Neurotoxic effect of cisplatin and the cisplatin-procaine complex DPR studied in organotypic cultures of chick embryonic dorsal root ganglia.
Neurotoxic effects of cisplatin and the cisplatin-procaine complex cis-diaminechloro-[2-(diethylamino)ethyl 4-aminobenzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR) were compared in organotypic cultures of chick embryonic dorsal root ganglia maintained in a semi-solid (soft agar) culture medium. The changes of two characteristics of the neurite outgrowth, the mean radial length of neuritic processes growing out from the ganglia and the area of neurite outgrowth around the ganglion, were used as parameters to evaluate the toxic effect of both compounds. The drugs were administered to the cultures at concentrations ranging from 13 to 120 microM. The half-maximum inhibition concentration (IC50) was determined from the concentration-response curves for both the mean radial length of neurites and the area of neurite outgrowth. An analysis of these parameters revealed that DPR was significantly less neurotoxic than cisplatin. In fact, considering the mean radial length of neurite processes, the IC50s of cisplatin were 56, 65 and 66 microM after 24, 48 and 72 h of exposure, respectively. By contrast, for DPR the IC50s were 116 microM after 24 h, and greater than 120 microM after 48 and 72 h of exposure. When we considered the area index (i.e. the area of neurite outgrowth normalized for the area of the ganglia), the IC50s for cisplatin were 41, 52 and 55 microM after 24, 48 and 72 h of exposure, respectively, whereas for DPR the IC50s were 59 microM after 24 h, and greater than 120 microM after 48 and 72 h of exposure. Our results support previous findings of lower toxicity of DPR to non-neoplastic tissues, as compared to cisplatin.
Department of Teratology, Institute of Experimental Medicine, Academy of Sciences of Czech Republic, Prague.
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Mandys
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Viale
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Vrana
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Cafaggi
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Esposito
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002642:Chick Embryo; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D011343:Procaine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C080075:cisplatin-procaine complex; D011343:Procaine; D002945:Cisplatin