase cyclophosphamide toxicity. Adverse
reactions should be observed and reported.
Uses and Considerations
For treatment of progressive carcinoma of prostate. Consists of estrogen
and nitrogen mustard.
Side Effects
Nausea
Peripheral edema
Thrombophlebitis
Breast tenderness
2. Antimetabolites
- They are classified as CCS and affect S phase (DNA synthesis and
metabolism) of the cell cycle. Many of the antimetabolites drugs resemble natural
metabolites; thus they disrupt the metabolic processes and some of the agents
inhibit enzyme synthesis.
Fluorouracil_____________________________________________
Pharmacokinetics
Fluorouracil is administered IV for carcinoma and topically for superficial
basal cell carcinoma. Protein-binding is less than 10% and the half-life for the IV
route is short (10 to 20 minutes). A small amount of the drug is excreted in the
urine, and up to 80% is excreted by the lungs as carbon dioxide.
Peripheral Edema (Feet)
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Pharmacodynamics
Fluorouracil, a CCS drug, blocks the enzyme action necessary for DNA
and ribonucleic acid (RNA) synthesis. The drug has a low therapeutic index.
Fluorouracil can be used alone or in a combination with other anticancer drugs.
Fluorouracil can cross the blood-brain barrier. Its duration of action is 30 days.
Uses and Considerations
To treat advanced or metastatic adenocarcinoma of the pancreas. Acts at
the S phase of cell cycle. To monitor leukocytes and platelet count; reduce dose
if these values are extremely low.
Side Effects
Anorexia
Nausea
Vomiting
Diarrhea
Stomatitis
Alopecia
Photosensitivity
Increased pigmentation
Rash
Erythema
Bone marrow suppression
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3. Antitumor Antibiotics
- Inhibit protein and RNA synthesis and bind DNA, causing fragmentation.
Doxorubicin and Plicamycin_______________________________
Pharmacokinetics
Doxorubicin and plicamycin are administered IV. Doxorubicin is
metabolized in the liver to active and inactive metabolites. The various
metabolites affect the half-life; the initial phase of the doxorubicin is 12 minutes,
the intermediate phase is 3.5 hours, and the final phase is 30 hours.
Pharmacodynamics
The primary effects of doxorubicin and plicamycin differ although they are
classified as antitumor antibiotics. Doxorubicin is prescribed in combination with
other anticancer agents for the treatment of breast cancer, ovaries, lung, and
bladder and, leukemias and lymphomas. Plicamycin may be used in combination
with other anticancer agents for the treatment of testicular carcinoma. Its primary
use is for correction of hypercalcemia.
Because plicamycin affects bleeding time, use of aspirin, anticoagulants,
and thrombolytic agents should be avoided. The use of cyclophosphamide with
doxorubicin can increase the chance of haemorrhagic cystitis.
Uses and Considerations
Doxorubicin
To treat breast, bladder, ovarian, and lung cancers; leukemias; lymphomas
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Plicamycin
To correct hypercalcemia, and hypercaliciuria; to treat testicular carcinoma
Side Effects
Doxorubicin
Alopecia
Nausea
Vomiting
Stomatitis
Leukopenia
Thrombocytopenia
Rash
Plicamycin
Dizziness
Weakness
Headache
Mental depression
4. Mitotic Inhibitors
- They block cell division at the M phase of the cell cycle. They are extracted
from plants and tree substances such as periwinkle tree, needles and bark of the
yew tree and mandrake plant.
A. Vinca Alkaloids Group
Vinblastine Sulfate (Velban)_______________________________
- used for treating breast cancer, testicular, and kidney and for treatment of
lymphomas, lumphosarcomas, and nueroblastomas. Check CBC before dosing.
Alopecia (Hair loss) Stomatitis
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Adverse Effects
Nausea
Vomiting
Partial to Complete Alopecia
Leukopenia
Stomatitis
Neurotoxicity
B. Antimicrotubule / Taxanes Group
Docetaxel (Taxotore)_____________________________________
- used to treat advanced or metastatic breast cancer. It inhibits mitosis in the
cells. Has a greater antitumor activity with lower toxicity effect than paclitaxel
(Taxol). Monitor WBC and platelet count; if low, dose may need to be decreased.
Stages of Cell Mitosis
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Adverse Effects
Alopecia
Diarrhea
Nausea
Vomiting
Peripheral neuropathy
Stomatitis
Fever
Fluid retention
C. Topoisomerase I inhibitors Group
Irinotecan Hydrochloride (Camptosar)_______________________
- used for advanced and metastatic carcinoma of the colon and rectum. Inhibits
the topoisomerase enzyme that is needed for DNA and RNA synthesis.
Increased fluid intake is necessary. Monitor WBC count.
Adverse Effects
Alopecia
Constipation
Nausea and vomiting
Peripheral neuropathy
Peripheral Neuropathy Stages. A. Nerve's myelin
sheeth begins to degenerate. B. Separation of the
axon. C. Degeneration of the rest of the nerve
parts.
Peripheral Neuropathy (Foot)
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D. Topoisomerase II Derivatives Group
Etoposide (VePesid, VP-16)________________________________
- used for treating refractory testicular tumors, small cell lung carcinoma,Hodgkins and non-Hodgkins lymphomas, and acute myelogenous leukemia.
Has standard chemotherapy side effects. Has long duration of action.
Adverse Effects
Alopecia
Anorexia
Nausea and vomiting
5. Hormones (Steroids), Hormone Antagonists, and
Enzymes
The anticancer hormones have 2 major actions:
1. As agonists that inhibit tumor cell growth
e.g. estrogen, progestins, androgens, and adrenocorticosteroids
2. As antagonists that compete with endogenous hormone
e.g. aminoglutethimide, flutamide, goserelin, acetate, and tamoxifen
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A. Hormone (Steroid)
Testolactone (Teslac)_____________________________________- used for palliative treatment of breast carcinoma in postmenopausal women.
Serum calcium levels should periodically be checked. Voice may deepen and
facial hair may occur.
B. Hormonal Antagonist
Aminoglutethimide (Cytadren)_____________________________
- used for treating adrenal carcinoma, ectopic adrenocorticotropic hormone
(ACTH)-producing tumors. Drug supresses adrenal activity. May be used in
breast cancer therapy. Treatment usually used for 3 months.
C. Enzyme
L-asparaginase (Elspar)___________________________________- used for treating acute lymphocytic leukemia. Used in combination with another
anticancer drug. Common side effects include nausea, vomiting, anorexia,
leukopenia, and impaired pancreatic function.
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Biologic Response Modifiers
Biologic Response Modifiers (BRMs)
- class of agents used to enhance the bodys immune system.
Two Advances in Production of BRMs_______________________
A. Recombinant DNA
- genetic engineering process that produces mass quantities of human proteins
B. Hybridoma Technology
- process that uses mice to mass produce monoclonal antibodies
Functions of BRM:
1. Enhance immunologic function (immunomodulation)
2. Destroy or interfere with tumor activities (cytotic/cystostatic effects)
3. Promote differentiation of stem cells
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Different Biologic Response Modifiers_______________
1. Interferons (IFNs)
- family of naturally occurring proteins
Three Major Types:
1. Alpha IFN-
2. Beta IFN-
3. Gamma IFN-
Interferon-______________________________________
- Produced by B cells, T cells, macrophages, and null cells in response to the
presence of viruses or tumor cells. It has been known to have antiviral,
antiproliferative, and immunomodulatory effects which means that it inhibits
intracellular replication of viral DNA, interferes with tumor cell growth, and
enhances natural killer cell (antitumor) activity. Recombinant IFN- is
manufactured as Roferon-A and Intron A.
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Pharmacokinetics
IFN- is metabolized by the liver and filtered by the kidney. The body,
however, absorbs approximately 80% of the dose. Peak serum concentrations
are reached 4-8 hours after administration. IFN- can be , administered
subcutaneously (SC), intramuscularly (IM), and intravenously (IV), although SC
or IM administration is preferred. SC administration is recommended for clients
with platelet count below 50, 000.
Side Effects
Flulike syndrome (chills, fever, malaise, fatigue and myalgias)
GI: nausea, vomiting, diarrhea, anorexia, taste alterations, xerostomia (dry
mouth)
Neurologic reversible side effects: mild confusion, somnolence (sleepiness),
irritability, poor concentrations, seizures, transient aphasia (temporary loss of
ability to speak), hallucinations, paranoia and psychoses
Cardiopulmonary: tachycardia, pallor, cyanosis, tachypnea, nonspecificelectrocardiographic changes, rare myocardial infarction, and orthostatic
hypotension
Renal and Hepatic: increased blood urea nitrogen (BUN) and creatinine levels,
proteinuria, and elevated transaminase
Hematologic: neutropenia (decreased number of neutrophils in the blood),
Thrombocytopenia
Dermatological: maculopapular rashes of the trunk and extremities, pruritus,
irritation at the injection site, desquamation, and alopecia
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2. Colony-Stimulating Factors (CSFs)
- Hematopoietic colony-stimulating factors (CSFs) are proteins that stimulate or
regulate the growth, maturation, and differentiation of bone marrow stem cells;
manufactured through recombinant DNA techniques.
Uses of CSFs
1. Decrease the length of posttreatment neutropenia (the length of time the
neutrophils [a type of white blood cell) are decreased secondary to
therapy)
2. Reduce bone marrow recovery time after bone marrow transplantation
3. Enhance macrophage or granulocyte tumor-, virus-, and fungus-
destroying ability
4. Prevent severe thrombocytopenia after myelosuppressive chemotherapy
Erythropoietin (EPO) (Procrit)______________________________
- A glycoprotein produced by the kidney that stimulates red blood cell production
in response to hypoxia. It also stimulates the division and differentiation of
committed red blood cell progenitors (parent cells destined to become circulating
red blood cells) in the bone marrow.
Pharmacokinetics
EPO can be administered IV (IV push) or SC. According to the
manufacturer, EPO administered by IV is eliminated at a rate consistent with first-
order kinetics (process by which the drug is eliminated in part by the hepatic andrenal blood flow). It has a circulating half-life ranging from approximately 4 to 13
hours in clients with CRF. Plasma levels of EPO have been detected for at least
24 hours. After SC administration of EPO to CRF clients, peak serum levels are
achieved with 5 to 24 hours. The half-life of IV-administered EPO is
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approximately 20% shorter in normal clients without CRF than in clients with
CRF. Pharmacokinetic studies have not been done with HIV-infected clients.
Side Effects
Hypertension
Headache
Arthralgia
Nausea
Edema
Fatigue
Diarrhea
Vomiting
Chest pain
Injection site skin reaction
Asthenia (weakness)
Dizziness
Seizures
Thrombosis
Allergic reactions
Granulocyte Colony-Stimulating Factor (G-CSF)______________
- marketed as filgrastrim (Neupogen), is a human granulocyte (type of white
blood cell responsible for fighting infection) colony-stimulating factor produced by
monocytes, fibroblasts, and endothelial cells. It regulates production of
neutrophils within the bone marrow.
Pharmacokinetics
Filgastrim administration results in a two-phase neutrophil response. An
early response is seen within 24 hours of administration. Following the
chemotherapy-induced nadir (low point), a second peak in circulating neutrophils
is observed. The proliferation-induced increase in neutrophils usually begins 4 to
5 days after administration is initiated but timing may vary based on the type and
dose and prior to treatment history. The elimination half-life of G-CSF in both
normal clients and those with cancer is 3.5 hours. Clearance rates are
approximately 0.5 to 0.7 ml/min/kg.
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Side Effects
Nausea
Vomiting
Skeletal pain
Alopecia
Diarrhea
Neutropenia
Fever
Mucositis
Fatigue
Anorexia
Dyspnea
Headache
Cough
Skin rash
Chest pain
Generalized weakness
Sore throat
Stomatitis
Constipation
Pain of unspecified origin
3. Neumega (Oprelvekin )
- is recombinant interleukin- 11, which is a platelet growth factor. It can potentially
prevent recurrent severe chemotherapy-induced thrombocytopenia. Oprelvekin
as an active ingredient stimulates megakaryocyte and thrombocyte production.
Pharmacokinetics
Neumega is available for SC administration in single-use vials containing
5 mg of oprelvekin as a sterile, lyophilized powder. When reconstituted with 1 ml
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of sterile water for injection, the resulting solution has a pH of 7.0 and a
concentration of 5mg/ml.
Product doing should begin 6 to 24 hours after the completion of
chemotherapy. SC dosing for 14 days increases the platelet count in a dose-
dependent way. Platelet counts begin to increase between 5 to 9 days after the
start of Neumega administration. After use of the product is stopped, platelet
counts continued to increase for up to 7 days and then return to baseline within
14 days.
The kidney is the primary route of elimination, although most of the
product is metabolized before excretion. Neumega is contraindicated with clients
with history of hypersensitivity to the product or any of its components.
Side Effects
Fluid retention
Cardiovascular events (Arrythmia)
Ophthalmologic effects (Blurry vision) Allergic reactions (Rash)
4. Interleukins
- are a group of proteins produced by the bodys WBCsthe lymphocytes.
Because interleukins are monelike glycoproteins manufactured by the
lymphocytes, they are sometime called lymphokines.
IL-2 is produced commercially through recombinant DNA technology. It is
marketed as aldesleukin (Proleukin) for use in the treatment of metastatic renal
cell carcinoma.
Pharmacokinetics
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IL-2, administered either by IV infusion or SC injection, and is rapidly
distributed to the extravascular, extracellular space and eliminated from the body
by metabolism in the kidney. The serum half-life of IL-2 is short. Because of this
rapid clearance, IL-2 is administered in frequent, short infusions.
Side Effects
Hypotension
Nausea
Vomiting
Diarrhea
Mental status changes
Oliguria/anuria
Anemia
Thrombocytopenia
Fever
Chills
Sinus tachycardia
Pulmonary congestion
Dyspnea
Pain at injection site
Fatigue
Weakness
Malaise
Elevated liver function test
5. Monoclonal Antibody
Transtuzumab (Herceptin)_________________________________
- is a recombinant humanized monoclonal antibody approved by the FDA for solo
treatment of metastatic breast cancer in clients whose condition is refractory to
chemotherapy or in combination with paclitaxel (Taxol) for first-line treatment of
metastatic breast cancer.
Pharmacokinetics
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The metabolism and elimination of transtuzumab is unknown. Following IV
infusion, the half-life is dose dependent; the half-life is about 6 days with a
weekly maintenance dose of 2mg/kg. The initial dose is 4mg/kg IV over 1.5 hours
followed by weekly maintenance doses of 2 mg/kg over half an hour. The
estimated cost for 23 weeks of treatment for a 120-pound woman is about $14,
000.
Side Effects
Fever
Chills
Nausea
Vomiting
Headache
Asthenia
Pain
Reference:
Kee, J.L., & Hayes, E. R. (2003). Pharmacology: A nursing process approach
(4th ed.). W. B. Saunders Co.
A diagram showing a monoclonal antibody attached into a
cell.