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New oncology strategy: molecular targeting of cancer cells.

The search for anti-cancer therapies which target cancer cells specifically and selectively with less toxicity has been a quest in oncology for many years. Conventional chemotherapeutic agents do not target cancer cells selectively, leading to widespread adverse systemic effects. Chemotherapy, radiation therapy, and biological agents all target cells that are in the process of proliferation. Therefore, both cancer cells and mitotically active healthy cells are subject to the cytotoxic effects of these therapies.

New understanding of how cancer cells survive, thrive, and metastasize has enabled researchers to create new targeted therapies for cancer treatments to minimize the harmful systemic effects of therapy on healthy cells. Cancer therapies are now in development which block or interrupt specific pathways or proteins that are intricately involved in the proliferation of cancer cells. Molecular targeting of cancer cells is the prevailing research field in oncologic pharmacology. The discovery of distinctive molecular pathways of cancer has engendered new targets for oncology pharmacotherapy. The specific and selective targets of future oncology drugs will require a detailed understanding of cancer cell biology, genetics, immunology, and biotechnology.

Molecular Targets of Cancer Cells under Investigation

To develop drugs which specifically attack the cancer cells requires an understanding of the distinct characteristics of those cells. One such characteristic unique to cancer cells is their secretion of growth factors which enable their unremitting proliferation and evasion of apoptasis (the process of cellular self-destruction). Growth factors under investigation include vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) and its receptor (EGFR). These growth factors are integral to the cancer cell's ability to obtain blood supply, proliferate, thrive, and metastasize. Investigators find that many of these growth factors are overexpressed in cancer cells and therefore serve as potential targets for cancer chemotherapy (Nam & Parang, 2003). Pharmacologic inhibition of these growth factors (for example, VEGF) and their receptors (for example, EGFR) is currently the most intensely scrutinized strategy in oncology treatment. Another cellular component which has been identified as a potential target for destroying cancer cells is the proteasome. The proteasome is a molecular complex that plays a central role in cell metabolism and regulates apoptosis. Selective inhibition of this proteasome blocks cancer cell proliferation and induces cancer cell self-destruction (Mitchell, 2003).

VEGF: Targeted Angiogenesis Factor of Cancer Cells

When tumor cells reach a certain mass, internal hypoxia triggers the secretion of vascular endothelial growth factor. This enables the tumor to develop new blood vessels (a process called angiogenesis). An increasing numbers of investigations focus on tumor angiogenesis as a target for cancer chemotherapy. Numerous antiangiogenic agents are currently in various phases of clinical trials. Pioneering research from the laboratory of Folkman and colleagues over the past 30 years has established that tumor growth depends on angiogenesis. Direct observation of tumor growth demonstrates that the rapid exponential growth of a tumor does not occur until neovascularization occurs (Folkman, 1971). Cancer cells have the ability to stimulate angiogenesis because they secrete growth factors such as VEGF, basic fibroblastic growth factor (bFGF), EGF, angiopoetin, integrins, interleukin-8 (IL-8), and platelet-derived endothelial cell growth factor (PDECGF) (Ellis, 2002). These growth factors are potent stimulators of endothelial cell proliferation, which enables the cancer to manufacture a network of capillaries. Although VEGF is believed to be the principal factor through which tumor cells induce the proliferation of endothelial cells and neovasculature, angiogenesis is a multifaceted process. Cancer depends on the establishment of blood vessels which connect the tumor to the body's circulatory system to bring it an ongoing supply of blood and nutrients. Evidence shows that tumors require angiogenesis to grow beyond 1 to 2 [mm.sup.3] (Folkman, 1992). The newly formed capillary network also makes it possible for cancer cells to connect to the rest of the body, spread hematogenously, embolize, and metastasize. Numerous investigators have established the association of tumor angiogenesis with metastasis. The degree of vascularity could be used to predict biologic aggressiveness of a tumor. The more aggressive cancers demonstrate higher degrees of vascularity (Hanahan & Folkman, 1996).

Although many synthetic and exogenous inhibitors of angiogenesis have been developed, the inhibitors that have received the most attention are the naturally derived endogenous proteins angiostatin and endostatin. These compounds are derived from human proteins which circulate in the body to naturally prevent tumor growth and metastasis. Angiostatin is a fragment of plasminogen, a physiologic compound involved in coagulation. Endostatin is a fragment of the physiologic protein collagen XVII. Both of these natural compounds inhibit growth of primary and metastatic tumors via degeneration of their blood supply. Preclinical studies involving these natural anti-angiogenesis compounds have produced dramatic results in breast, colon, prostate, and lung cancers. No significant drug resistance or toxicity has been demonstrated in clinical trials (Entremed Pipeline Candidates, n.d.).

EGFR: Targeted Growth Factor Receptor on Cancer Cells

The epidermal growth factor receptor (EGFR) has emerged in recent years as a key target of molecular therapy for solid tumors. EGFR in cancer plays a central role in many of the processes involved in tumor progression, such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Blocking the receptor of ECF inhibits pathways which in turn inhibit DNA synthesis, proliferation, cell maturation, and migration of cancer cells. Blockade of the receptor of EGF thus has become a target of new anticancer therapies. Currently, the most actively investigated is the family of EGF receptors, which include HER1, HER2, HER3, and HER4. These receptors are found on many cancer cells, notably breast cancer, and correlate with a poor prognosis (Gale, 2003; Gemmill & Idell, 2003).

The Proteasome: Targeted Metabolic Pathway of Cancer Cells

The proteasome is a macromolecular complex within all cells with catalytic activity to degrade and eliminate intracellular proteins. The proteasome is an organdie similar to the lysosome, which is also involved in enzymatic degradation of cellular substances. The proteins which are degraded by the proteasome include those which regulate various metabolic functions such as the cell cycle, transcription, apoptosis, angiogenesis, chemotaxis, and cellular adhesion. Selective inhibition of cancer cell proteasomes blocks the cancer cell's metabolic regulators and induces cancer cell apoptosis. In addition, studies show that inhibition of the cancer cell proteasome sensitizes malignant cancer cells to conventional chemotherapeutic agents and radiation therapy (Mitchell, 2003; Voorhees, Dees, O'Neil, & Orlowski, 2003).

Cancer Drugs with Specific Molecular Targets

VEGF Inhibitors

Bevacizumab (Avastin[R]). Bevacizumab is a monoclonal antibody directed against VEGF. A monoclonal antibody is a genetically engineered, humanized antibody which targets and attacks a specific antigen. In cancer, monoclonal antibodies are designed to target specific cancer cell antigens. The antibody initiates an immunologic response which eliminates cells associated with the antigen. Bevacizumab is a monoclonal antibody designed to attack cells that over-express the VEGF protein as an antigen. By inhibiting vascular endothelial growth factor, the drug acts as an anti-angiogenesis agent.

Currently, bevacizumab is in clinical trials in renal cell carcinoma, nonsmall cell lung cancer, and metastatic breast cancer. Therapeutic dosages are still under investigation. Recently, it was approved for first-line treatment of metastatic colorectal cancer. Used in combination with intravenous 5fluorouracil (FU)-based chemotherapy, bevacizumab has shown increased survival in patients with metastatic colorectal cancer. The recommended dose is 5 mg/kg given once every 14 days as an intravenous infusion. This drug should not be administered as an IV push or bolus dose. Infusions should not be mixed with dextrose solutions. The half-life of this drug is approximately 20 days. The most serious adverse effects associated with bevacizumab are gastrointestinal perforation, wound healing complications, hemorrhage, hypertensive crises, nephrotic syndrome, and congestive heart failure. Serious episodes of hemoptysis have been reported in patients with lung cancer. No studies have been conducted in patients with renal or hepatic impairment. Bevacizumab therapy should not be initiated for at least 28 days following major surgery because of the potential for impaired wound healing. Infusion reactions have been rare (Genentech, n.d.; National Cancer Institute, n.d.).

AE-941 (Neovastat[R]). AE-941 (shark cartilage) targets several steps in tumor angiogenesis, including the blockade of VEGF. However, its primary mechanism is inhibition of matrix metalloproteases (MMPs). MMPs, which are enzymes liberated by cancer cells that allow for invasion of surrounding tissues, are secreted by tumor cells to break down surrounding connective tissue and basement membranes to enable their spread to distant sites. Inhibition of VEGF and MMPs also inhibits cancer blood supply and distant spread. Currently, this orally administered drug is used in multiple myeloma, nonsmall cell lung cancer, and renal cell carcinoma. The only adverse effect reported to date is a skin rash (The Cleveland Clinic Multiple Myeloma Research Center, n.d.; Muehlbauer, 2003).

Thalidomide (Thalomid[R]). Banned in the 1950s because of severe teratogenicity, thalidomide is an effective anti-angiogenic agent. Prior to 1950, the drug was prescribed to women to counteract severe nausea and vomiting associated with pregnancy. However, it caused severe congenital limb malformations of the fetus and was banned as a result. Renewed investigation into the drug has demonstrated thalidomide's ability to inhibit VEGF, bFGF, tumor necrosis factor, and endothelial cell function. Thus far, studies demonstrate promising results in multiple myeloma. Other clinical trials are using thalidomide in Kaposi's sarcoma; breast, colon, prostate, lung, and brain cancers; and melanoma. Because of the birth defects associated with thalidomide, strict guidelines exist for those using the drug in clinical trials. The mandatory patient education materials include a video of babies born with thalidomide-induced limb malformations, strict birth control instructions, and a detailed consent form. A pregnancy test is required weekly while on thalidomide therapy. Aside from teratogenicity, thalidomide's side effects include peripheral neuropathy, somnolence, constipation, increased appetite, and weight gain (Lafitte & Revuz, 2004; Rajkumar, 2001).

EGFR Inhibitors

Cetuximab (Erbitux[R]). Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor. The EGFR is widely expressed in advanced colorectal cancers, and higher levels of EGFR are inversely related to survival in patients. In clinical trials, cetuximab in combination with other forms of chemotherapy and radiation has shown decreased cancer cell growth in pancreatic cancer and nonsmall cell lung cancer. The most common adverse effects associated with cetuximab monotherapy are acne-like rash, asthenia, abdominal pain, nausea, and vomiting (Cohen, 2003; Reynolds & Wagstaff, 2004).

Gefitinib (Iressa[R]). Gefitinib is the first orally active, selective EGFR inhibitor recommended for monotherapy. Studies show evidence of tumor regression in patients with advanced nonsmall cell lung cancer. It has been used as a third-line treatment of chemoresistant nonsmall cell lung cancer. Available as a 250 mg tablet, it is administered once a day. Adverse reactions include interstitial lung disease with cough, fever, and dyspnea. Other possible side effects include diarrhea, rash, acne, dry skin, nausea, vomiting, pruritus, anorexia, asthenia, weight loss, eye pain, and corneal erosion. Periodic liver function testing is needed because asymptomatic increases in liver transaminases have been observed. Caution must be used with renal impairment and drugs which increase or decrease liver enzyme activity. Increases in international normalized ratio (INR) and/or bleeding episodes have been reported when used with warfarin (Coumadin[R]). This drug is not recommended for pregnant women (Santoro et al., 2004; van Zandwijk, 2003).

Trastuzumab (Herceptin[R]). Trastuzumab is a monoclonal antibody which targets tumors that over-express the HER2 protein, an epidermal growth factor. The over-expression of HER2 occurs in 25 to 30% of persons with breast cancer (Slamon et al., 2001). Trastuzumab binds to the specific epidermal growth factor receptor (HER2) and initiates cell-mediated immunity responses which destroy the cancer cells. The drug is indicated for treatment of patients with metastatic breast cancer whose tumors over-express the HER2 protein and who have received one or more chemotherapy regimens. Special directions call for reconstitution of each vial of trastuzumab with bacteriostatic water only and a strict 28-day expiration date with refrigeration. The recommended initial loading dose is 4 mg/kg given over 90 minutes. The weekly maintenance dose is 2 mg/kg over 30 minutes. The medication should not be administered as IV push or bolus. Because cardiotoxicity has been observed as an adverse effect in some patients, a baseline cardiac assessment is necessary for all patients. Hypersensitivity reactions have been reported infrequently. During the first infusion of this drug, reaction can occur which consists of chills and fever. These initial infusion reaction effects can be treated symptomatically and occur infrequently in subsequent infusions. Anemia, leukopenia, diarrhea, and an increased incidence of upper-respiratory infections have been observed as adverse effects (Medical Economics, 2003).

Proteasome Inhibitors

Bortezomib (Velcade[R]). Bortezomib is a proteasome inhibitor which has demonstrated antitumor activity in multiple myeloma. Bortezomib and other proteasome inhibitors specifically induce apoptosis in cancer cells. This drug is recommended for patients who have received at least two prior therapies without results. Available as an injectable, it is given initially as an IV bolus twice weekly for 2 weeks followed by a 10-day rest period. Therapy should be withheld if nonhematologic or hematologic toxicity develops, then reinitiated after symptoms resolve. Peripheral neuropathy is the most common adverse reaction, and the dose should be decreased or the medication stopped if severe. Caution should be observed with concomitant use of other medications associated with peripheral neuropathy such as statins (Pravachol[R], Lipitor[R]), isoniazid (INH), nitrofurantoin (Macrodantin[R]), or amiodarone (Cordarone[R]). Hepatic and renal impairment may cause decreased clearance. Other adverse reactions include fatigue, weakness, nausea, diarrhea, anorexia, constipation, thrombocytopenia, fever, vomiting, anemia, pneumonia, orthostatic hypotension, and dehydration. Patients on oral antidiabetic agents may require close monitoring of blood glucose levels. Bortezomib is not recommended during pregnancy or nursing (Kane, Bross, Farrell, & Pazdur, 2003; Thomson PDR, 2004).

Nursing Implications of Targeted Cancer Therapy

Molecular targeting in cancer is a relatively new treatment modality. Many agents are in clinical trials undergoing scrutiny of their indications, therapeutic benefits, adverse effects, and contraindications. Each drug will have different administration methods and recommendations regarding handling and disposal. Patient education will be a major responsibility of nurses. Patients and significant others who may be involved in their day-to-day care should understand how these agents work, possible adverse effects, how to manage these at home, as well as when to call a health care professional for assistance. Teaching aids are available from pharmaceutical companies, the American Cancer Society, and the National Cancer Institute. Many of the pharmaceutical manufacturers have Web sites with teaching modules for health care professionals which describe how their drugs work. The Web sites also have downloadable patient education materials.

Targeted cancer drugs which can be administered orally tend to be much less toxic than conventional chemotherapy. Many current clinical trials will evaluate targeted molecular agents alone and in combination with other chemotherapy agents or radiation. Hypersensitivity reactions are possible with administration of any new agent, and the nurse should be aware of the signs and symptoms of anaphylaxis. Patients should be observed for at least 15 minutes after receiving injectable medications. Signs of anaphylaxis include rash, bronchospasm, hypotension, angioedema, dyspnea, and tachycardia. Infusion reactions may be experienced by those patients receiving injectable medications for the first time. They often include chills, fever, nausea, headache, dizziness, dyspnea, hypotension, rash, and asthenia. Infusion reactions should be treated symptomatically with such agents as antipyretics, corticosteroids, and diphenhydramine (Benadryl[R]) (Medical Economics, 2003). Drugs such as bevacizumab, thalidomide, and trastuzumab have specific possible adverse effects of which the nurse should be knowledgeable. Every new drug will require a thorough review of the accompanying prescribing information. The nurse should pay particular attention to adverse effects, contraindications, and directions for administration.

Importantly, the nurse should recognize that many of the patients receiving these agents have experienced prior episodes of cancer chemotherapy that proved unsuccessful. The patient will need emotional support to continue cancer treatments. The nurse can be an advocate who can instill hope, offer education, and refer the patient to appropriate support groups.

Molecular targeting of cancer will require the nurse to be knowledgeable of concepts regarding cancer cell biology, immunology, and biotechnology. Continuing education programs and tutelage from pharmaceutical manufacturers of the new drugs will be needed. Clinical trials of these new agents are growing in number, and the nurse will also be increasingly involved in research protocols. The nurse will need to play many roles: direct caregiver, patient educator, patient advocate, and researcher. Lastly, the nurse must also be a student to understand the widening array of therapeutic options for patients with cancer.

Glossary

Angiogenesis--The development of new blood vessels from pre-existing vasculature.

Apoptosis--Genetically controlled programmed cell death; allows the body to eliminate aged or defective cells or remodel tissues; a cascade of proteolytic enzymes destroys the cells destined for apoptosis. Drugs are under investigation which will specifically provoke apoptosis of cancer cells.

bFGF--Basic fibroblastic growth factor; stimulates endothelial cell growth.

Endothelium (endothelial cells)--Cells that make up structure of blood vessels.

EGF--Epidermal growth factor; stimulates proliferation of many cell types, particularly epithelial and endothelial cells.

EGFR--Epidermal growth factor receptor.

HER2--A type of epidermal growth factor receptor on certain cancer cells.

MMPs--Matrix metalloproteases; enzymes which degrade extracellular matrix, connective tissue, and basement membranes of surrounding tissue.

Monoclonal antibody--Genetically engineered antibody which targets specific tumor-associated antigen and induces an immune response which lyses the tumor cells.

Proteasome--A macromolecular complex within all cells with catalytic activity to degrade and eliminate intracellular proteins; inhibition of cancer cell proteasomes blocks the cancer cell's metabolic regulators and induces cancer cell apoptosis.

VEGF--Vascular endothelial growth factor; a key angiogenic factor which stimulates endothelial cells to divide and migrate.

References

Cleveland Clinic Multiple Myeloma Research Center, The. (n.d.). What is Neovastat? Retrieved January 19, 2004, from http://www.clevelandclinic.org/myeloma/N eovastat.htm

Cohen, R.B. (2003). Epidermal growth factor receptor as a therapeutic target in colorectal cancer. Clinical Colorectal Cancer, 2(4), 246-251.

Ellis, L.M. (2002). Tumor angiogenesis. Horizons in Cancer Therapeutics: From Bench to Bedside, 3(1), 4-22.

Entremed Pipeline Candidates. (n.d.) Angiostatin. Retrieved January 19, 2004, from http://www.entremed.com/pipeline/ angiostatin.cfm

Entremed Pipeline Candidates. (n.d.) Endostatin. Retrieved January 19, 2004, from http://www.entremed.com/pipeline/ endostatin.cfm

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Folkman, J. (1992). The role of angiogenesis in tumor growth. Seminars in Cancer Biology, 3, 65-71.

Gale, D.M. (2003). Molecular targets in cancer therapy. Seminars in Oncology Nursing, 19(3), 193-205.

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Kane, R.C., Bross, RE, Farrell, A.T, & Pazdur, R. (2003). Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist, 8(6), 508-513.

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National Cancer Institute. (n.d.) Bevacizumab (Avastin[R]) improves survival in metastatic colorectal cancer. Retrieved January 19, 2004, from http://www.cancer.gov/ clinicaltrials/results/bevacizumab-and-colorectal-cancer0601

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Reynolds, N.A., & Wagstaff, A.J. (2004). Cetuximab: In the treatment of metastatic colorectal cancer. Drugs, 64(1), 109-118.

Santoro, A., Cavina, R., Latteri, R, Zucali, P.A., Ginanni, V., Campagnoli, E., et al. (2004). Activity of a specific inhibitor, gefitinib (Iressa[TM], ZD1839), of epidermal growth factor receptor in refractory non-small cell lung cancer. Annals of Oncology, 15(1), 33-37.

Slamon, D.J., Leyland-Jones, B., Shak, S., Fuchs, H., Paten, V., Bajamonde, A., et al. (2001). Use of chemotherapy plus monoclonal antibody against HER2 for metastatic breast cancer that over-expresses HER2. New England Journal of Medicine, 344(11), 783-792.

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Van Zandwijk, N. (2003). Tolerability of gefinitib in patients receiving treatment in everyday clinical practice. British Journal of Cancer, 89(Suppl. 2), S9-S14.

Voorhees, RM., Dees, E.C., O'Neil, B., & Orlowski, R.Z. (2003). The proteasome as a target for cancer therapy. Clinical Cancer Research, 9(17), 16-25.

Teri Capriotti, DO, MSN, CRNP, is a Clinical Assistant Professor, Villanova University, College of Nursing, Villanova, PA.
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Title Annotation:Nursing Pharmacology
Author:Capriotti, Teri
Publication:MedSurg Nursing
Date:Jun 1, 2004
Words:3420
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