Many different modes of therapy, including angiogenesis inhibitors, which keep tumors from building new blood vessels to supply themselves with food and oxygen, have demonstrated effectiveness in the treatment of cancer (Table 1).
Table1. Immunotherapy in Malignant Disease
Chemotherapeutic Agents
Drugs are used in cancer therapy for cure, palliation, and research to develop more effective therapy. The mechanisms of drug action are linked to the mitotic cell cycle; thus, antitumor drugs may be placed in the following three classes:
• Cell cycle active, phase-specific
• Cell cycle active, phase-nonspecific
• Non–cell cycle active
Cell Cycle Active, Phase Specific
Drugs in the cell cycle active, phase-specific category act on the S, G2, or M phase of mitosis. S phase–active drugs are divided into antimetabolites, antifolates, and synthetic enzyme inhibitors. Antimetabolites act through the incorporation of a nucleotide analogue into DNA, resulting in an abnormal nucleic acid (e.g., 5-fluorouracil, 6- mercaptopurine, 6-thioguanine, fludarabine). The antifols act as competitive inhibitors of the enzyme dihydrofolate reductase, which is necessary for the generation of CH3 groups required for thymidine synthesis (e.g., methotrexate). Synthetic enzyme inhibitors include DNA polymerase inhibitor (cytosine arabinoside) and nucleotide reductase inhibitor (hydroxyurea).
G2 phase active drugs include bleomycin, which is thought to cause fragmentation of DNA, and etoposide (Eposin, Etopophos, VePesid, VP-16), which is thought to cause double stranded breaks in DNA by complexing with topoisomerase.
M phase active drugs include vinca alkaloids (e.g., vincristine, vinblastine), which are thought to inhibit the mitotic spindle apparatus, and paclitaxel (Taxol), which stabilizes microtubules.
Cell Cycle Active, Phase-Nonspecific
Drugs in the cell cycle active, phase-nonspecific category are intercalating agents, alkylating agents, and 5-fluorouracil. Examples of intercalating agents are anthracyclines (Adriamycin, Daunomycin, Idarubicin, Mitoxantrone) and actinomycin D (dactinomycin; Cosmegen, Lyovac). The alkylating agents in this category include cyclophosphamide and ifosfamide. These drugs act by distorting normal DNA through the insertion of flat, aromatic ring systems between the levels of base pairs into the DNA double helix.
Non–Cell Cycle Active
Drugs in the non–cell cycle active category can be divided into five types—alkylating agents, l-asparaginase, corticosteroids, hormone antagonists, and miscellaneous. Alkylating agents (e.g., nitrogen mustard and mustard derivatives—mechloreth amine [Mustargen], cyclophosphamide [Cytoxan], chlorambucil [Leukeran], and melphalan [Alkeran]) act by interstrand cross-linking of DNA, thereby preventing normal DNA replication. This interference is not only cytotoxic, but also potentially mutagenic and carcinogenic. l-Asparaginase inhibits protein synthesis.
Glucocorticosteroids are the most frequently used steroids. Steroids control the damaging inflammatory immune response. T he target cells are monocytes and T lymphocytes. Monocytes block IL-1 production, block TNF-γ, and reduce chemotaxis. T he consequences are inhibition of T cell activation, activation and recruitment of monocytes and neutrophils, and inhibition of the migration of cells to the site of inflammation. The steroids used in cancer oncology include glucocorticoids (prednisone), estrogens (diethylstilbestrol), androgens (testosterone propionate), and progestational agents (medroxyprogesterone, megestrol acetate).
Hormone estrogen antagonists (e.g., tamoxifen) competitively bind to specific cytoplasmic receptors.
Cytokines
Cytokines constitute another group of cancer chemotherapy drugs. IFN, IL-2, and colony-stimulating fac tors (CSFs) have been used to treat certain types of cancer in patients. Currently, IFNs are used to treat patients with hairy cell leukemia, chromic myelogenous leukemia, and multiple myeloma. IL-2 is used in the treatment of renal cell carcinoma and melanoma. CSFs decrease the duration of chemotherapy induced neutropenia and may permit more dose-intensive therapy.
Interferon. The clinical development of recombinant IFN-α represents the most rapid development of any antineoplastic drug in the United States. IFN was first recognized as a naturally occurring antiviral substance in 1957 and identified for its antineoplastic properties. IFN-α appears to have activity in a wide range of malignancies.
Effects of Drug-Induced Immunosuppression
Drugs used to treat malignancies such as solid tumors or leukemia can have profoundly suppressive effects on the inflammatory response, delayed hypersensitivity, and specific antibody production (Table 2). Examples of the immune depression induced by drugs include depletion of T cells by corticosteroids, caused by the blocking of egress from the bone marrow into the circulation, and dysfunction of the antibody response, caused by folate antagonists and purine analogues. Thus, infection secondary to immune suppression is a major cause of death in cancer patients beginning therapy and those who are in clinical remission.
Table2. Effects of Chemotherapy on the Immune Response
Recent Advances
Monoclonal antibody (MAb) technology began with the winning contribution of Köhler, Milstein, and Jerne, who won the Nobel Prize in Physiology or Medicine in 1984. This led to great expectation that MAbs would provide effective targeted therapy for cancer. After early enthusiasm for MAbs, clinical trials were disappointing in the 1980s and early 1990s with one exception, antiidiotype antibodies in follicular lymphoma. When success was finally observed in hematologic malignancies, the importance of the antigen target specificity and developing humanized MAbs was recognized. The major success of mAB therapy has been seen with anti-CD20 MAbs. Anti-CD20 rituximab (Table 3) was the first MAb to be approved by FDA for use in relapsed indolent lymphoma. Today, rituximab is widely accepted to be the single most important factor leading to improved prognosis in a range of B cell lymphomas and, more recently, in B cell chronic lymphocytic leukemia (CLL). However, some patients develop resistance to rituximab, which provides a challenge for research.
Table3. Current FDA-Approved Antibodies for Cancer Treatment
Immunotherapy for tumors can take the form of active or passive therapy. Active host immune responses may be achieved by the following:
• Vaccination with killed tumor cells or with tumor antigens or peptides. New research studies have suggested that anti-CD20 MAb may induce an adaptive antitumor immune response or vaccination effect, which may underlie the durable remissions experienced by some patients after anti-CD20 MAb treatment.
• Enhancement of cell-mediated immunity to tumors by expressing costimulators and cytokines and treating with cytokines that stimulate the proliferation and differentiation of T lymphocytes and NK cells.
• Nonspecific stimulation of the immune system by the local administration of inflammatory substances or by systemic treatment with agents that function as polyclonal activators of lymphocytes.
• For the first time in the history of cancer treatment, gene therapy has apparently succeeded in shrinking and even eradicating large metastatic tumors. Inserting genes into a patient’s cells enables the body to fight a disease on its own, without medication.
Passive immunotherapy consists of the following:
• Adoptive cellular therapy by transferring cultured immune cells with antitumor reactivity into a tumor-bearing host.
• Administration of tumor-specific MAbs for specific tumor immunotherapy.
What’s New in Drug Therapy?
The development of inhibitors to target proteins encoded by mutated cancer genes has now been achieved, with repeated success. The first victory was imatinib (Gleevec), approved by the FDA in 2001, a potent inhibitor of the Abelson (ABL) kinase in chronic myeloid leukemia (CML).
This is an important example of therapeutic targeting of the products of genomic alterations in a specific cancer. After the referencing of the genome sequence, cancer genomes have been identified for several new mutated cancer genes. Unfortunately, many mutated cancer genes do not make tractable targets for new drug development. The International Cancer Genome Consortium and the Cancer Genome Atlas are using next-generation sequencing technologies for tumors from 50 different cancer types to generate more than 25,000 genomes at genomic, epigenomic, and transcriptomic levels. This should generate a complete catalogue of oncogenic mutations, some of which may prove to be new therapeutic targets.
The list of drugs used for cancer therapy continues to grow. The new therapeutic agents target various modes of action and applications (Table 4).
Table4. Targeted Therapeutic Agents in Cancer
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