Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 55 Adjuvant Antineoplastic Drugs

MAJOR DRUG CLASSES

Aromatase inhibitors

Hormonal agents

Kinase inhibitors

Proteosome inhibitors

Recombinant proteins

Therapeutic Overview

Immunotherapy, vaccines, drugs affecting angiogenesis, specific tumor growth factor receptor antagonists, and other forms of biological therapies are becoming more common in the treatment of neoplastic disease. Traditional chemotherapy, as discussed in Chapter 54, is aimed at destruction of rapidly dividing tumor cells. However, newer approaches involve drugs that are aimed at more specific cellular targets on the cancer cells with reduced effects on normal cells. Thus these agents typically have fewer side effects than the traditional chemotherapeutic agents. In addition to being administered alone for the treatment of certain cancers, many of these compounds are also used in combination with traditional chemotherapeutic regimens.

The cell targets and agents directed towards these targets are summarized in the Therapeutic Overview Box.

Mechanisms of Action

Hormonal Agents

Steroids act by passing through the plasma membrane and binding to cytoplasmic receptors, which then enter the

Abbreviations

ADCC

Antibody-dependent cell-mediated cytotoxicity

ATP

Adenosine triphosphate

EGFR

Epidermal growth factor receptor

HPV

Human papilloma virus

IFN-α

Interferon alpha

IL-2

Interleukin-2

IV

Intravenous

mRNA

Messenger ribonucleic acid

NK

Natural killer (cell)

PDGFR

Platelet-derived growth factor receptor

VEGFR

Vascular endothelial growth factor receptor

Therapeutic Overview

Targets

The immune system

Growth factors and their receptors

Intracellular signaling molecules

Angiogenesis

Agents

Hormones and antihormones

Cytokines

Monoclonal antibodies

Vaccines

Small molecules

nucleus and interact with specific hormone-responsive elements on chromatin to induce synthesis of specific messenger ribonucleic acids (mRNAs). Translation of these mRNA species leads to formation of new proteins that alter physiological or biochemical reactions in a beneficial manner. Most of the proteins involved, however, have not yet been identified and characterized.

Antihormonal drug treatment strategies for breast cancer include:

• Blockade of estrogen receptors with antiestrogen drugs

• Destruction of estrogen receptors

• Inhibition of estrogen production by the adrenals

Approximately 70% of all postmenopausal patients whose breast tumors show the presence of estrogen receptors respond favorably to antiestrogen therapy, as opposed to only approximately 10% of those whose tumors do not express receptors. Tamoxifen is the main antiestrogen used clinically, and it acts by binding to estrogen receptors and blocking estrogen-dependent transcription of cells in the G1phase. By blocking the binding of estrogens, tamoxifen (see Chapter 40) may decrease estrogen stimulation of the production of transforming growth factor-α and secretion of associated proteins.Toremifene, closely related to tamoxifen, is a newer estrogen receptor antagonist that is also used to treat estrogen receptor-positive breast cancer, or when estrogen sensitivity is unknown. It is indicated in postmenopausal women whose cancer has metastasized. Fulvestrant has also been recently approved for the treatment of estrogen receptor-positive breast cancer in postmenopausal women. However, in contrast to tamoxifen and toremifene, instead of blocking estrogen receptors, fulvestrant destroys them.

Although postmenopausal women have very low levels of estrogen, small amounts are produced through the conversion of androstenedione, secreted by the adrenal glands, to estrogen via an aromatase enzyme (see Fig 38-1). Even these low levels can stimulate estrogen-sensitive breast cancer. The aromatase inhibitors letrozole, anastrazole, and exemestane effectively block the production of estrogen from the adrenals and are alternatives to the estrogen receptor antagonists in postmenopausal women. These drugs do not affect ovarian secretion of estrogen and for this reason are not used in the treatment of breast cancer in premenopausal women.

In metastatic prostate cancer, as in breast cancer, hormonal manipulations can produce objective responses. For prostate cancer this involves either orchiectomy or pharmacological castration. Testosterone concentrations can be reduced by the estrogen diethylstilbestrol or by suppression of the pituitary gonadotropic axis. Leuprolide and goserelin are analogs of gonadotropic-releasing hormones that inhibit release of gonadotropins and result in reduced testosterone concentrations. The two agents are available in depot form and can be given monthly. Both are agonists and antagonists of luteinizing hormone-releasing hormone. They produce an initial rise in gonadotropin concentrations, followed by a decline in 2 to 3 weeks.

Flutamide is an antiandrogen that inhibits androgen binding to receptors in the nucleus. Unlike other agents discussed, it increases concentrations of testosterone; however, the testosterone is ineffective because flutamide blocks its action. There has been recent interest in achieving total androgen blockade (both testis and adrenal) through concurrent use of flutamide and luteinizing hormone-releasing hormone analogs.

Biological Therapy

Harnessing intrinsic biological systems for treatment of disease is an appealing concept, because theoretically it could be highly targeted and of limited toxicity. “Biological therapy” attempts to use our native host defense system and its humoral and cellular components as weapons to fight cancer (see Chapter 6). Many of these weapons are intended to stimulate the immune system for destruction of malignant cells. The immune system involves the action of many different cell types acting in concert, particularly lymphocytes, which can be classified as B, T, or null cells. These cells can secrete proteins, including antibodies, which possess unique affinity for their conjugate antigens and impart specificity to the immune system. They also secrete cytokines, which have wide-ranging cellular influences. Use of these systems may introduce remarkable therapeutic target specificity at the risk of induction of autoimmunity and unique toxicities. Agents currently in use include cytokines, monoclonal antibodies, and vaccines.

Interleukin 2 (IL-2) is one of a family of soluble glycoproteins that is involved in direct communication between leukocytes. IL-2 is produced by activated T lymphocytes and is a growth factor for T cells. Recombinant IL-2 therapy as a single agent has activity in treatment of melanoma and renal cell carcinoma, producing durable resolution of all disease in 6% to 7% of patients with metastatic disease. IL-2 is also being investigated as an adjunct with chemotherapy, monoclonal antibodies, and vaccines.

Interferon-alpha (IFN-α) is one of a family of glycoproteins, the interferons, which are synthesized by macrophages and lymphocytes that have been stimulated by mitogens, antigens, RNA, or infected by a virus. Interferons also express a wide variety of biologic activities, often making it difficult to determine which ones might be operant in a particular context. They modulate immune responses, augmenting T-cell and natural killer (NK) cell-mediated cytotoxicity; participate in the regulation of cellular differentiation and antigenic expression; and possess antiviral activity. Thus, they are useful clinically for the treatment of viral hepatitis and as anti-tumor agents due to their antiangiogenic and antiproliferative effects. IFN-α has clinical activity in the treatment of hairy cell leukemia, chronic myelogenous leukemia, indolent lymphoma, multiple myeloma, Kaposi’s sarcoma, superficial bladder carcinoma, renal cell carcinoma, and melanoma. Benefit from adjuvant therapy with high-dose IFN-α after resection of high-risk cutaneous melanoma remains controversial.

Antibodies are products of B cells produced as a result of exposure to specific stimulating agents or antigens. Technological advances, including development of hybridoma methodologies, have allowed production of large quantities of pure antibodies specific for individual epitopes. These can be used as an informer, identifying malignant cells as targets for attack by antibody-dependent cell-mediated cytotoxicity (ADCC). Bi-specific antibodies simultaneously and specifically target a tumor cell antigen and “trigger” molecules on neighboring effector cells, inducing cytotoxicity. Antibodies have been constructed to target and then block selected growth factor receptors and affect cellular growth. Cetuximab is an example of an antibody directed against the epidermal growth factor receptor (EGFR). Antibodies may also be used as the missile of biological “smart bombs” carrying a radiopharmaceutical or biologic toxin warhead to a specific target.

Rituximab is a chimeric immunoglobulin G1-κ monoclonal antibody raised against the CD20 antigen, constructed with a murine light and heavy-chain variable region and a human constant region sequence. CD20 is a transmembrane protein expressed by most B cells at various stages of development and by malignant B lymphocytes. It is found on more than 90% of B cell non-Hodgkin’s lymphomas, but importantly, is not expressed by hematopoietic stem cells or other normal tissues. Rituximab binds to B lymphocytes after intravenous (IV) administration; therefore serum concentrations vary inversely with tumor burden. Complement-dependent cytotoxicity and ADCC are both mechanisms through which this agent may cause target cell lysis. Rituximab is used in the treatment of indolent low-grade non-Hodgkin’s lymphoma, where it may be used as monotherapy, and in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy as treatment for CD20-positive diffuse large B-cell non-Hodgkin’s lymphoma. Rituximab is a component of a combination regimen using ibritumomab tiuxetan and is being evaluated in the treatment of chronic lymphocytic leukemia, thrombocytopenic purpura, and Waldenström’s macroglobulinemia.

I131-tositumomab is composed of the monoclonal murine anti-CD20 antibody tositumomab linked to I131, which is both a β and γ emitter. This drug may induce apoptosis, incite complement-dependent cytotoxicity or ADCC, and can cause cell death from radiation. Before administration, thyroprotection is provided with potassium iodide, and then unlabeled tositumomab is administered to saturate non-tumor sites. A test dose of I131-tositumomab is given to calculate the appropriate therapeutic dose based on the rate of clearance, terminal t1/2, and volume of distribution. In patients with a high tumor burden, splenomegaly, or bone marrow involvement, clearance is faster, and the volume of distribution is larger. I131 is excreted in the urine. This drug is not appropriate as initial therapy, because resultant cytopenias may eliminate other potential effective therapies. However, tositumomab is efficacious when administered as a single-course treatment in patients with relapsed, CD20-positive, follicular non-Hodgkin’s lymphoma, with or without transformation, who are refractory to rituximab. Radiotherapeutic dosimetry must be appropriately pursued or profound, and durable toxicity may result.

Y90-Ibritumomab tiuxetan is composed of ibritumomab, a murine anti-CD20 monoclonal antibody related to rituximab, linked to a moiety, tiuxetan, designed to chelate a radioisotope. Indium-111 is attached to the complex, creating an agent that can be used for imaging. If yttrium-90 is attached, an agent is created that can be used therapeutically. An initial rituximab infusion is given to clear peripheral B cells before treatment to permit more effective targeting, because Y90-ibritumomab tiuxetan is cleared from plasma mainly by cellular or tumor binding with minimal urinary and no fecal excretion. Although there is no correlation between the pharmacokinetics of Y90-ibritumomab tiuxetan and severity of hematologic toxicity, the extent of baseline bone marrow involvement and level of the platelet count accurately predict hematotoxicity and indicate necessary dose adjustments when taken into account with weight. This agent is used for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma, including patients with rituximab refractory follicular non-Hodgkin’s lymphoma. Further study, however, is needed to establish the role of this agent in various therapeutic regimens and to clarify its effectiveness relative to that of tositumomab.

Gemtuzumab ozogamicin is a recombinant humanized monoclonal antibody against CD33 designed to deliver calicheamicin, a chemotherapeutic agent, to the myeloid cell surface, where the chemotherapeutic agent can be internalized by the cell and cause cytotoxicity. Treatment with gemtuzumab ozogamicin is indicated for patients who are 60 years of age or older with no other alternatives for therapy who suffer from CD33-positive acute myeloid leukemia in first relapse.

Growth Factor Receptors: Anti-EGFR Therapy

The EGFR is present on a variety of solid tumors including non-small-cell lung cancer, head and neck cancer, and malignant gliomas. EGFR expression correlates with poor clinical outcome and resistance to cytotoxic agents. The EGFR consists of an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and an intracellular domain with tyrosine kinase activity. Upon stimulation by ligand, the EGFR dimerizes, which initiates an intracellular pro-survival signaling cascade, resulting in increased cell proliferation, metastasis, and decreased apoptosis (Fig. 55-1). The EGFR pathway can be inhibited by either blocking the extracellular domain with monoclonal antibodies or by small molecule tyrosine kinase inhibitors that block adenosine triphosphate (ATP)-binding and inhibit kinase activity.

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FIGURE 55–1 The EGFR family is a group of structurally similar growth factor receptors with tyrosine kinase activity (K); these receptors play a critical role in regulating cell cycle progression and metastasis. Upon stimulation by ligands including EGF, transforming growth factor, and mitogenic signals, the receptor (R) dimerizes and the intracellular tyrosine kinase is activated, which transmits the pro-growth signal to the effector molecules as shown. The EGFR pathway can be inhibited either immunologically with the monoclonal antibody cetuximab or pharmacologically by inhibiting the tyrosine kinase ATP-binding site as shown with gefitinib. Overexpression of EGFR is frequent in non-small-cell lung cancers and in head and neck cancers.

Trastuzumab is a recombinant deoxyribonucleic acid-derived humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human EGFR2 protein HER2. The HER2 (or C-ERBB2) protooncogene encodes a transmembrane receptor protein structurally related to the EGFR. Trastuzumab inhibits the proliferation of human tumor cells that overexpress HER2 and is approved for treatment of patients with metastatic breast cancer. As a single agent, it is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for metastatic disease. It is also indicated for administration in combination with paclitaxel for treatment of patients with metastatic breast cancer who are chemotherapy naive and whose tumors overexpress the HER2 protein. Cetuximab is the first monoclonal antibody directed against the EGFR to be approved for treatment of colorectal cancer, either alone or in combination with irinotecan. Cetuximab is a genetically engineered version of a mouse antibody that contains both human and mouse components targeting EGFRs.

Gefitinib, an orally available small-molecule tyrosine kinase inhibitor, was approved as third-line treatment for non-small-cell lung cancer. This was based on a 10% objective response rate and an improvement in quality of life. Several other small-molecule tyrosine kinase inhibitors and monoclonal antibodies directed against the EGFR are in late-stage clinical trials.

Vaccines

Vaccines for the prevention and treatment of cancer have been studied for many years, but advances in this area have been slow to develop. For the most part, vaccines are still primarily experimental treatments. The one notable exception is the approval of a recombinant quadrivalent human papillomavirus (HPV)-like particle vaccine to prevent diseases related to HPV types 6, 11, 16, and 18, including precancerous cervical lesions, cervical cancer, vaginal or vulvar lesions, and genital warts. HPV is sexually transmitted, but initial infections typically go undetected. However, the presence of the virus can lead to abnormalities in the cervical epithelium that may progress to cancer. The most appropriate use of this vaccine is to administer it to young girls before sexual activity; however, girls and women who are sexually active should also be vaccinated. The United States Advisory Committee on Immunization Practice recommends vaccination in all girls and women between 11 and 26 years of age.

Inhibitors of Intracellular Signaling

Anti-ABL Protein Kinase Inhibitors

Imatinib is an orally available inhibitor of the ABL group of tyrosine kinases whose activity is unregulated in chronic myelogenous leukemia. The constitutively active BCR-ABL oncoprotein results from the chromosomal translocation known as the Philadelphia chromosome, which is found in 95% of patients with chronic myelogenous leukemia. Imatinib competitively inhibits the BCR-ABL kinase by binding to the ATP binding domain of the inactive conformation of C-ABL. Imatinib has revolutionized the treatment of chronic myelogenous leukemia by producing complete remissions in the vast majority of patients with Philadelphia-positive chronic myelogenous leukemia. Despite the success of imatinib, mutations in the BCR-ABL kinase domain occur that lead to resistance. Imatinib also produces responses in an unusual tumor known as gastrointestinal stromal cell tumor. This tumor is known to contain a C-KIT protooncogene mutation that results in increased tyrosine kinase activity.

Sunitinib and sorafenib are two oral tyrosine kinase inhibitors that have been approved for treatment of advanced renal cell carcinoma. Sunitinib is also approved for the treatment of gastrointestinal stromal tumors that do not respond to imatinib. Sunitinib inhibits several transmembrane tyrosine kinases including vascular endothelial growth factor receptors (VEGFR) types 1, 2 and 3, and platelet derived growth factors (PDGFR) types α and β; these are important for cellular signaling in tumor proliferation and angiogenesis. Sorafenib also targets multiple intracellular and cell surface kinases similar to sunitinib, although it has a lower affinity for VEGFR-2 and PDGFR-β than sunitinib.

Proteosome Inhibitors

The proteosome is a large multiprotein complex present in both the cytoplasm and nucleus of all eukaryotic cells. The 26S proteosome is a primary component of the protein degradation pathway of cells. Targeted degradation of proteins via the proteosome is key to many cellular processes including cell cycle progression and apoptosis. Proteins that are targeted for degradation are first marked with a polyubiquitin chain on specific lysine residues. The basis for proteosome inhibition as an antineoplastic strategy is uncertain. However, inhibition of proteosome degradation by such agents as bortezomibhas been shown to be beneficial. Bortezomib is indicated for treatment of refractory multiple myeloma.

Angiogenesis Inhibitors

Bevacizumab is a recombinant humanized monoclonal antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor, inhibiting stimulation of new blood vessel formation. Tumor growth is slowed because a decreased blood supply results in decreased oxygen and other nutrients needed for growth. Bevacizumab is approved for first-line treatment of metastatic colorectal cancer.

Pharmacokinetics

The pharmacokinetics of the drugs described in this chapter are summarized in Table 55-1. Of major consideration when administering these drugs is the fact that many of them are extensively metabolized by cytochrome P450 enzymes; thus the potential for serious drug interactions exists. Patients receiving these drugs typically receive other medications as well, including chemotherapeutic drugs, anti-infectives, anti-emetics, and drugs to stimulate the bone marrow.

TABLE 55–1 Pharmacokinetic Parameters for Selected Drugs

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It is important to note that the pharmacokinetics of bevacizumab vary with age, gender, body weight, and tumor burden. Therefore the dosing of this agent must be individualized for each patient. Dosage adjustments may be required for any of these drugs in the presence of hepatic or renal failure, and therefore careful monitoring of the patient’s status is required.

Relationship of Mechanisms of Action to Clinical Response

Most of these agents are used in multiple-drug protocols in which the cytolytic effects of the different agents interact in a complex manner. The clinical use of combination chemotherapy is discussed inChapter 53.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Toxicities of IL-2, although extensive and potentially severe, are manageable and include symptoms unlike those of chemotherapy. Patients routinely develop features of inflammatory disease including flu-like symptoms with fever, chills, and myalgias; capillary leak syndrome with attendant hypotension, acute kidney failure, adult respiratory distress syndrome, and, rarely, respiratory failure requiring intubation; diarrhea, nausea, and emesis; anorexia; confusion and seizures; sepsis; and intensification or induction of autoimmune and inflammatory disorders.

IFN-α toxicities are multiple and include features of inflammatory disease like those of IL-2: flu-like symptoms such as fever, chills, fatigue, and myalgia; gastrointestinal toxicities such as anorexia, nausea, vomiting, and weight loss; depression; hepatotoxicity; neutropenia and thrombocytopenia; autoimmune diseases; renal toxicity; and thyroid abnormalities induced by autoimmunity.

Because rituximab is a protein, severe hypersensitivity reactions may occur. Infusion reactions may include life-threatening cardiac arrhythmias and angina. A less severe infusion-related complex of symptoms often includes fever, chills, hypotension, nausea, urticaria, and bronchospasm. These symptoms may be attenuated by reducing the infusion rate. Tumor lysis syndrome, hemolytic anemia, and severe mucocutaneous reactions (i.e., Stevens-Johnson syndrome) have also been reported.

Adverse effects of I131-tositumomab are similar to those seen with rituximab, including hypersensitivity reactions and anaphylaxis, fever, rigors, hypotension, dyspnea, bronchospasm, nausea, vomiting, abdominal pain, and diarrhea. Development of human antimurine antibodies has been reported with the use of tositumomab as with most other murine antibodies. The addition of I131 adds the potential for additional radiation-induced toxicities of hypothyroidism, prolonged and severe cytopenias and associated infection and bleeding, myelodysplastic syndrome, and secondary malignancies including acute leukemia. This drug is not appropriate as initial therapy, because resultant cytopenias may eliminate other potentially effective therapies.

Gemtuzumab ozogamicin causes the conventional side effects of monoclonal antibodies including infusion-related reactions, hypersensitivity reactions, hypotension, tumor lysis syndrome, and pulmonary events. In addition, this agent can cause serious and sometimes fatal hepatotoxicity, and because myeloid precursors may also be targeted, it may cause severe myelosuppression.

The most significant toxicities of trastuzumab include cardiomyopathy, hypersensitivity reactions including anaphylaxis, infusion reactions, pulmonary events, and exacerbation of chemotherapy induced neutropenia. The two most common side effects of gefitinib are skin rash and diarrhea. Toxicities of bortezomib include peripheral neuropathy and myelosuppression. The most common toxicities of bevacizumab are hypertension, fatigue, blood clots, diarrhea, neutropenia, headache, appetite loss, and mouth sores. Less common but more serious side effects include gastrointestinal perforations that may require surgery, impaired wound healing, and bleeding from the lungs or other organs.

The side effects of the antihormonal agents are related to the antagonism of the normal hormones. Hot flashes are the most common side effects reported for all of the hormone antagonists and aromatase inhibitors. These episodes can be intense and frequent but often abate with time. Other side effects common to these classes of drugs include the risk of blood clots, mood swings, and changes in libido.

Tamoxifen can induce changes in the endometrium leading to endometrial hyperplasia, endometriosis, or

CLINICAL PROBLEMS

Anastrozole

Hot flashes; ischemic heart disease; venous thromboembolic events; osteoporosis

Bevacizumab

Impaired wound healing (potentially fatal); hypertension; arterial thromboembolic events; neutropenia

Bortezomib

Sensory neuropathy, cardiomyopathy, hypotension; thrombocytopenia; neutropenia; infiltrative pneumonitis; reversible posterior leukoencephalopathy syndrome (RPLS)

Flutamide

Hot flashes; diarrhea; nausea; gynecomastia; impotence

Imatinib

Dermatologic reactions including erythema multiforme and Stevens-Johnson syndrome; pronounced fluid retention and edema; gastrointestinal irritation; anemia; neutropenia; hepatotoxicity

Interferon-α

Flu-like symptoms; cytopenias; anorexia and weight loss; fatigue; depression; and intensification or induction of autoimmune and inflammatory disorders

Interleukin-2

Flu-like symptoms; cytopenias; hypotension; capillary leak syndrome; acute kidney failure; adult respiratory distress syndrome; intensification or induction of autoimmune and inflammatory disorders

Tamoxifen

Thromboembolic events; endometrial hyperplasia; endometrial cancer

Trastuzumab

Cardiomyopathy, especially when coadministered with doxorubicin; infusion reactions, pulmonary toxicity, myelosuppression

endometrial cancer. The incidence of these alterations is lower in premenopausal as compared with postmenopausal women; however, continued surveillance during therapy is required.

Aromatase inhibitors, by virtue of blocking the production of even low levels of estrogen that are produced in postmenopausal women, lead to the development of osteoporosis. The use of bone density-supportive drugs such as the bisphosphonates (see Chapter 44) is often required to diminish this effect. Additional adverse effects include bone and joint pain and elevated serum cholesterol levels.

The most commonly observed side effects for representative agents are listed in the Clinical Problems Box.

New Horizons

Research continues to discover specific tumor cell targets for therapeutic action that will reduce toxicity to

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are available in the United States.)

Hormonal Agents

Flutamide (Eulexin)

Goserelin (Zoladex)

Leuprolide (Lupron)

Prednisone (Deltasone)

Tamoxifen (Nolvadex)

Anastrozole (Arimidex)

Exemestane (Aromasin)

Letrozole (Femara)

Antibodies

Bevacizumab (Avastin)

Cetuximab (Erbitux)

Gemtuzumab ozogamicin (Mylotarg)

Trastuzumab (Herceptin)

Y90 Ibritumomab tiuxetan (Zevalin IN111 or Y90)

Rituximab (Rituxan)

Tositumomab (Bexxar)

Kinase Inhibitors

Gefitinib (Iressa)

Imatinib (Gleevec)

Sorafenib (Nexavar)

Sunitinib (Sutent)

Recombinant Proteins

Interferon-α2b, recombinant (Intron A)

Interferon-α2a, recombinant (Roferon-A)

Interleukin-2, aldesleukin (Proleukin)

Proteosome Inhibitors

Bortezomib (Velcade)

Vaccine

Human papilloma virus vaccine (Gardisil)

normal cells. Many of these agents will continue to be adjuvant therapy administered in conjunction with, or after, traditional cytoxic chemotherapy.

One such class of drugs is the farnesyl transferase inhibitors. Members of the RAS gene family signal transduction pathway have been implicated in several malignancies. RAS exists in an inactive guanosine diphosphate-bound form and an active guanosine triphosphate-bound form. Oncogenic mutations result in rendering the P21RAS guanosine triphosphate form insensitive to hydrolysis. For RAS to be membrane-associated and active after synthesis, it requires posttranslational modification at its carboxy terminal, requiring farnesylation of a sulfur residue. Farnesyl transferase inhibitors have shown impressive in vivo activity in inhibiting cellular growth and inducing apoptosis, although none has been approved yet for clinical use.

The development of the HPV vaccine is an example of an antigen-based vaccine to stimulate immunity against a specific virus. Tumor cell vaccines are yet another approach currently under development. The production of these vaccines is patient-specific and involves removal of tumor cells from the patient and treating the cells in vitro with radiation so that they cannot form new tumors. Specific tumor antigens are identified that will be recognized by the patient’s immune system, amplified either chemically or through gene amplification, and then injected back into the patient. The goal is to stimulate the patient’s immune response to the foreign tumor cells. Newer modifications of this type of patient-specific vaccine are to fuse the tumor cells to dendritic cells, again with the objective of stimulating an immune response.

FURTHER READING

Anonymous. Chemotherapy for esophageal, gastric and colorectal cancers. Treat Guidel Med Lett. 2006;4:55-60.

Anonymous. A human papillomavirus vaccine. Med Lett. 2006;48:65-66.

Anonymous. Two new drugs for renal cell carcinoma. Med Lett. 2007;49:18-19.

Carlson et al. 2006 Carlson RW, Brown E, Burstein HJ, et al. NCCN taskforce report: Adjuvant Therapy for Breast Cancer. J Nat Comp Cancer Network. 2006;4:S1-S26.

SELF-ASSESSMENT QUESTIONS

1. Several drugs are administered as adjuvant agents in the treatment of estrogen receptor-positive breast cancer. Which of the following works by inhibiting the conversion of androstenedione from the adrenals to estrogen?

A. Anastrazole

B. Fulvestrant

C. Rituximab

D. Tamoxifen

E. Trastuzumab

2. A 59-year-old patient is receiving a monoclonal antibody that inhibits vascular endothelial growth factor for the treatment of metastatic colorectal cancer. While receiving therapy he cuts his foot on a piece of glass requiring stitches. One month later the wound has not healed and has become severely infected. Which of the following drugs is responsible for this effect?

A. Bevacizumab

B. Bortezomib

C. Cetuximab

D. Gefitinib

E. Rituximab

3. A 72-year-old woman with advanced renal carcinoma has not responded to traditional chemotherapeutic agents. Which of the following drugs can be added to her regimen to inhibit tyrosine kinase activity associated with vascular endothelial growth factor and platelet-derived growth factor?

A. Bevacizumab

B. Fulvestrant

C. Gefitinib

D. Interferon α2b

E. Sunitinib

4. A 64-year-old man is prescribed a drug for the treatment of his prostate cancer that blocks testosterone from binding to its intracellular receptor. Which of the following drugs has this mechanism of action?

A. Flutamide

B. Fulvestrant

C. Goserelin

D. Leuprolide

E. Tamoxifen