Articles

Radiolabeled Antibodies

Radiolabeled antibodies have been used both in the diagnosis (radioimmunodiagnosis) and in the therapy (radioimmunotherapy) of cancer. The approach is founded on the ability to generate antibodies against tumor-associated antigens. Such "tumor-targeting" antibodies are then used to deliver radionuclides specifically to antigen-positive cells. The choice of radionuclide will depend on whether the radiolabeled antibody will be used for diagnosis or therapy.

Monoclonal Antibodies: Leukemia and Lymphoma

Monoclonal antibodies (mAbs) have become part of the standard treatment of cancer. Nonetheless, the optimistic view of the early 1980s that mAbs were "magic bullets" has now been replaced by a more realistic understanding of their therapeutic potential. Some of the most encouraging results using mAbbased treatments have been seen in hematologic cancers. These diseases are ideally suited to mAb therapy because of the accessibility of malignant cells in the blood, bone marrow, lymph nodes, and spleen.

Macrophages

Macrophages are an essential part of homeostasis. The major function of macrophages is to regulate tissue turnover and dispose of damaged cells and invading microorganisms. Normal macrophages can become cytotoxic against tumor cells after they undergo a complex biochemical process termed activation. Macrophages are activated to become cytotoxic after contact with microorganisms or their products, such as endotoxin or cell wall skeleton, by interaction with lymphokines, or by interaction with both.

Interleukins

Interleukins (IL) are a specialized group of cytokines identified by their ability to influence the function of lymphocytes (Table I). These proteins act as the primary means of signaling between cells of the immune system. They are produced by a variety of cells, including lymphocytes, phagocytes, and endothelial cells. There are currently 18 defined interleukins, and several substances undergoing physiologic identification will likely be added to this list.

TABLE I Interleukins

Interferons: Cellular and Molecular Biology of Their Actions

Interferons (IFNs) are secretory proteins produced by virus-infected cells. The name interferon refers to their ability to interfere with viral replication. However, IFNs induce several pleiotropic responses, including antiviral, antitumor, immunomodulatory, antiparasitic, and antiproliferative activities. In addition to viral infection, double-stranded RNA (dsRNA), fungal cell wall products, and other cytokines also induce the production of IFNs. dsRNA may be a physiologically relevant regulator of IFN synthesis because it is thought to be an intermediate product of viral infection.

Graft versus Leukemia and Graft versus Tumor Activity

Since the 1950s there has been experimental and subsequently clinical evidence for an effect of allogeneic hematopoetic cells against leukemias (graft versus leukemia, GvL) and, more recently, solid tumors (graft versus tumor, GvT). The success of donor leukocyte infusions (DLI) as a therapy for relapsed chronic myelogenous leukemia (CML) after bone marrow transplant (BMT) is the ultimate proof of the antitumor activity of allogeneic cells.

DNA-Based Cancer Vaccines

Plasmid DNA vaccines represent a relatively new approach to immunization against antigens present on cancer cells. DNA vaccines are relatively simple to prepare and administer and present multiple epitopes within the complete coding sequence of an antigen. Immunostimulatory sequences naturally occurring in bacterial DNA may add to the ability of DNA vaccines to induce both antibody and T-cell responses. The results of experiments using mouse melanoma models have suggested that DNA immunization is a promising new approach to cancer vaccine therapy.

I. BACKGROUND

DNA Damage, DNA Repair, and Mutagenesis

DNA damage consists of (a) formation of carcinogen-DNA adducts and other chemical modifications of DNA bases and (b) alterations in DNA ultrastructure (DNA strand cross-links/DNA strand breaks/chromatid exchanges/chromosomal loss). DNA damage can be induced by endogenous processes and by exogenous chemical and physical agents. A potential consequence of DNA damage is mutagenesis, i.e., a permanent alteration in DNA structure that produces miscopying of information during DNA replication and yields abnormal gene products (proteins).

Cell-Mediated Immunity to Cancer

Cell-mediated immunity to cancer principally relies on the specificity of the interaction between T cells and tumor antigens presented by tumors and antigen-presenting cells (APC), although other types of cells may be the ultimate effectors. Many tumor antigens have been discovered in recent years. The immune system has been shown to recognize antigens that are shared between cancer and normal tissue, as well as those that are created by genetic alterations in the tumor.

Carbohydrate-Based Vaccines

Carbohydrate antoantigens have proven to be suitable targets for immune recognition and attack against cancer cells, because of their abundance at the cell surface and their unexpected immunogenicity.       
Carbohydrates play key roles in intracellular interactions as targets for selectins and adhesins, which may be crucial, not discretionary, to tumor cell survival and the metastatic process. Passively administered and vaccine-induced antibodies in preclinical models are capable of interfering with these processes directly, inducing complement-mediated inflammation and lysis and mediating opsonization, inflammation, and tumor cell death by other Fc-mediated mechanisms.