Antineoplastic Agents

Anticancer/Antineoplastic Drugs
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 the early 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
Antineoplastic Agents and Biologic Response Modifiers

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.

Antineoplastic Agents and Biologic Response Modifiers

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.

Antineoplastic Agents and Biologic Response Modifiers

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
Peripheral Edema (Feet)

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.
Antineoplastic Agents and Biologic Response Modifiers

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

Antineoplastic Agents and Biologic Response Modifiers

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

Antineoplastic Agents and Biologic Response Modifiers

Plicamycin To correct hypercalcemia, and hypercaliciuria; to treat testicular carcinoma Side Effects

Doxorubicin Alopecia Nausea Vomiting Stomatitis Leukopenia Thrombocytopenia Rash

Alopecia (Hair loss) Stomatitis

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.
Antineoplastic Agents and Biologic Response Modifiers

Adverse Effects Nausea Vomiting Partial to Complete Alopecia Leukopenia Stomatitis Neurotoxicity

Stages of Cell Mitosis

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.
Antineoplastic Agents and Biologic Response Modifiers

Adverse Effects Alopecia Diarrhea Nausea Vomiting Peripheral neuropathy Stomatitis Fever Fluid retention
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.

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 (Foot)

Antineoplastic Agents and Biologic Response Modifiers

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
Antineoplastic Agents and Biologic Response Modifiers

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.

Antineoplastic Agents and Biologic Response Modifiers

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

Antineoplastic Agents and Biologic Response Modifiers

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.
Antineoplastic Agents and Biologic Response Modifiers

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, nonspecific

electrocardiographic 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

Antineoplastic Agents and Biologic Response Modifiers

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 fungusdestroying 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 firstorder kinetics (process by which the drug is eliminated in part by the hepatic and renal 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

Antineoplastic Agents and Biologic Response Modifiers

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.

Antineoplastic Agents and Biologic Response Modifiers

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

Antineoplastic Agents and Biologic Response Modifiers

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 dosedependent 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
Antineoplastic Agents and Biologic Response Modifiers

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

Antineoplastic Agents and Biologic Response Modifiers

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

A diagram showing a monoclonal antibody attached into a cell.

Reference: Kee, J.L., & Hayes, E. R. (2003). Pharmacology: A nursing process approach (4th ed.). W. B. Saunders Co.
Antineoplastic Agents and Biologic Response Modifiers