Usefulness of combination with both continuous administration of hypoxic cytotoxin and mild temperature hyperthermia in boron neutron capture therapy in terms of local tumor response and lung metastatic potential

Abstract

Purpose: To evaluate the usefulness of combined treatment with both continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ) and mild temperature hyperthermia (MTH) in boron neutron capture therapy (BNCT) in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells.

Materials and methods: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2’-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumors received reactor thermal neutron beam irradiation following the administration of a ¹⁰B-carrier (L-para-boronophenylalanine-¹⁰B (BPA) or sodium mercaptoundecahydrododecaborate-¹⁰B (BSH)) after single intraperitoneal injection of an acute hypoxia-releasing agent (nicotinamide), MTH (40 °C for 60 min), and 24-h continuous subcutaneous infusion of TPZ or combined treatment with both TPZ and MTH. Immediately after irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (=P + Q) tumor cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated.

Results: BPA-BNCT increased the sensitivity of the total tumor cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without a ¹⁰B-carrier, combination with continuously administered TPZ with or without MTH enhanced the sensitivity of the both total and Q cells, especially Q cells. Even without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with combined treatment with both TPZ and MTH as well as nicotinamide treatment, showed the potential to reduce the number more than BSH-BNCT.

Conclusion: BSH-BNCT combined with TPZ with or without MTH improved local tumor control, while BPA-BNCT in combination with both TPZ and MTH as well as nicotinamide is thought to reduce the number of lung metastases. It was elucidated that control of the chronic hypoxia-rich Q cell population in the primary solid tumor has the potential to impact the control of local tumors as a whole and that control of the acute hypoxia-rich total tumor cell population in the primary solid tumor has the potential to impact the control of lung metastases.

Keywords:

• Boron neutron capture therapy
• ¹⁰B-carrier
• quiescent tumor cell
• tirapazamine
• nicotinamide
• mild temperature hyperthermia

Disclosure statement

The authors have no conflicts of interest. The authors are responsible for the content and writing of the manuscript.

Additional information

Funding

This study was supported in part by a Grant-in-aid for Scientific Research (B) [15H04295] and (C) [19K08171] from the Japan Society for the Promotion of Science.

Notes on contributors

Shin-ichiro Masunaga

Shin-ichiro Masunaga, MD, PhD, is a Professor of Particle Radiation Biology, Division of Radiation Life Science, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan. He tries to develop less-toxic anticancer therapy including BNCT that can cure local solid tumor and suppress distant metastatic potential.

Yoshinori Sakurai

Yoshinori Sakurai, PhD, is an Associate Professor of Particle Radiation Medical Physics, Parctile Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan. He is a radiation medical physicist, especially majoring in achieving reactor-based BNCT at KUR.

Hiroki Tanaka

Hiroki Tanaka, PhD, is an Associate Professor of Particle Radiation Medical Physics, Parctile Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan. He is a radiation medical physicist, especially majoring in achieving accelerator-based BNCT.

Takushi Takata

Takushi Takata, PhD, is an Assistant Professor of Particle Radiation Medical Physics, Parctile Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan. He is a radiation medical physicist, majoring in achieving reactor and accelerator-based BNCT.

Minoru Suzuki

Minoru Suzuki, MD, PhD, is a Professor of Particle Radiation Oncology, Parctile Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan. He tries to popularize clinical BNCT and develop basic research especially concerning BNCT.

Yu Sanada

Yu Sanada, PhD, is an Assistant Professor of Particle Radiation Biology, Division of Radiation Life Science, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan. His research is focused on the mechanism by which radio-resistance of tumor cells can be acquired in the tumor microenvironment.

Keizo Tano

Keizo Tano, PhD, is an Associate Professor of Particle Radiation Biology, Division of Radiation Life Science, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan. He tries to elucidate molecular and cellular mechanisms on DNA repair in vertebrate cells using reverse genetics approach.

Akira Maruhashi

Akira Maruhashi, PhD, is a Professor emeritus of Particle Radiation Medical Physics, Parctile Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan. He tries to bring up professionals especially for achieving clinical BNCT.

Koji Ono

Koji Ono, MD, PhD, is a Head of Kansai BNCT Medical Center, Osaka Medical College, Takatsuki, Osaka, Japan. He is also a Professor emeritus of Particle Radiation Oncology, Parctile Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan. He tries to bring up professionals especially for researching BNCT basically and clinically.