An attempt to improve the therapeutic effect of boron neutron capture therapy using commonly employed 10B-carriers based on analytical studies on the correlation among quiescent tumor cell characteristics, tumor heterogeneity and cancer stemness

Abstract

Based on our previously published reports concerning the response of quiescent (Q) tumor cell populations to boron neutron capture therapy (BNCT), the heterogeneous microdistribution of 10B in tumors, which is influenced by the tumor microenvironment and the characteristics of the 10B delivery carriers, has been shown to limit the therapeutic effect of BNCT on local tumors. It was also clarified that the characteristics of 10B-carriers for BNCT and the type of combined treatment in BNCT can also affect the potential for distant lung metastases from treated local tumors. We reviewed the findings concerning the response of Q tumor cell populations to BNCT, mainly focusing on reports we have published so far, and we identified the mode of BNCT that currently offers the best therapeutic gain from the viewpoint of both controlling local tumor and suppressing the potential for distant lung metastasis. In addition, based on the finding that oxygenated Q tumor cells showed a large capacity to recover from DNA damage after cancer therapy, the interrelationship among the characteristics in Q tumor cell populations, tumor heterogeneity and cancer stemness was also discussed.

The impact ofTP53status of tumor cells including the type and the concentration of administered 10B delivery agents on compound biological effectiveness in boron neutron capture therapy

“…LI reached a plateau level at these stages. Therefore, tumor cells that did not incorporate BrdU after continuous labeling for 7 days were considered Q tumor cells [ 6 ].…”

“…The neutron capture reaction was carried out with a 10 B delivery agent, boronophenylalanine- 10 B (BPA, C 9 H 12 10 BNO 4 ) or sodium mercaptoundecahydrododecaborate- 10 B (BSH, Na 2 10 B 12 H 11 SH). Regarding the local tumor response, the effect not only on the total (= proliferating [P] + quiescent [Q]) tumor cell population, but also on the Q tumor cell population, was evaluated using our originally developed method for selectively detecting the response of Q tumor cells within solid tumors [ 6 ].…”

Molecular Mechanisms of Specific Cellular DNA Damage Response and Repair Induced by the Mixed Radiation Field During Boron Neutron Capture Therapy

“…Only a limited number of in vitro studies during BNCT have been undertaken regarding the heterogeneity of the tumor microenvironment including hypoxia, cancer stem cells, low blood flow, or low nutrition ( 60 ). These factors can cause tumor cells to become quiescent (Q), reducing radiosensitivity or inhibiting drug entrance, making the tumor more resistant to the treatment and causing recurrence.…”

“…These factors can cause tumor cells to become quiescent (Q), reducing radiosensitivity or inhibiting drug entrance, making the tumor more resistant to the treatment and causing recurrence. Oxygenated Q tumor cells have a greater ability to recover from DNA damage after anti-cancer therapy and suggest an interrelationship with CSCs ( 60 , 61 ). CSCs are a subpopulation of cells within a tumor with stem cell-like properties ( 62 ).…”

Advances of Tumorigenesis, Diagnosis at Early Stage, and Cellular Immunotherapy in Gastrointestinal Malignancies

“…Previously, clinical professionals supposed that apoptotic cancer cells or chemotherapy-induced mutation should have expressed more neoantigens; however, this idea is highly likely a misconception (284), but through applying histone deacetylase inhibitors or radioactive treatments, neoantigens expressed on cancer cells are notably beneficial for cellular immunotherapy due to enormously increased antigenicity (285,286). Moreover, boron-neutron capture therapy (BNCT) not only precisely and largely eliminates tumor volume but also produces a large amount of various neoantigens due to radiation-damaged DNAs extensively existing in survived cancer cells, which are specifically utilized by cellular immunotherapy for constantly attacking (287,288). As given knowledge, DCs are the most powerful antigen presentation immunocytes, which directly command cytotoxic T lymphocytes to attack cancer cells; therefore, depending on DC-mediated recruitment of CIKs through tumor-associated antigens, DC-CIK therapy efficiently and specifically eliminates malignant cells (295).…”