title: Convection-enhancement delivery of platinum-based drugs and Lipoplatin(TM) to optimize the concomitant effect with radiotherapy in F98 glioma rat model.
abstract: The prognosis for patients with glioblastoma remains poor with current treatments. Although platinum-based drugs are sometimes offered at relapse, their efficacy in this setting is still disputed. In this study, we use convection-enhanced delivery (CED) to deliver the platinum-based drugs (cisplatin, carboplatin, and Lipoplatin(TM) - liposomal formulation of cisplatin) directly into the tumor of F98 glioma-bearing rats that were subsequently treated with γ radiation (15 Gy). CED increased by factors varying between 17 and 111, the concentration of these platinum-based drugs in the brain tumor compared to intra-venous (i.v.) administration, and by 9- to 34-fold, when compared to intra-arterial (i.a.) administration. Furthermore, CED resulted in a better systemic tolerance to platinum drugs compared to their i.a. injection. Among the drugs tested, carboplatin showed the highest maximum tolerated dose (MTD). Treatment with carboplatin resulted in the best median survival time (MeST) (38.5 days), which was further increased by the addition of radiotherapy (54.0 days). Although the DNA-bound platinum adduct were higher at 4 h after CED than 24 h for carboplatin group, combination with radiotherapy led to similar improvement of median survival time. However, less toxicity was observed in animals irradiated 24 h after CED-based chemotherapy. In conclusion, CED increased the accumulation of platinum drugs in tumor, reduced the toxicity, and resulted in a higher median survival time. The best treatment was obtained in animals treated with carboplatin and irradiated 24 h later.
authors.affiliation: Center for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
authors.forename: Minghan
authors.initials: M
authors.lastname: Shi
authors.forename: David
authors.initials: D
authors.lastname: Fortin
authors.forename: Léon
authors.initials: L
authors.lastname: Sanche
authors.forename: Benoit
authors.initials: B
authors.lastname: Paquette
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D018481:Convection; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy*; D020714:Maximum Tolerated Dose; D010984:Platinum / Q000009:adverse effects / Q000627:therapeutic use*; D011916:Rats, Inbred F344; D015203:Reproducibility of Results; D016019:Survival Analysis; D023382:Toxicity Tests, Acute
chemical_list: D000970:Antineoplastic Agents; C503131:lipoplatin; D010984:Platinum; D002945:Cisplatin