Cellular distribution of cis-diamminedichloroplatinum(II)-DNA binding in rat dorsal root spinal ganglia: effect of the neuroprotecting peptide ORG.2766.
The in situ binding of the anticancer drug cis-diamminedichloroplatinum(II) (cisDDP) to DNA was studied in the rat dorsal root spinal ganglion (DRG), using an antiserum against cisDDP-modified calf thymus DNA in a quantitative immunocytochemical assay. Rats received a dose of cisDDP (1 mg/kg), two times a week, up to a cumulative dose of 15 mg/kg (group I) or 34 mg/kg (group II). Rats of group III were given a single dose of 15 mg/kg. Rats were killed 48 hr (groups I and II) or 6 hr (group III) after the last injection. In groups I and II cisDDP-induced neurological damage was assessed by measuring both motor and sensory nerve conduction velocities (MNCV and SNCV). Whereas the MNCV was not influenced by the treatment with cisDDP, the SNCV decreased significantly. The level of cis-DDP-DNA binding in DRG satellite cells equalled that in liver cells, but binding could not be shown in DRG neuron nuclei. The level of cisDDP-DNA binding in spinal cord and brain was very low. The neuroprotecting peptide ORG.2766, an ACTH4-9 analog, was given sc (10 micrograms/rat) four times a week concomitantly with cisDDP to some rats of groups I and II. ORG.2766 prevented the decrease of the SNCV, but did not change the extent of cisDDP-DNA binding in satellite or liver cells. It is concluded that the amelioration of cisDDP toxicity by ORG.2766 is not directly related to the cisDDP-DNA binding in satellite cells.
Terheggen
P M
PM
Division of Chemical Carcinogenesis, The Netherlands Cancer Institute, Amsterdam.
van der Hoop
R G
RG
Floot
B G
BG
Gispen
W H
WH
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism* / Q000633:toxicity; D004247:DNA / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D010446:Peptide Fragments; C013765:Org 2766; D000324:Adrenocorticotropic Hormone; D004247:DNA; D002945:Cisplatin