M. Octaveprignot

The effect of 2'-2' difluorodeoxycytidine (dFdC, gemcitabine) on radiation-induced cell lethality in two human head and neck squamous carcinoma cell lines differing in intrinsic radiosensitivity.

PURPOSE The present study investigated in vitro radio-enhancement by gemcitabine (dFdC) in two head and neck squamous cell carcinomas with different intrinsic cellular radiosensitivity. MATERIALS AND METHODS Radiosensitive (SCC61, SF2=0.16) and radioresistant (SQD9, SF2=0.49) human head and neck squamous cell carcinomas were used. Confluent cells were incubated with dFdC and irradiated in drug-free medium with a single dose of 250 kV X-rays (0-12Gy). Cell survival curves were corrected for the toxicity of the drug alone. RESULTS In both cell lines, radio-enhancement was observed with 5 microM dFdC incubated for 3 h prior to irradiation. Dose modification factors (DMF) at a surviving fraction level of 0.5 reached 1.3 (95% CI 1.1-1.6) and 1.5 (95% CI 1.4-1.5) for SQD9 and SCC61 cells, respectively. Radio-enhancement was associated with a modest increase in the alpha term of the linear-quadratic model. In SQD9 cells, radio-enhancement increased with dFdC incubation time. At 24h, DMF reached a value of 1.5 (95% CI 0.9-3.2). In SCC61 cells at 24h, DMF reached a value of 1.1 (95% CI 0.9-1.2). In both cell lines, radio-enhancement increased with dFdC concentration up to 5-10 microM from which values it levelled off up to 100 microM. CONCLUSIONS The data indicated that dFdC induced a modest radio-enhancement in both cell lines. For a short incubation time, dFdC did not radio-enhance preferentially the more radio-resistant cells, whereas the opposite was observed for a longer time. In both cell lines, radio-enhancement was saturated above a dFdC concentration of 5-10 microM.

Intestinal crypt regeneration in mice : a biological system for quality assurance in non-conventional radiation therapy

BACKGROUND AND PURPOSE The Relative Biological Effectiveness (RBE) of 8 fast-neutron beams, 5 proton beams and 1 carbonion beam was determined using as biological criterion intestinal crypt regeneration in mice, i.e. an in vivo system. These beams are used or planned for clinical cancer therapy applications. In addition, the RBE of 6 epithermal neutron beams, used or planned for Boron Neutron Capture Therapy (BNCT), was determined; no boron was administered. The goal of the program was to improve the exchange of information between the centers, facilitate the interpretation of the results and increase the safety of the clinical applications. MATERIALS AND METHODS In all visited centers, the same technique was applied in the same conditions by the same radiobiology team. The number of regenerating crypts per circumference was scored 3.5 days after single fraction total body irradiation. The control irradiations were performed locally using cobalt-60 units. The mice were randomized according to radiation quality and dose level. RESULTS (1) For fast neutron beams, the RBE (Ref. cobalt-60 gamma rays) increases with decreasing energy (from approximately 1.7 for p(65)+Be neutrons to approximately 2.4 for d(14.5)+Be neutrons). In addition, it is specific to each facility and depends on the nuclear reaction (p or d + Be), target and collimation type. (2) For proton beams, the RBEs (Ref cobalt-60 gamma rays) at the reference position (middle of a 7-cm Spread Out Bragg Peak, SOBP) range between 1.08 and 1.18. They might differ by approximately 6-8% according to the mode of beam production or delivery. The RBEs at the end of the SOBP are always 5-10 % higher than at the middle of the SOBP. (3) For the carbon ion beam studied at NIRS in Chiba, Japan, the RBE significantly increases with depth. Relative to gamma rays, it ranges from 1.3 in the initial plateau, 1.6 at the beginning, 1.7 at the middle and 1.9 at the end of a 6-cm SOBP. 4) In BNCT beams, the radiation quality (in particular the relative contribution of the different dose components) varies rapidly with depth and depends strongly on the arrangement of the irradiation set-up (e.g. presence or not of back scattering material). Moreover, the (total) dose rates are highly variable (from 0.05 to approximately 0.5 Gy/min) according to the power of the reactors. Wide range of RBE values (Ref. gamma rays) was thus obtained (RBE = 1.4 - 2.2) at shallow depths of 1.5 - 2.5 cm. DISCUSSION AND CONCLUSION Intestinal crypt regeneration in mice is an in vivo system perfectly suitable to perform intercomparisons between centers applying different types of non-conventional radiation qualities. It was proven to be reproducible, reliable and accurate, and becomes progressively recognized worldwide as part of the Quality Control (QA) procedures for new beams. It should be stressed that the observed RBE for intestinal crypt cells after a single high dose provide some radiobiological characterization of the radiation quality but cannot be used as the RBE weighting factor in clinical prescriptions.

Effect of gemcitabine on the tolerance of the lung to single-dose irradiation in C3H mice.

In an early phase II trial combining gemcitabine (dFdC) and radiotherapy for lung carcinomas, severe pulmonary toxicity was observed. In this framework, the objective of this study was to investigate the effect of dFdC on the tolerance of the lungs of C3H mice to single-dose irradiation. The thoraxes of C3H mice were irradiated with a graded single dose of 8 MV photons; dFdC (150 mg/kg) or saline (control animals) was administered i.p. 3 or 48 h prior to irradiation. Lung tolerance was assessed by the LD50 at 7-180 days after irradiation. For irradiation alone, the LD50 reached 14.45 Gy (95% CI 13.33-15.66 Gy). With a 3-h interval between administration of dFdC and irradiation, the LD50 reached 13.29 (95% CI 12.26-14.44 Gy); the corresponding value with a 48-h interval reached 13.01 Gy (95% CI 11.92-14.20 Gy). Our data also suggested a possible effect of dFdC on radiation-induced esophageal toxicity. dFdC has a minimal effect on lung tolerance after single-dose irradiation. However, a proper phase I-II trial should be designed before any routine use of combined dFdC and radiotherapy in the thoracic region.

Variation of RBE between p(75) + Be and d(50) + Be Neutrons Determined for Chromosome Aberrations in Allium cepa

The RBE of p(75) + Be neutrons relative to d(50) + Be neutrons has been determined for chromosome aberrations induced in Allium cepa (onion) roots. Two biological criteria were selected: the average number of aberrations (mainly fragments) per cell in anaphase and telophase, and the percentage of aberration-free cells. The influence of sampling time (3 to 7 h incubation) between irradiation and fixation was investigated systematically. This factor did not significantly influence the results. The RBE values of p(75) + Be neutrons compared to those of d(50) + Be neutrons were 0.85 (0.79-0.91) and 0.87 (0.80-0.95) for the first and the second criteria, respectively. In previous experiments for the same beams, we found an RBE of 0.90 (0.86-0.94) for survival of V79 cells (D0 ratio), 0.96 (0.93-0.99) for the intestinal crypt cell system, and 0.83 (0.70-0.96) for Vicia faba growth delay.

Comparison of Neutron Therapy Beams Produced by 50 MEV Deuterons and 65 MEV Protons on Beryllium

Neutron beams produced by bombarding a 10 cm thick beryllium target with 50 MeV deuterons have been used at Louvain-la-Neuve since nearly 4 years for routine therapeutic applications. At the end of 1981 they were replaced by neutron beams produced by 65 MeV protons on beryllium, mainly in order to improve the beam penetration in tissues. However, produced of neutrons from the p leads to Be reaction implies some disadvantages, mainly a lower dose rate and a higher activation level. In order to solve the problem a new target configuration was designed, consisting of a remote handled system which permits the use of 2 different target assemblies. The irradiated target is automatically removed immediately after the irradiation which greatly protects against exposure to the staff. The dosimetric characteristics of the d(50)-Be and p(65)-Be neutrons beams are compared.