title: Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain.
abstract: Treatment of glioblastoma with platinum compounds modestly improves progression-free survival and may cause toxic effects which prevent use at higher dose that would otherwise improve the antineoplastic effect. To reduce toxicity, we propose to encapsulate the platinum drug in a liposome. We have also tested three methods of drug administration (intra-venous, intra-arterial and intra-arterial combined with blood brain barrier disruption) to determine which one optimizes the tumor cell uptake, limits the toxicity and delivers the best concomitance effect with radiotherapy. Cisplatin, oxaliplatin, their respective liposomal formulations, Lipoplatin™ and Lipoxal™, and carboplatin were assessed in F98 glioma, orthotopically implanted in Fischer rats. We found that the modest accumulation of drugs in tumor cells after intra-venous injection was significantly improved when the intra-arterial route was used and further increased after the transient opening of the blood brain barrier with mannitol. The liposomal formulations have largely reduced the toxicity and have allowed a better exploitation of the anti-cancer activity of platinum agent. Although the liposomes Lipoplatin™ and Lipoxal™ have shown a similar ability to that of carboplatin, to accumulate in brain tumors, the highest additive effect with radiotherapy was obtained with carboplatin. We conclude that the intra-arterial infusion of carboplatin or Lipoxal™ in concomitance with radiation therapy leads to the best tumor control as measured by an increase of mean survival time in Fischer rats implanted with the F98 glioma with a benefit in survival time of 13.4 and 6.5 days respectively compared to intra-venous.
authors.affiliation: Center for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Heath Science, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada, Gabriel.Charest@USherbrooke.ca.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Charest
authors.forename: Léon
authors.initials: L
authors.lastname: Sanche
authors.forename: David
authors.initials: D
authors.lastname: Fortin
authors.forename: David
authors.initials: D
authors.lastname: Mathieu
authors.forename: Benoit
authors.initials: B
authors.lastname: Paquette
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016190:Carboplatin / Q000008:administration & dosage; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D004333:Drug Administration Routes; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008081:Liposomes; D008297:Male; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate
chemical_list: D008081:Liposomes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016190:Carboplatin; D002945:Cisplatin
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