Introduction to Molecular Biology: From Cells to Atoms - Anthony Rees, Michael Sternberg 2002

Cells and Molecules at Work
Antitumor Antibiotics

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Fig. 43.1. MECHANISM OF ACTION of a DNA-intercalating antitumor antibiotic.

ANTITUMOR Antibiotics are a group of substances used to treat various malignant diseases; many of these compounds are naturally occurring and produced by various species of actinomycetes (e.g., Streptomyces). While not all of these substances are exclusively toxic to tumor Cells, because they typically target Replication mechanisms, rapidly dividing tumor cells are affected to a much greater extent than normal cells.

Mitomycins are antibiotics produced by streptomycetes which, following enzymatic modification in vivo, appear to alkylate DNA by forming cross-links that disrupt replication. The fact that some tumors are sensitive to these antibiotics while others are not is likely due to differences in the capacity of various tumor cells to repair damaged DNA or neutralize alkylating agents.

Bleomycin is a sulfur-containing peptide with a complex Structure that is thought to act on tumor cells by inducing DNA strand breaks. The efficacy of this antibiotic against various tumor cells also depends on the latter's repair activity (which, incidentally, is extremely high in normal cells).

Agents capable of intercalating into DNA constitute the third class of antitumor antibiotics. These are typically flat molecules containing condensed rings that bind tightly to DNA by inserting themselves between adjacent Base Pairs in The Double Helix, thereby reducing its degree of coiling. The intercalation of such molecules into DNA generally completely inhibits replication. A prominent example is actinomycin D, frequently used by researchers to arrest DNA Synthesis in studied cells; however, it is too toxic for clinical application.

Daunomycin is another member of the group of antibiotics that act via intercalation into double-stranded DNA (see Fig. 43.1). Its four condensed rings, forming a nearly planar structure, are able to fit between any base pairs in the double helix, while the aminosugar resides in the minor groove of the helix, anchored by Hydrogen Bonds formed between the DNA and the ring projecting from the main plane of the condensed system. Such fixation within the DNA Structure may be a crucial factor in The Mechanism of action of daunomycin, which inhibits The activity of both DNA and RNA polymerases. Rich and colleagues suggested that when RNA polymerase on DNA encounters an intercalated antibiotic, its movement is halted due to binding with the aminosugar; however, the precise mechanism of the inhibitory action of DNA-intercalating agents remains incompletely understood. In the future, it may be possible to develop novel drugs of this type capable of selectively suppressing viral replication and tumor growth by specifically binding to nucleotide sequences in DNA and RNA that are unique to Viruses or characteristic of transformed (i.e., tumor) cells.

INTERFERONS are Proteins produced in the bodies of many vertebrates (including humans) that exhibit antiviral and/or antitumor activity. Interferons were discovered in the late 1950s by Isaacs and Lindenmann, who demonstrated that virus-infected cells can induce the synthesis of one or more types of molecules which, when added to cells not yet exposed to the virus, significantly reduce the efficiency of subsequent infection. This phenomenon is known as Interference, from which the name "interferon" is derived. Interferons also possess numerous other properties. Of particular interest is their ability to suppress Cell proliferation, which makes them potential antitumor agents. There are Three types of interferons: α, β, and γ. The specific type of interferon synthesized by infected cells depends on both The Cell type itself and The Nature of the inducer triggering interferon production. The synthesis of α- and β-interferons can be induced in A wide variety of cells by certain viruses and Bacteria, as well as by double-stranded RNA, whereas γ-interferon is produced only by a restricted range of cells in response to specific mitogens or antigenic material to which the cells have been previously sensitized. The mechanism of action of interferons is currently under active investigation. It is already known that they affect numerous Enzymes and the Protein Synthesis machinery within the cell, but a detailed understanding of the mechanism of viral interference is still quite far off.