Applicability of the 2-nitroimidazole-sodium borocaptate-10B conjugate, TX-2060, as a 10B-carrier in boron neutron capture therapy.

Abstract

BACKGROUND:

It is difficult to deliver a therapeutic amount of 10B from conventional 10B-carriers for boron neutron capture therapy (BNCT) throughout the target tumors, especially into the intratumor hypoxic cells which have low uptake capacities. We evaluated the usefulness of 5 new 10B-compounds (TX-2041, TX-2042, TX-2058, TX-2059 and TX-2060) as 10B-carriers in BNCT. They are 2-nitroimidazole-sodium borocaptate-10B (BSH) conjugates, that is, hybrid compounds that have both a hypoxic tumor cell sensitizing unit under gamma-ray irradiation, 2-nitroimidazoles and a thermal neutron-sensitizing unit, BSH.

MATERIALS AND METHODS:

The 5 new compounds were administered to SCC VII tumor-bearing mice intraperitoneally. As a control, BSH was also administered in the same manner. Then, the 10B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Based on the data of the pharmacokinetics analyses, TX-2060 was chosen for a subsequent tumor-irradiation study. SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2060 or BSH in the same manner as in the pharmacokinetics analyses. To obtain similar intratumor 10B concentrations during radiation exposure, irradiation with thermal neutrons or gamma-rays was started from 60 min after administration of the 10B-carrier. Right after irradiation, the tumors were excised, minced and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU-labelling (= quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in total (P + Q) tumor cells was determined from the tumors that were not pretreated with BrdU. The clonogenic cell survival was also determined in mice given no BrdU.

RESULTS:

10B distribution analyses in tumors, muscles, blood and liver indicated that TX-2060 has the most favorable characteristics for concentrating a sufficient amount of 10B in tumors and maintaining a high enough 10B concentration during irradiation. In addition, TX-2060 had a significantly stronger radio-sensitization effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2060 clearly exhibited a radio-sensitization effect with gamma-rays, not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH.

CONCLUSION:

10B-carrier, with a gamma-ray-sensitizing effect on tumor cells as well as the potential to keep 10B in tumors and sensitize tumor cells more markedly than conventional 10B-carriers, such as TX-2060, is a promising candidate for use in BNCT.

• Authors: Shin-Ichiro Masunaga, Hideko Nagasawa, Masamitsu Hiraoka, Yoshinori Sakurai, Yoshihiro Uto, Hitoshi Hori, Kenji Nagata, Minoru Suzuki, Akira Maruhashi, Yuko Kinashi, Koji Ono
• Journal: Anticancer research (Anticancer Res) 2004 Sep-Oct Vol. 24 Issue 5A Pg. 2975-83 ISSN: 0250-7005 [Print] Greece
• PMID: 15517904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Borohydrides
• Isotopes
• Nitroimidazoles
• Sulfhydryl Compounds
• TX-2060
• mercaptoundecahydrododecaborate
• Boron

Topics

• Animals
• Borohydrides (chemistry, pharmacokinetics, pharmacology)
• Boron (chemistry)
• Boron Neutron Capture Therapy (methods)
• Carcinoma, Squamous Cell (metabolism, radiotherapy)
• Female
• Isotopes
• Mice
• Mice, Inbred C3H
• Micronucleus Tests
• Nitroimidazoles (chemistry, pharmacokinetics, pharmacology)
• Sulfhydryl Compounds (chemistry, pharmacokinetics, pharmacology)
• Tissue Distribution