Antineoplastic and Immunomodulating Drugs



Antineoplastic and Immunomodulating Drugs



Classification of Antineoplastic and Immunomodulating Drugs



Antineoplastic Drugs







aAlso cladribine, clofarabine, fludarabine, and nelarabine.


bAlso capecitabine, floxuridine, and gemcitabine.


cAlso ifosfamide, chlorambucil, mechlorethamine, and melphalan.


dAlso lomustine and streptozocin.


eAlso carboplatin and oxaliplatin.


fAlso dacarbazine, mitomycin, and temozolomide.


gAlso daunorubicin, idarubicin, mitoxantrone, and dactinomycin


hAlso teniposide and topotecan.


iAlso docetaxel, cabazitaxel, vinblastine, vinorelbine, and ixabepilone.


jAlso dasatinib, gefitinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, vemurafenib, and bortezomib.


kAlso alemtuzumab, bevacizumab, cetuximab, panitumumab, 90Y-ibritumomab, and 131I-tositumomab.


lAlso belatacept, muromonab-CD3, and palivizumab.




Overview


Cancer is a disease in which normal cells are transformed into neoplastic cells through alteration of their genetic material, leading to expression of oncogenes, inhibition of tumor suppressor genes, and uncontrolled growth. Oncogenes typically encode growth factors, many of which are kinases that activate cellular regulatory proteins that promote cell division. For example, the cyclins are proteins that activate cyclin-dependent kinases, leading to activation of enzymes that promote progress through the cell cycle of replication (Fig. 45-1). Some oncogenes express kinases that activate growth factor receptors, such as the epidermal growth factor receptor and the vascular endothelial growth factor receptor. In addition to their uncontrolled proliferation, neoplastic cells often invade previously unaffected organs through a process called metastasis. This process is dependent on angiogenesis, which is the formation of new blood vessels to support metastatic invasion and growth.


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FIGURE 45-1 Cell cycle activity of antineoplastic drugs. The cycle of cell replication includes the sequential phases of G1 (gap 1), S (DNA synthesis), G2 (gap 2), and M (mitosis). Differentiated cells can enter a resting state called G0. Growth factors may stimulate resting cells to reenter the cell cycle. Progress through the cycle is promoted by proteins called cyclins (A, B, D, E), which activate cyclin-dependent kinases. Two checkpoints, which often malfunction in cancer cells, control entry into the critical phases of DNA synthesis and mitosis. Cell cycle–specific drugs primarily act during the designated phase of the cycle. Cell cycle–nonspecific drugs act throughout the cell cycle.

Increased understanding of cancer cell proliferation has led to the development of drugs that target specific growth factors involved in this process, including agents that inhibit tyrosine kinases and growth factor receptors involved in cell replication and metastasis. These are often referred to as targeted chemotherapy. Drugs that increase cancer cell apoptosis (programmed cell death) are being developed, and it may be eventually possible to develop agents that reverse the malignant transformation of cells.


Antineoplastic drugs can be divided into two broad categories: (1) cytotoxic agents that nonspecifically inhibit DNA replication or mitosis, and (2) targeted anticancer drugs that inhibit specific proteins involved in tumor cell growth. The introduction of new anticancer drugs has accelerated with the release of a growing number of monoclonal antibodies and tyrosine kinase inhibitors linked to growth factor receptors. New cytotoxic agents have also contributed to the explosion of antineoplastic drugs.


Drugs that alter activity of the immune system are called immunomodulators. This group of drugs can be divided into immunosuppressants or immunostimulants agents, though a few drugs can both inhibit and stimulate the immune system through actions on different cells and receptors. A number of monoclonal antibody preparations are used as immunosuppressants to treat rheumatoid arthritis (see Chapter 30). The last major section of this chapter focuses on immunosuppressants that are used to treat autoimmune diseases and to prevent allograft rejection after organ or bone marrow transplantation. In the latter case, the drugs act by inhibiting the immune response to foreign antigens (alloantigens) contained in an allograft, which is a graft (transplant) of tissue between individuals of the same species but of disparate genotypes.


Because of the growing number of similar antineoplastic agents, this chapter focuses on the most important examples in each drug class. Owing to the large number of agents included in the classification table and use of generic drug names in this field, trade names have been omitted.



Principles of Cancer Chemotherapy


Uses and Goals of Treatment


Antineoplastic drugs are used to treat hematologic cancers that cannot be surgically excised, such as leukemia and lymphoma. They are also used in combination with surgery or radiation therapy to treat solid tumors. In patients with solid tumors that can be surgically removed, chemotherapy may eliminate micrometastases and slow or prevent recurrence of the malignant growth. In patients with inoperable tumors, chemotherapy is often palliative rather than curative. Palliative therapy is intended to prolong life and reduce incapacitating symptoms but does not eradicate the malignancy.



Treatment Regimens and Schedules


Drug regimens for cancer chemotherapy are designed to optimize the synergistic effects of drug combinations while minimizing toxicity. The regimens often use drugs that have different toxicities and different mechanisms of action to maximize cytotoxic effects on tumor cells while sparing host tissue.


In the treatment of some types of cancer, specific drug regimens are used for induction of remission, consolidation therapy, and maintenance therapy. Induction therapy, such as that used in acute lymphocytic leukemia, seeks to produce a rapid reduction in the tumor cell burden and thereby produce a symptomatic response in the patient. Consolidation therapy seeks to complete or extend the initial remission, and it often uses a different combination of drugs than that used for induction. Maintenance therapy aims to sustain the remission as long as possible, and it can use less-frequent courses of chemotherapy and different classes of drugs than were used for induction and consolidation.


Cancer chemotherapy regimens are probably the most complicated form of drug therapy in use today. These regimens often employ multiple drugs administered as intermittent courses of therapy rather than as continuous therapy. Intermittent combination therapy allows the bone marrow and other normal host cells to recover between treatment courses and reduces the level of toxicity. The selection of drugs is largely based on clinical trials comparing the effectiveness of various drug combinations in patients with particular stages of a specific type of cancer, and the treatments for each stage of a particular cancer sometimes vary considerably. First-line drugs are used for the initial treatment of tumors, whereas other drugs are indicated for patients who have relapsed after first-line therapy. These regimens are continuously evolving with the introduction of new drugs and completion of new trials. The dosage and frequency of treatment are typically based on such factors as drug kinetics, tumor cell cycle kinetics, and drug toxicity.



Cell Cycle Specificity


The cytotoxic antineoplastic drugs can be classified as cell cycle–specific and cell cycle–nonspecific agents. As shown in Figure 45-1, the cycle of cell replication includes the G1, S, G2, and M phases. DNA is replicated during the S phase, and mitosis occurs during the M phase. Because early cytologists observed no activity between the S and M phases, they referred to the period before S as G1 (gap 1) and to the period before M as G2 (gap 2). It is now known that cells are actively preparing for DNA synthesis and mitosis during the G1 and G2 phases, respectively. Cyclins are growth factors that regulate the progression of cells through the cell cycle and are targets of new drug development. Examples of cyclins are shown in Figure 45-1.


Drugs that act during a specific phase of the cell cycle are called cell cycle–specific drugs, whereas drugs that are active throughout the cell cycle are called cell cycle–nonspecific drugs. Cell cycle–specific drugs include all DNA synthesis inhibitors and mitotic inhibitors. Cell cycle–nonspecific drugs include all DNA alkylating agents and most DNA intercalating agents.



Limitations of Cancer Chemotherapy


Most antineoplastic drugs have three major limitations: susceptibility to tumor cell resistance, production of host toxicity, and an inability to suppress metastasis. Newer drugs have had some success in overcoming these obstacles, though a cure for many cancers is yet to be developed.



Drug Resistance


Drug resistance is a major cause of cancer treatment failure. As with microbial drug resistance, tumor cell resistance can be innate or acquired. Innate drug resistance is seen when initial exposure to anticancer drugs does not produce a response in cancer cells. This occurs because of the mutations in the cancer cell genome, which are thought to have created the malignancy in the first place. For example, mutations in tumor suppressor genes are found in more than 50% of all malignancies. These mutations are linked to initial treatment failure with both radiation therapy and a number of anticancer agents.


Acquired drug resistance can result from genomic mutations or abnormal gene expression as cancer cells continuously evolve. The mechanisms of tumor cell resistance include induction of drug efflux pumps, decreased affinity or overexpression of target enzymes, and decreased drug activation or increased drug inactivation. Altered expression of proapoptotic and antiapoptotic molecules and increased tumor cell repair may also be mechanisms of drug resistance.


Drug resistance can occur through failure of the drug to reach its target because of drug efflux from tumor cells. Two important efflux pumps are the P-glycoprotein (Pgp) and the multidrug-resistance protein (MRP) as mentioned in Chapter 2 in the context of drug distribution. Pgp is the product of the multidrug resistance–1 gene and acts to transport many naturally occurring drugs out of neoplastic cells, including anthracyclines, taxanes, and vinca alkaloids (Fig. 45-2). Induction of Pgp by antineoplastic drugs can lead to multidrug resistance.


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FIGURE 45-2 The P-glycoprotein mechanism of drug efflux. P-glycoprotein uses adenosine triphosphate to actively export bleomycin and many other naturally occurring antineoplastic drugs from the cell. Because some agents (e.g., verapamil) inhibit the P-glycoprotein pump and thereby allow antineoplastic drugs to stay in the cell, these agents are being studied as potential adjuncts to cancer chemotherapy. ADP, Adenosine diphosphate; ATP, adenosine triphosphate.

MRP removes drugs from tumor cells after conjugation of drugs with glutathione. The drugs transported by MRP are similar to those transported by Pgp except that the taxane drugs are poorly transported by MRP. Several drugs that block both Pgp and MRP are undergoing clinical trials as antineoplastic drug enhancers.


Other examples of acquired drug resistance include topoisomerase mutations that convey resistance to topoisomerase inhibitors (e.g., etoposide). Resistance to methotrexate (MTX) can occur through mutations in its target enzyme, dihydrofolate reductase, or through overexpression of the enzyme. Mutations in genes for tubulin or microtubule-associated proteins can cause resistance to the vinca alkaloids and taxane drugs. Finally, expression of antiapoptotic proteins (e.g., Bcl-2) can produce resistance to many drugs by interfering with the cell death signal induced by an antineoplastic agent.



Drug Toxicity


The most common toxicities of traditional antineoplastic drugs (Table 45-1) result from nonspecific inhibition of cell replication in the bone marrow, gastrointestinal epithelium, and hair follicles. Many antineoplastic drugs also stimulate the chemoreceptor trigger zone in the medulla and thereby elicit nausea and vomiting.



TABLE 45-1


Major Clinical Uses and Adverse Effects of Selected Antineoplastic Drugs








































































































































































































































































































DRUG MAJOR CLINICAL USES ACUTE TOXICITY DELAYED TOXICITY
DNA Synthesis Inhibitors
Cladribine Hairy cell leukemia, non-Hodgkin lymphoma Mild nausea and vomiting Myelosuppression
Cytarabine AML, non-Hodgkin lymphoma Diarrhea, mild nausea and vomiting Hepatotoxicity, gastrointestinal and oral ulcers, myelosuppression
Floxuridine Colorectal and hepatic carcinoma Diarrhea, mild nausea and vomiting Alopecia, gastrointestinal and oral ulcers, myelosuppression
Fludarabine CLL, non-Hodgkin lymphoma Mild nausea and vomiting Myelosuppression
Fluorouracil Breast, colorectal, gastric, and skin cancer Diarrhea, mild nausea and vomiting Alopecia, gastrointestinal and oral ulcers, myelosuppression
Gemcitabine Pancreatic, non–small cell lung, biliary tract, and breast cancers Mild nausea Myelosuppression, alopecia, gastrointestinal ulcers
Hydroxyurea CML, sickle cell anemia Mild nausea and vomiting Myelosuppression
Mercaptopurine AML, ALL, CML Usually well tolerated Hepatotoxicity, myelosuppression
Methotrexate ALL, breast cancer, osteosarcoma, trophoblastic tumors Diarrhea, nausea Gastrointestinal and oral ulcers, hepatotoxicity, myelosuppression, renal toxicity
Pemetrexed Non–small cell lung cancer Nausea Myelosuppression
Thioguanine AML, ALL, CML Usually well tolerated Myelosuppression
DNA Alkylating Drugs
Busulfan CML Diarrhea, mild nausea and vomiting Myelosuppression, pulmonary fibrosis
Carboplatin Ovarian cancer Moderate nausea and vomiting Myelosuppression
Carmustine Brain tumors, melanoma, myeloma, non-Hodgkin lymphoma Severe nausea and vomiting Myelosuppression, pulmonary fibrosis, renal toxicity
Chlorambucil CLL Well tolerated Myelosuppression, sterility
Cisplatin Bladder, cervical, ovarian, and testicular cancer; melanoma, myeloma, non-Hodgkin lymphoma Acute renal failure, severe nausea and vomiting Mild myelosuppression, ototoxicity, renal toxicity
Cyclophosphamide Breast and lung cancer; CLL, ALL, myeloma, neuroblastoma, non-Hodgkin lymphoma Nausea and vomiting Alopecia, hemorrhagic cystitis, myelosuppression, pulmonary fibrosis
Dacarbazine Hodgkin disease, melanoma Severe nausea and vomiting Alopecia, myelosuppression
Ifosfamide Sarcoma, testicular cancer Nausea and vomiting Alopecia, hemorrhagic cystitis, myelosuppression, pulmonary fibrosis
Lomustine Brain tumors, non-Hodgkin lymphoma Severe nausea and vomiting Myelosuppression, pulmonary toxicity
Mechlorethamine Hodgkin disease, lymphoma Mild nausea Alopecia, myelosuppression
Melphalan Breast and ovarian cancer, myeloma Severe nausea and vomiting Myelosuppression
Mitomycin Bladder, breast, lung, pancreatic, and cervical cancer Nausea and vomiting Alopecia, myelosuppression, pulmonary and renal toxicity, stomatitis
Oxaliplatin Colon cancer Nausea and vomiting Peripheral neuropathy, myelosuppression
Streptozocin Carcinoid tumor, pancreatic islet cell tumor Severe nausea and vomiting Renal toxicity
DNA Intercalating Drugs
Bleomycin Cervical, head, neck, and testicular cancer; Hodgkin and non-Hodgkin lymphoma Fever, mild nausea and vomiting Alopecia, mild myelosuppression, mucocutaneous toxicity, pneumonitis, pulmonary fibrosis
Dactinomycin Ewing sarcoma, trophoblastic tumors, Wilms tumor Diarrhea, nausea and vomiting Alopecia, myelosuppression, oral ulcers
Daunorubicin ALL, AML Nausea and vomiting Alopecia, cardiotoxicity, mucosal ulcers, myelosuppression
Doxorubicin ALL; bladder, breast, lung, ovarian, soft tissue, and thyroid cancer; myeloma, neuroblastoma Nausea and vomiting Alopecia, cardiotoxicity, mucosal ulcers, myelosuppression
Idarubicin AML Nausea and vomiting Alopecia, cardiotoxicity, mucosal ulcers, myelosuppression
Mitoxantrone AML Nausea and vomiting Alopecia, cardiotoxicity, mucosal ulcers, myelosuppression
Mitotic Inhibitors
Docetaxel Breast and ovarian cancer, non–small cell lung cancer Usually well tolerated Alopecia, myelosuppression, neurotoxicity
Paclitaxel Breast and ovarian cancer; non–small cell lung cancer Usually well tolerated Alopecia, myelosuppression, neurotoxicity
Vinblastine Bladder, breast, ovarian, and testicular cancer; Hodgkin and non-Hodgkin lymphomas Nausea and vomiting Alopecia, myelosuppression, stomatitis
Vincristine ALL; Hodgkin and non-Hodgkin lymphoma, lung cancer, myeloma, neuroblastoma, sarcoma Usually well tolerated Alopecia, mild myelosuppression, peripheral neurotoxicity
Vinorelbine Non–small cell lung cancer Nausea and vomiting Myelosuppression
Topoisomerase Inhibitors
Etoposide Non-Hodgkin lymphoma, small cell lung cancer, testicular cancer, AML Mild nausea and vomiting Alopecia, myelosuppression
Irinotecan Ovarian and colorectal cancer Diarrhea, mild nausea and vomiting Alopecia, myelosuppression
Teniposide ALL, AML Mild nausea and vomiting Alopecia, myelosuppression
Topotecan Lung and ovarian cancer Mild nausea and vomiting Alopecia, myelosuppression
Hormones and Hormone Antagonists
Anastrozole, letrozole Breast cancer Nausea and hot flashes None
Flutamide Prostate cancer Nausea and vomiting Impotence
Leuprolide Prostate cancer Nausea and vomiting Hot flashes, gynecomastia
Prednisone ALL, breast cancer, CLL, Hodgkin and non-Hodgkin lymphoma, myeloma None Hyperadrenocorticism
Tamoxifen Breast cancer Nausea and vomiting Hot flashes, hypercalcemia
Protein Kinase Inhibitors
Imatinib Chronic myeloid leukemia Nausea Edema, rash, diarrhea, pain
Nilotinib Chronic myeloid leukemia Nausea QT-interval prolongation, arrhythmia
Erlotinib Non–small cell lung cancer Nausea Rash, diarrhea, fatigue, dyspnea
Cytokines, Interferons, and Monoclonal Antibodies
Aldesleukin Colorectal cancer, melanoma, renal cell carcinoma Varies with dosage and route of administration Fluid retention, hematologic deficiencies, hypotension, neuropsychiatric effects, renal dysfunction, skin lesions
Bevacizumab Colorectal cancer None Gastrointestinal bleeding and perforation, pulmonary hemorrhage
Cetuximab Colon cancer Nausea Skin rash, allergic reactions
Interferon-alfa CML, hairy cell leukemia, Kaposi sarcoma Flulike illness Fatigue
Rituximab Non-Hodgkin lymphoma, chronic lymphocytic leukemia Chills, fever, headache, nausea Myelosuppression
Trastuzumab Breast cancer Chest pain, chills, dyspnea, fever, nausea, vomiting Heart failure, pulmonary toxicity


image


image


ALL, Acute lymphocytic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia.


The myelosuppression (bone marrow suppression) produced by many antineoplastic drugs often results in leukopenia and thrombocytopenia, although anemia can also occur. Leukopenia predisposes patients to serious infections, whereas thrombocytopenia can lead to bleeding. The onset of leukopenia is delayed because of the time required to clear circulating cells before the effect that drugs have on precursor cell maturation in the bone marrow becomes evident. With many drugs, including MTX, fluorouracil, and cyclophosphamide, the leukocyte count reaches its nadir in about 7 days and recovery occurs in 2 to 4 weeks. Nitrosourea drugs (e.g., carmustine) produce a more delayed and long-lasting suppression of leukocyte production. Bleomycin, cisplatin, and vincristine produce less myelosuppression than do other antineoplastic drugs, so they are often used in combination with myelosuppressive drugs.


The nausea and vomiting caused by antineoplastic drugs range from mild to severe. Among the antineoplastic drugs, the most emetic are cisplatin and carmustine. Their adverse effects can be prevented or substantially reduced, however, by pretreatment with a combination of antiemetic drugs, including serotonin antagonists (e.g., ondansetron) and corticosteroids (e.g., dexamethasone). The antiemetics are discussed in greater detail in Chapter 28.


Alopecia is a cosmetically distressing but less-serious adverse effect of chemotherapy. It is generally reversible after treatment ends, although the hair might differ in texture and appearance from its previous condition.


Several antineoplastic drugs have characteristic organ system toxicities that appear unrelated to inhibition of cell division. For example, use of doxorubicin and other anthracyclines can cause cardiotoxicity; use of cyclophosphamide and ifosfamide can cause hemorrhagic cystitis; use of cisplatin can cause renal toxicity; use of bleomycin or busulfan can cause pulmonary toxicity; and use of vincristine, paclitaxel, and other vinca alkaloids and taxanes can cause neurotoxicity.


Agents have been developed to prevent some of these organ system toxicities. For example, dexrazoxane was developed to prevent anthracycline-induced cardiotoxicity. Another cytoprotective drug, mesna, was developed to prevent cyclophosphamide-induced hemorrhagic cystitis. Cisplatin-induced renal toxicity can be partly prevented by administering fluids, along with mannitol and sodium thiosulfate. Mannitol maintains renal blood flow and tubular function, whereas sodium thiosulfate inactivates the drug in the kidneys. No specific agents currently exist to prevent pulmonary toxicity and neurotoxicity; therefore patients at risk should be closely monitored so that treatment can be discontinued if these toxicities develop.



Cytotoxic Agents


DNA Synthesis Inhibitors


Most of the DNA synthesis inhibitors are analogues of purine or pyrimidine bases found in DNA or of folic acid. They act as antimetabolites to inhibit enzymes catalyzing various steps in DNA synthesis. The uses and adverse effects of selected inhibitors are listed in Table 45-1.



Folate Antagonists



Methotrexate.

Nearly 50 years ago, MTX was used successfully to induce remission in patients with acute childhood leukemia. Today it is the most widely used antimetabolite in cancer chemotherapy, and it is also used as an immunosuppressive drug in the treatment of rheumatoid arthritis, lupus erythematosus, and other conditions (see Chapter 30).



Chemistry and Mechanisms.

The structures of MTX and folic acid are similar. MTX, however, has an amino group substituted for a hydroxyl group on the pteridine ring, and it also has an additional methyl group.


MTX is actively transported into mammalian cells and inhibits dihydrofolate reductase, the enzyme that normally converts dietary folate to the tetrahydrofolate form required for thymidine and purine synthesis (Fig. 45-3).


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FIGURE 45-3 Inhibition of DNA synthesis by methotrexate and fluorouracil. Methotrexate inhibits dihydrofolate reductase and the conversion of dihydrofolate to tetrahydrofolate. This reduces the supply of 5,10-methylenetetrahydrofolate, a substance required for the synthesis of deoxythymidine monophosphate (dTMP). The conversion of deoxyuridine monophosphate (dUMP) to dTMP, a critical step in DNA synthesis, is catalyzed by thymidylate synthetase. This enzyme is inhibited by 5-fluorodeoxyuridine monophosphate (5-FdUMP), which is the active form of fluorouracil.
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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Antineoplastic and Immunomodulating Drugs

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