title: Determination of an optimal dosing schedule for combining Irinophore C™ and temozolomide in an orthotopic model of glioblastoma.
abstract: Our laboratory reported that Irinophore C™ (IrC™; a lipid-based nanoparticulate formulation of irinotecan) is effective against an orthotopic model of glioblastoma (GBM) and that treatment with IrC™ was associated with vascular normalization within the tumor. Here, the therapeutic effects of IrC™ when used in combination with temozolomide (TMZ) in concurrent and sequential treatment schedules were tested. It was anticipated that IrC™ engendered vascular normalization would increase the delivery of TMZ to the tumor and that this would be reflected by improved treatment outcomes. The approach compared equally efficacious doses of irinotecan (IRN; 50 mg/kg) and IrC™ (25 mg/kg) in order to determine if there was a unique advantage achieved when combining TMZ with IrC™. The TMZ sensitive U251MG(O) cell line (null expression of O-6-methylguanine-DNA methyltransferase (MGMT)) modified to express the fluorescent protein mKate2 was inoculated orthotopically into NOD.CB17-SCID mice and treatment was initiated 14 days later. Our results demonstrated that IrC™ and TMZ administered concurrently resulted in optimal treatment outcomes, with 50% long term survivors (>180 days) in comparison to 17% long term survivors in animals treated with IRN and TMZ or TMZ alone. Indeed, the different treatments resulted in a 353%, 222% and 280% increase in median survival time (MST) compared to untreated animals for, respectively, IrC™ combined with TMZ, IRN combined with TMZ, and TMZ alone. When TMZ was administered after completion of IRN or IrC™ dosing, an increase in median survival time of 167-174% was observed compared to untreated animals and of 67% and 74%, respectively, when IRN (50 mg/kg) and IrC™ (25mg/kg) were given as single agents. We confirmed in these studies that after completion of the Q7D×3 dosing of IrC™, but not IRN, the tumor-associated vascular was normalized as compared to untreated tumors. Specifically, reductions in the fraction of collagen IV-free CD31 staining (p<0.05) and reductions in tumor vessel diameter were observed in tumors from IrC™-treated animals when compared to tumors from untreated or IRN treated animals. Analysis by transmission electron microscopy of the ultra-structure of tumors from IrC™-treated and untreated animals revealed that tumor-associated vessels from treated animals were smaller, more organized and exhibited a morphology comparable to normal blood vessels. In conclusion, optimal treatment outcomes were achieved when IrC™ and TMZ were administered concurrently, whereas IrC™ followed by TMZ treatment given sequentially did not confer any therapeutic advantage.
authors.affiliation: Brain and Spine Institute Research Center, 47 Bd de l'Hopital, Paris, 75013, France. Electronic address: maiteverreault@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Verreault
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, V5Z 1L3, BC, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver V6T 1Z3, BC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Wehbe
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, V5Z 1L3, BC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Strutt
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, V5Z 1L3, BC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Masin
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, V5Z 1L3, BC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Anantha
authors.affiliation: Ultrastructural Imaging, UBC James Hogg Research Laboratories (iCAPTURE), Providence Heart and Lung Institute, St. Paul's Hospital, Rm 166, 1081 Burrard St, Vancouver, BC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Walker
authors.affiliation: Ultrastructural Imaging, UBC James Hogg Research Laboratories (iCAPTURE), Providence Heart and Lung Institute, St. Paul's Hospital, Rm 166, 1081 Burrard St, Vancouver, BC, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Chu
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, V5Z 1L3, BC, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Backstrom
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, V5Z 1L3, BC, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Kalra
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, V5Z 1L3, BC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Waterhouse
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, V5Z 1L3, BC, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver V6T 1Z3, BC, Canada.
authors.forename: D T
authors.initials: DT
authors.lastname: Yapp
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, V5Z 1L3, BC, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver V6T 1Z3, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver V6T 2B5, BC, Canada; Center for Drug Research and Development, Vancouver V6T 1Z4, BC, Canada. Electronic address: mbally@bccrc.ca.
authors.forename: M B
authors.initials: MB
authors.lastname: Bally
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000737:chemistry; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004334:Drug Administration Schedule; D004339:Drug Compounding; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D000077204:Temozolomide; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D008081:Liposomes; D000077146:Irinotecan; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide
keywords: Cancer; Drug delivery; Glioblastoma; Irinotecan; Liposomes; Tumor-associated vasculature