anticancer agents 1

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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.


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.


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.

anticancer agents 1

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