title: Combination of the antivascular agent ZD6126 with hypoxic cytotoxin treatment, with reference to the effect on quiescent tumor cells and the dependency on p53 status of tumor cells.
abstract: Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector as a control (SAS/neo) were inoculated subcutaneously into both the hind legs of Balb/cA nude mice. Mice bearing the tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells in the tumors. The mice then received a hypoxic cytotoxin, tirapazamine (TPZ) or TX-402, with or without a vascular targeting agent (VTA), ZD6126. Another group of mice given ZD6126 received a series of test doses of gamma-rays while alive or after tumor clamping to obtain hypoxic fractions (HFs) in the tumors. After each treatment, the tumor cells were isolated and incubated with a cytokinesis blocker (cytochalasin-B), and the micronucleus (MN) frequency in cells without BrdU labeling [quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. The MN frequency in total (P+Q) tumor cells was determined from the tumors that were not pretreated with BrdU. Both hypoxic cytotoxins showed significantly greater toxicity toward SAS/mp53 and Q than SAS/neo and total tumor cells, respectively. The sensitivity to TX-402 was significantly higher than that to TPZ in both total and Q tumor cells of both tumors. The significant enhancive effect by ZD6126 combined with each hypoxic cytotoxin was similar irrespective of p53 status, and slightly greater for total than Q cells probably because of a more marked increase in the size of the HFs in total than Q cells on the use of ZD6126 in both tumors, resulting in a reduction of the difference in the sensitivity to the hypoxic cytotoxin between total and Q cells. In the treatment of conventional cancer therapy-resistant Q tumor cells or p53-mutated tumor cells, the use of hypoxic cytotoxin was very promising either alone or when VTA was co-administered. TX-402 might be more promising than TPZ, although further study of the toxicity to normal tissue is needed.
authors: Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan. smasuna@rri.kyoto-u.ac.jp
authors: Shin-Ichiro
authors: S
authors: Masunaga
authors: Hideko
authors: H
authors: Nagasawa
authors: Yoshihiro
authors: Y
authors: Uto
authors: Hitoshi
authors: H
authors: Hori
authors: Ken
authors: K
authors: Ohnishi
authors: Akihisa
authors: A
authors: Takahashi
authors: Takeo
authors: T
authors: Ohnishi
authors: Minoru
authors: M
authors: Suzuki
authors: Kenji
authors: K
authors: Nagata
authors: Yuko
authors: Y
authors: Kinashi
authors: Koji
authors: K
authors: Ono
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D005720:Gamma Rays; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015162:Micronucleus Tests; D009154:Mutation; D009943:Organophosphorus Compounds / Q000008:administration & dosage; D011810:Quinoxalines / Q000008:administration & dosage; D011878:Radiotherapy / Q000379:methods; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: C503709:3-amino-2-quinoxalinecarbonitrile; D003497:Cyclic N-Oxides; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D011810:Quinoxalines; D014227:Triazines; D016159:Tumor Suppressor Protein p53; D000077704:Tirapazamine