Zbigniew P Kortylewicz1, Don W Coulter2, Janina Baranowska-Kortylewicz1. 1. J. Bruce Henriksen Cancer Research Laboratories, Department of Radiation Oncology, University of Nebraska Medical Center, 986850 Nebraska Medical Center, Omaha, Nebraska. 2. Division of Hematology/Oncology, Department of Pediatrics, University of Nebraska Medical Center, 982168 Nebraska Medical Center, Omaha, Nebraska.
Abstract
Background: Resistance of cancer to chemo- and radiotherapy remains a major clinical problem. This study contributes to the ongoing search for agents that can bypass this resistance by developing a novel antimitotic theranostic. Materials and Methods: Methyl N-[5-(3'-iodobenzoyl)-1H-benzimidazol-2-yl]carbamates 1 and 2 were synthesized from a common precursor 3 or its 3'-stannylated derivative. The cytotoxicity of compound 1 was evaluated in several neuroblastoma and glioblastoma cell lines and in the NCI 60-cell assay. Biodistribution was conducted in mice after oral administration of compound 2 to determine tissue and brain uptake. Result: Lethal concentrations (LC50s) of compound 1 in neuroblastoma and glioblastoma are >15 × lower compared with compound 3, a drug currently tested in clinical studies in pediatric and adult brain tumors. Growth inhibition concentrations (GI50) are in the nanomolar range in 60 cancer cell lines. When compound 1 is combined with a 4-Gy dose of radiation, <0.5% of cells retain their reproductive integrity. Increased hydrophobicity of new agents greatly enhances their brain uptake after oral administration. Conclusions: Compound 1 is potently cytotoxic in a wide range of human cancer cell lines. Its structure allows incorporation of imaging and therapeutic radionuclides. It is therefore expected that compound 1 can be developed into a novel theranostic modality across a wide range of malignancies.
Background: Resistance of cancer to chemo- and radiotherapy remains a major clinical problem. This study contributes to the ongoing search for agents that can bypass this resistance by developing a novel antimitotic theranostic. Materials and Methods: Methyl N-[5-(3'-iodobenzoyl)-1H-benzimidazol-2-yl]carbamates 1 and 2 were synthesized from a common precursor 3 or its 3'-stannylated derivative. The cytotoxicity of compound 1 was evaluated in several neuroblastoma and glioblastoma cell lines and in the NCI 60-cell assay. Biodistribution was conducted in mice after oral administration of compound 2 to determine tissue and brain uptake. Result: Lethal concentrations (LC50s) of compound 1 in neuroblastoma and glioblastoma are >15 × lower compared with compound 3, a drug currently tested in clinical studies in pediatric and adult brain tumors. Growth inhibition concentrations (GI50) are in the nanomolar range in 60 cancer cell lines. When compound 1 is combined with a 4-Gy dose of radiation, <0.5% of cells retain their reproductive integrity. Increased hydrophobicity of new agents greatly enhances their brain uptake after oral administration. Conclusions: Compound 1 is potently cytotoxic in a wide range of humancancer cell lines. Its structure allows incorporation of imaging and therapeutic radionuclides. It is therefore expected that compound 1 can be developed into a novel theranostic modality across a wide range of malignancies.
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