Evaluation of hypoxia-specific cytotoxic bioreductive agent-sodium borocaptate-10B conjugates as10B-carriers in boron neutron capture therapy

• Published in: Japanese journal of radiology Vol. 24; no. 2; pp. 98 - 107
• Main Authors: Masunaga, Shin-ichiro, Nagasawa, Hideko, Gotoh, Keiko, Sakurai, Yoshinori, Uto, Yoshihiro, Hori, Hitoshi, Nagata, Kenji, Suzuki, Minoru, Maruhashi, Akira, Kinashi, Yuko, Ono, Koji
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Nature B.V 01.02.2006
• Subjects: Cancer; Hypoxia; Tumors
• ISSN: 0288-2043; 1867-1071; 1862-5274; 1867-108X
• DOI: 10.1007/BF02493275

To evaluate the usefulness of 5 new^sup 10^B-compounds (TX-2091, TX-2095, TX-2097, TX-2100, and TX-2110) as^sup 10^B-carriers in boron neutron capture therpy (BNCT). They were conjugates that had been synthesized from a hypoxia-specific cytotoxic bioreductive agent, quinoxaline oxide TX-402 and a clinically used^sup 10^B-carrier, sodium borocaptate-^sup 10^B (BSH). The 5 new compounds were hybrid compounds that have both a hypoxic cytotoxin unit and a thermal neutron-sensitizing unit, BSH. These new compounds and BSH were administered intraperitoneally to SCC VII tumor-bearing mice. Then, the^sup 10^B concentrations in the tumors and normal tissues were measured by γ-ray spectrometry. Subsequently, 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-2100, which was chosen based on the results of the above-mentioned biodistribution analyses, or BSH in the same manner as in the biodistribution studies. Right after irradiation, during which intratumor^sup 10^B concentrations were kept at levels similar to each other, 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 labeling [=quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in the total (P+Q) tumor cell population was determined from the tumors that were not pretreated with BrdU. Clonogenic cell survival was also determined in mice given no BrdU. ^sup 10^B biodistribution analyses in tumors, brain, skin, muscles, blood, and liver indicated that TX-2100 has the most favorable characteristics for concentrating a sufficient amount of^sup 10^B in tumors and maintaining a high enough^sup 10^B concentration during irradiation. In addition, TX-2100 had a significantly stronger radio-sensitizing effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2100 clearly exhibited a radio-sensitizing effect with γ-rays not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH. A^sup 10^B-carrier that acts as a hypoxic cytotoxin on tumor cells as well as having the potential to keep^sup 10^B in tumors and sensitize tumor cells more markedly than conventional^sup 10^B-carriers, such as TX-2100, is a promising candidate for use in BNCT.[PUBLICATION ABSTRACT]