The dependency of compound biological effectiveness factors on the type and the concentration of administered neutron capture agents in boron neutron capture therapy

Abstract

Purpose: To examine the effect of the type and the concentration of neutron capture agents on the values of compound biological effectiveness (CBE) in boron neutron capture therapy.

Methods and materials: After the subcutaneous administration of a (10) B-carrier, boronophenylalanine- (10) B (BPA) or sodium mercaptododecaborate- (10) B (BSH), at 3 separate concentrations, the (10) B concentrations in tumors were measured by γ-ray spectrometry. SCC VII tumor-bearing C3H/He mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells, then treated with BPA or BSH. Immediately after reactor neutron beam irradiation, during which intratumor (10) B concentrations were kept at levels similar to each other, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled quiescent (Q) and total (= P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU.

Results: The CBE values were higher in Q cells and in the use of BPA than total cells and BSH, respectively. In addition, the higher the administered concentrations were, the smaller the CBE values became, with a clearer tendency in the use of BPA than BSH. The values for neutron capture agents that deliver into solid tumors more dependently on uptake capacity of tumor cells became more changeable.

Conclusion: Tumor characteristics, such as micro-environmental heterogeneity, stochastic genetic or epigenetic changes, or hierarchical organization of tumor cells, are thought to partially influence on the value of CBE, meaning that the CBE value itself may be one of the indices showing the degree of tumor heterogeneity.

Keywords: Boron neutron capture therapy; Compound biological effectiveness; Neutron capture agent; Quiescent cell; Relative biological effectiveness; Tumor heterogeneity.

Figure 1

Time course of changes in ¹⁰ B concentrations in the solid tumors (a) and blood collected from the hearts (b) of SCC VII tumor-bearing mice after subcutaneous administration of each ¹⁰ B-carrier. Left panel of (a) shows time course of changes in tumors following administration of boronophenylalanine-¹⁰B at doses of 250 (●), 500 (▲), or 750 (■) mg·kg⁻¹. Right panel of (a) shows time course of changes in tumors following administration of sodium mercaptododecaborate-¹⁰B at doses of 125 (●), 250 (▲), or 375 (■) mg·kg⁻¹. (b) shows time course of changes in blood following administration of each ¹⁰B-carrier. Solid lines represent boronophenylalanine-¹⁰B at the doses of 250 (○), 500 (△), or 750 (□) mg·kg⁻¹. Dotted lines represent sodium mercaptododecaborate-¹⁰B at doses of 125 (○), 250 (△), or 375 (□) mg·kg⁻¹. Bars represent standard errors.

Figure 2

Left and right panels show cell survival curves and the net micronucleus (MN) frequencies after in vivo irradiation with γ-rays only, respectively, as a function of the physical radiation dose in total (open symbols) and quiescent (Q, (solid symbols)) tumor cell populations. Bars represent standard errors (n = 9).

Figure 3

Cell survival curves (a) and the net micronucleus (MN) frequencies (b) after in vivo irradiation using neutron beams without the ¹⁰ B-carrier as a function of the physical radiation dose in total (open symbols) and quiescent (Q, (solid symbols)) tumor cell populations. The data for irradiation with reactor “neutron beams” and with “neutrons only” are shown at left and right panels, respectively. Bars represent standard errors (n = 9).

Figure 4

Cell survival curves (a) and the net micronucleus frequencies (b) after in vivo irradiation using neutron beams following subcutaneous administration of boronophenylalanine- ¹⁰ B at dose of 250 (circles), 500 (triangles), or 750 (squares) mg·kg ^-1 as a function of the physical radiation dose in total (open symbols) and quiescent (Q, (solid symbols)) tumor cell populations. The data for irradiation with reactor “neutron beams”, with “neutrons only”, and at the “¹⁰B dose” are shown at the left, central, and right panels, respectively. Bars represent standard errors (n = 9).

Figure 5

Cell survival curves (a) and the net micronucleus frequencies (b) after in vivo irradiation using neutron beams following subcutaneous administration of sodium mercaptododecaborate- ¹⁰ B at dose of 125 (circles), 250 (triangles), or 375 (squares) mg·kg ^-1 as a function of the physical radiation dose in total (open symbols) and quiescent (Q, (solid symbols)) tumor cell populations. The data for irradiation with reactor “neutron beams”, with “neutrons only”, and at the “¹⁰B dose” are shown at the left, central, and right panels, respectively. Bars represent standard errors (n = 9).