title: Preliminary studies with a new hypoxia-selective cytotoxin, KS119W, in vitro and in vivo.
abstract: Agents with selective toxicity to hypoxic cells have shown promise as adjuncts to radiotherapy. Our previous studies showed that the bioreductive alkylating agent KS119 had an extremely large differential toxicity to severely hypoxic and aerobic cells in cell culture, and was effective in killing the hypoxic cells of EMT6 mouse mammary tumors in vivo. However, the limited solubility of that compound precluded its development as an anticancer drug. Here we report our initial studies with KS119W, a water-soluble analog of KS119. The cytotoxicity of KS119W to EMT6 cells in vitro was similar to that of KS119, with both agents producing only minimal cytotoxicity to aerobic cells even after intensive treatments, while producing pronounced cytotoxicity to oxygen-deficient cells. This resulted in large differentials in the toxicities to hypoxic and aerobic cells (>1,000-fold at 10 μM). Low pH had only minimal effects on the cytotoxicity of KS119W. Under hypoxic conditions, EMT6 cells transfected to express high levels of either human or mouse versions of the repair protein O(6)-alkylguanine-DNA alkyltransferase, which is also known as O(6)-methylguanine DNA-methyltransferase, were much more resistant to KS119W than parental EMT6 cells lacking O(6)-alkylguanine-DNA alkyltransferase, confirming the importance of DNA O-6-alkylation to the cytotoxicity of this agent. Studies with EMT6 tumors in BALB/c Rw mice using both tumor cell survival and tumor growth delay assays showed that KS119W was effective as an adjunct to irradiation for the treatment of solid tumors in vivo, producing additive or supra-additive effects in most combination regimens for which the interactions could be evaluated. Our findings encourage additional preclinical studies to examine further the antineoplastic effects of KS119W alone and in combination with radiation, and to examine the pharmacology and toxicology of this new bioreductive alkylating agent so that its potential for clinical use as an adjuvant to radiotherapy can be evaluated.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520-8040, USA.
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Kim
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Liu
authors.forename: Oluwatoyin M
authors.initials: OM
authors.lastname: Akintujoye
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Shyam
authors.forename: Tina A
authors.initials: TA
authors.lastname: Grove
authors.forename: Alan C
authors.initials: AC
authors.lastname: Sartorelli
authors.forename: Sara
authors.initials: S
authors.lastname: Rockwell
mesh_terms: D000332:Aerobiosis; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006863:Hydrogen-Ion Concentration; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: C118156:1,2-bis(methylsulfonyl)-1--(2-chloroethyl)-2-((1-(4-nitrophenyl)ethoxy)carbonyl)hydrazine; D000970:Antineoplastic Agents; D006834:Hydrazines; D014867:Water