Cytotoxic ribonucleases and chimeras in cancer therapy.
Ribonucleases serve as cytotoxic agents during host defense and physiological cell death pathways. In bacteria, higher plants, and mammals, ribonucleases appear to bind cells, enter the cytosol where they degrade RNA, and kill the target cell. This process functions in interstrain competition in bacteria, in the death of incompatible pollen in higher plants, and likely plays a role in the antiparasitic and anticancer activity of eosinophils in man. One can alter the target cell specificity of RNases by coupling them to new cell-binding domains. Chemically coupling RNases to new binding moieties or fusing RNase genes to antibody genes results in chimeric molecules with specified cell-type cytotoxicity. Thus, one can target one's own host defense cytotoxins to select cell populations. This allows the use of human proteins, instead of plant and bacterial toxins, in the construction of immunotoxins. RNases also can be engineered to kill cells by cytosolic expression or to kill viruses by packaging into viruses. Engineering RNases into cell-type-specific cytotoxins may result in a new class of therapeutic reagents. We review a number of interesting physiological cell cytotoxicity pathways utilizing RNases and then describe the recent results on engineering RNases for therapeutic use.
Youle
R J
RJ
Biochemistry Section, NINDS, NIH, Bethesda, MD 20892.
Newton
D
D
Wu
Y N
YN
Gadina
M
M
Rybak
S M
SM
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003087:Colicins / Q000627:therapeutic use; D005658:Fungi / Q000201:enzymology; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D010944:Plants / Q000201:enzymology; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D012260:Ribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D016415:Sequence Alignment
D000970:Antineoplastic Agents; D003087:Colicins; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; D012260:Ribonucleases