title: Avoidance of bone marrow suppression using A-5021 as a nucleoside analog for retrovirus-mediated herpes simplex virus type I thymidine kinase gene therapy.
abstract: Gene therapy using the herpes simplex virus thymidine kinase (HSV-TK) gene combined with an anti-herpes drug, ganciclovir (GCV), has been applied for human diseases, especially for cancer treatment. However, bone marrow toxicity has been the most consistent adverse effect of GCV treatment in clinical settings. We evaluated the cytotoxic activity of a novel guanosine analog, (1'S,2'R)-9[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanin e (A-5021), against retrovirus-mediated HSV-TK gene-transduced human lung cancer cells. The bone marrow toxicity of A-5021 and GCV was studied by colony formation assay in both rodent and human bone marrow specimens. We demonstrated that A-5021 had potent cytotoxic activity equal to that of GCV against the retroviral vector-mediated HSV-TK gene-transduced lung cancer cell lines. Further, phosphorylated A-5021 could be transferred to neighboring cells, and this analog killed HSV-TK- neighboring cells, as was the case for GCV. In contrast, A-5021 did not exhibit an inhibitory effect on bone marrow progenitor cells and colony formation (the 50% inhibitory concentration of the colony-forming units in culture = >100 microg/mL in human bone marrow specimens and >66 microg/mL in rodent bone marrow specimens). These results indicate that A-5021 has potent cytotoxic activity as a nucleoside analog for gene therapy using HSV-TK gene, and can be used much more safely than GCV.
authors.affiliation: First Department of Internal Medicine, Nagoya University School of Medicine, Japan. yhasega@tsuru.med.nagoya-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Y
authors.initials: Y
authors.lastname: Nishiyama
authors.forename: K
authors.initials: K
authors.lastname: Imaizumi
authors.forename: N
authors.initials: N
authors.lastname: Ono
authors.forename: T
authors.initials: T
authors.lastname: Kinoshita
authors.forename: S
authors.initials: S
authors.lastname: Hatano
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Shimokata
mesh_terms: D000230:Adenocarcinoma; D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D018288:Carcinoma, Small Cell; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015774:Ganciclovir / Q000633:toxicity; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006147:Guanine / Q000031:analogs & derivatives* / Q000633:toxicity; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms; D051379:Mice; D012190:Retroviridae; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C111645:9-((cis-1,2-bis(hydroxymethyl)cycloprop-1-yl)methyl)guanine; D000998:Antiviral Agents; D006147:Guanine; D013937:Thymidine Kinase; D015774:Ganciclovir