Toxicity of an antitumor ribonuclease to Purkinje neurons.
Purkinje cell toxicity is one of the characteristic features of the Gordon phenomenon, a syndrome manifested by ataxia, muscular rigidity, paralysis, and tremor that may lead to death (Gordon, 1933). Two members of the RNase superfamily found in humans, EDN (eosinophil-derived neurotoxin) and ECP (eosinophil cationic protein), cause the Gordon phenomenon when injected intraventricularly into guinea pigs or rabbits. We have found that another member of the RNase superfamily, an antitumor protein called onconase, isolated from Rana pipiens oocytes and early embryos, will also cause the Gordon phenomenon when injected into the cerebrospinal fluid of guinea pigs at a dose similar to that of EDN (LD50, 3-4 micrograms). Neurologic abnormalities of onconase-treated animals were indistinguishable from those of EDN-treated animals, and histology showed dramatic Purkinje cell loss in the brains of onconase-treated animals. The neurotoxic activity of onconase correlates with ribonuclease activity. Onconase modified by iodoacetic acid to eliminate 70% and 98% of the ribonuclease activity of the native enzyme displays a similar decrease in ability to cause the Gordon phenomenon. In contrast, the homologous bovine pancreatic RNase A injected intraventricularly at a dose 5000 times greater than the LD50 dose of EDN or onconase is not toxic and does not cause the Gordon phenomenon. A comparison of the RNase activities of EDN, onconase, and bovine pancreatic RNase A using three pancreatic RNA substrates demonstrates that onconase is orders of magnitude less active enzymatically than EDN and RNase A. Thus, another member of the RNase superfamily in addition to EDN and ECP can cause the Gordon phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)
Newton
D L
DL
Biochemistry Section, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Walbridge
S
S
Mikulski
S M
SM
Ardelt
W
W
Shogen
K
K
Ackerman
S J
SJ
Rybak
S M
SM
Youle
R J
RJ
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001798:Blood Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D004527:Egg Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D047091:Eosinophil Granule Proteins; D047208:Eosinophil-Derived Neurotoxin; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D011689:Purkinje Cells / Q000187:drug effects* / Q000473:pathology; D011817:Rabbits; D012259:Ribonuclease, Pancreatic / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D012260:Ribonucleases / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D017386:Sequence Homology, Amino Acid; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D001798:Blood Proteins; D004527:Egg Proteins; D047091:Eosinophil Granule Proteins; D009498:Neurotoxins; D047208:Eosinophil-Derived Neurotoxin; D012260:Ribonucleases; D012259:Ribonuclease, Pancreatic; C058703:ranpirnase