Ionizing radiation and the thymus : effects of whole-body irradiation with fast fission neutrons and X-rays on the murine thymus

As described in Chapter I of this thesis, the thymus is an extremely complex lympho-epithelial organ in which bone marrow-derived lymphoid precursor cells, i.e. prothymocytes, differentiate and mature in a stromal matrix. During their differentiation in this specialized microenvironment, thymocytes are selected on the basis of tolerance to self-MHC gene products and they acquire the capacity to recognize foreign antigens in the context of self-MHC antigens. Furthermore, during this differentiation, the thymocytes acquire a number of cell surface differentiation antigens. It is generally accepted that the thymic stromal cells are involved in the process of differentiation and maturation of T cells- When animals are subjected to whole-body irradiation, severe effects develop in the thymus. As shown by many authors, irradiation with X-rays or gamma-rays, i.e. low LET radiation types, leads to a severe depopulation of the thymus and, subsequently, thymus recovery has been shown to follow a biphasic pattern (reviewed by Sharp & Crouse, 1980 and Watkins et al., 1980)- The initial phase in this biphasic thymic recovery is brought about by radioresistant intrathymic precursor cells which are not derived immediately from bone marrow stem cellsLimited proliferative capacity and the resulting exhaustion of these intrathymic precursor cells as well as an impaired production of thymus precursor cells in the bone marrow are responsible for a second thymus involution- The final recovery of the thymus is due to its replenishment from extrathymic precursors in the regenerated bone marrow

Sensitivity of murine haemopoietic stem cell populations to X-rays and I MeV fission neutrons in vitro and in vivo under hypoxic I. Conditions

The radiosensitivity of primitive haemopoietic stem cells that repopulate the bone marrow with precursors of granulocytes and macrophages (MRA[CFU-C]), mature stem cells capable of forming spleen colonies in lethally irradiated recipients (CFU-S-7) and colony-forming units in culture (CFU-C) were determined in vitro and under hypoxic conditions in vivo for 1 MeV fission neutrons and 300 kV X-rays. The obtained D0's were compared with previously observed D0's after irradiation in vivo under normal oxic conditions. With 1 MeV fission neutron irradiation no significant difference in radiosensitivity of the cell populations was observed between normal in vivo irradiation and in vitro irradiation. With 300 kV X-rays a lower radiosensitivity for all three cell populations was observed after in vitro compared to in vivo irradiation. In vivo irradiation with fission neutrons under hypoxic conditions led to a small decrease in radiosensitivity. The obtained oxygen enhancement ratio (OER) for fission neutrons varied from 1.2 for MRA[CFU-C] to 1.5 for CFU-C. After in vivo irradiation with 300 kV X-rays under hypoxic conditions much higher OERs were observed. An OER= 1.8 was obtained for CFU-S and for MRA[CFU-C] and for CFU-C OER 3.0 and 2.9 were observed. These results indicate that the radioresistance of primitive haemopietic stem cells (MRA[CFU-C]) compared to mature stem cells (CFU-S-7) is mainly due to intrinsic factors and not to differences in localization or oxygenation between primitive and mature stem cells

A stochastic model for subcellular dosimetry in boron neutron capture therapy

The therapeutic effectiveness of boron neutron capture therapy is highly dependent on the microscopic distribution of the administered boron compound. Two boron compounds with different uptake mechanisms in the tumour cells may thus cause effects of different degrees even if the macroscopic boron concentrations in the tumour tissue are the same. This difference is normally expressed quantitatively by the so-called relative local efficiency (RLE). In this work, a stochastic model for the subcellular dosimetry has been developed. This model can be used to calculate the probability for an energy deposition above a certain threshold level in the cell nucleus due to a single neutron capture reaction. If a threshold cell-kill function is assumed, and if the dose is low enough that multiple energy depositions are rare, the model can also be applied to calculations of the survival probability for a cell population. Subcellular boron distributions in rats carrying RG 2 rat gliomas were measured by subcellular fractionation after administration of two different boron compounds: a sulphydryl boron hydride (BSH) and a boronated porphyrin (BOPP). Based on these data, the RLE factors were then calculated for these compounds using the stochastic model

Performance of sulfhydryl boron hydride in patients with grade III and IV astrocytoma: a basis for boron neutron capture therapy

This study investigated the rationale of boron neutron capture therapy (BNCT) for the treatment of Grade III and IV astrocytoma. The European Community joint research program on BNCT plans to use sulfhydryl boron hydride (BSH) in clinical trials. The work presented here, examines the performance of BSH in eight patients with Grade III and IV astrocytoma using a measurement technique which precisely correlates the boron uptake with the histology of the tumor and the peritumoral brain. Astrocytomas are exceptionally heterogeneous and spread migrating tumor cells into the surrounding brain. The patients were infused with 50 mg BSH per kilogram of body weight at 12, 18, 24 or 48 hours before surgery. At the time of operation, specimens were obtained of the tumor, skin, muscle, dura, blood, urine, and, when surgically possible, the brain adjacent to tumor. In three patients the intracellular boron distribution was investigated by subcellular fractionation. The blood clearance was biphasic with half-lives of 0.6 and 8.2 hours. After 3 days, approximately 70% of the dose injected was excreted in the urine. The maximum boron concentration in the tumor was 20 ppm, 12 hours after the infusion. The tumor-to-blood ratios ranged between 0.2 and 1.4, with the highest values after 18 to 24 hours. In the brain specimens the boron concentration never exceeded 1 ppm. This work confirms a selective uptake of boron in the tumor compared to the surrounding brain and that boron, to some extent, is incorporated in the tumor cells