The developmental neurotoxicity study of platinum compounds. Effects of cisplatin versus a novel Pt(II) complex on rat cerebellum.
In the field of experimental oncology, many efforts are being carried out to search new platinum-based drugs overcoming the CNS toxicity and drug resistance. One of the adopted strategies is the synthesis of platinum compounds able to form Pt-DNA adducts different from the cisplatin ones or to react with other subcellular targets. In this context a novel Pt(II) complex, [Pt(O,O'-acac)(γ-acac)(DMS)](PtAcacDMS), was synthesized which reacts preferentially with protein thiols or thioethers. In this work we investigated the in vivo effects of cisplatin and PtAcacDMS on normal development. Moreover, to verify the dose-dependence of the effects, different groups of animals were treated with 5 μg/g or 10 μg/g body weight of cisPt and PtAcacDMS. We have focused our attention on the cerebellum because it provides a useful model system to evaluate the outcomes of perinatal treatment with chemotherapeutic agents on key CNS developmental processes such as neural cells proliferation, migration and differentiation. We have demonstrated the ability of both cisPt and PtAcacDMS to reach the brain tissue once injected. The brain platinum content after PtAcacDMS treatment was notably higher (approximately 4-fold as much) than after cisPt. The platinum accumulation in the brain was still considerable 7 days after PtAcacDMS administration. However, compared with cisplatin, PtAcacDMS induces less severe changes on fundamental events of neuroarchitecture development, such as no high apoptotic events, less altered granule cell migration and Purkinje cell dendrite growth, suggesting a low neurotoxicity of this new Pt complex for normal CNS. The mild damages could be attributable to the different subcellular target of this compound as well as to a greater efficiency of the cell repair system to recognize the drug-target adducts and to repair them. Together with the previously demonstrated antineoplastic effectiveness in vitro, the findings here reported suggest PtAcacDMS as a potential alternative to cisplatin indicating, at the same time, that the choice of platinum compounds with new subcellular targets could be a strategy to prevent neurotoxicity induced by cisplatin and overcome drug resistance induced by mutations in the intrinsic apoptotic pathway.
Cerri
Silvia
S
Dipartimento di Biologia Animale, Laboratorio di Biologia Cellulare e Neurobiologia, Università di Pavia, via Ferrata 1, 27100 Pavia, Italy. cerri.silvia@libero.it
Piccolini
Valeria M
VM
Santin
Giada
G
Bottone
Maria G
MG
De Pascali
Sandra A
SA
Migoni
Danilo
D
Iadarola
Paolo
P
Fanizzi
Francesco P
FP
Bernocchi
Graziella
G
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C527556:Pt(O,O'-acac)(gamma-acac)(DMS); D002945:Cisplatin