Estimating human cancer risk from the results of animal experiments: relationship between mechanism and dose-rate and dose.

Experimental animals are often used as surrogate models in estimating human cancer risk from environmental agents when adequate epidemiological data are not available. Studies in experimental animals have usually evaluated the effects of exposure to single substances; however, humans receive combinations of exposures, to both initiators and promoters of carcinogenesis. Exposure to several agents may modify the carcinogenic process of one of them. For many agents, the relationship between dose and carcinogenic response depends on both dose-rate and cumulative dose. For a given total dose, dose-rate may affect carcinogenic potency both qualitatively (target organ) and quantitatively. The effects of dose-rate are a function of total dose, species, and most importantly, the mechanism by which the agent exerts its carcinogenic effect. Prediction of the effects of different dose-rates of potentially carcinogenic agents can be based on knowledge of its mechanism of action.     

Impact of dose-rate on the low-dose hyper-radiosensitivity and induced radioresistance (HRS/IRR) response

Abstract

Purpose: To ask whether dose-rate influences low-dose hyper- radiosensitivity and induced radioresistance (HRS/IRR) response in rat colon progressive (PRO) and regressive (REG) cells.

Methods: Clonogenic survival was applied to tumorigenic PRO and non-tumorigenic REG cells irradiated with ⁶⁰Co γ-rays at 0.0025–500 mGy.min^?1. Both clonogenic survival and non-homologous end-joining (NHEJ) pathway involved in DNA double-strand breaks (DSB) repair assays were applied to PRO cells irradiated at 25 mGy.min^?1 with 75 kV X-rays only.

Results: Irrespective of dose-rates, marked HRS/IRR responses were observed in PRO but not in REG cells. For PRO cells, the doses at which HRS and IRR responses are maximal were dependent on dose-rate; conversely exposure times during which HRS and IRR responses are maximal (t_HRSmax and t_IRRmax) were independent of dose-rate. The t_HRSmax and t_IRRmax values were 23 ± 5 s and 66 ± 7 s (mean ± standard error of the mean [SEM], n = 7), in agreement with literature data. Repair data show that t_HRSmax may correspond to exposure time during which NHEJ is deficient while t_IRRmax may correspond to exposure time during which NHEJ is complete.

Conclusion: HRS response may be maximal if exposure times are shorter than t_HRSmax irrespective of dose, dose-rate and cellular model. Potential application of HRS response in radiotherapy is discussed.     

Pulsed Dose-Rate Perioperative Interstitial Brachytherapy for Soft Tissue Sarcomas of the Extremities and Skeletal Muscles of the Trunk

Background This study evaluated the role of pulsed dose-rate (PDR) brachytherapy (BRT), delivered alone or as a boost to external beam radiotherapy, as adjuvant therapy for the local control of soft tissue sarcomas of the extremities and skeletal muscles of the trunk that have undergone surgical treatment. Methods Between July 1998 and January 2002, 42 patients were treated with a combination of surgery and BRT alone (18 patients) or BRT/external beam radiotherapy (24 patients) for the treatment of primary (n = 32) and recurrent (n = 10) soft tissue sarcomas located in the proximal extremity (n = 17), distal extremity (n = 17), and trunk (n = 8). Tumor size was <5 cm in 20 cases and >5 cm in 22 cases, with histological grading of 1 (n = 7), 2 (n = 18), or 3 (n = 17). The median BRT dose delivered was 15 Gy, and the median external beam irradiation dose was 50 Gy. Results With a median follow-up of 34 months, the 36-month survival was 83.9% (SE, 6.1%), and the local control was 89%. Conclusions PDR interstitial BRT for soft tissue sarcoma is an effective, well-tolerated adjuvant radiation treatment that offers several practical advantages, among which are low acute and late toxicity with maximum normal tissue and critical structure sparing and overall shorter radiotherapy and hospital stay.     

Response-surface analysis of exposure-duration relationships: the effects of hyperthermia on embryonic development of the rat in vitro.

In developing exposure standards, an assumption is often made in the case of less-than-lifetime exposures that the probability of response depends on the cumulative exposure, i.e., the product of exposure concentration and duration. Over the last two decades, the general applicability of this assumption, referred to as Haber's Law, has begun to be questioned. This study examined the interaction of exposure concentration and duration on embryonic development during a portion of organogenesis. Embryos were exposed in whole embryo culture to various temperature-duration combinations and evaluated for alterations in development 24 h later. The specific purpose of the study was to assess whether the developmental responses followed Haber's Law, or whether an additional component of exposure was needed to model the relationship. The current study demonstrated that the response of the developing embryo to hyperthermia, with rare exception, was dependent on an additional component of exposure beyond the cumulative exposure. For the vast majority of the parameters measured in this study, the probability of an effect was greater at higher temperatures for short durations than at lower temperatures for long durations, given the same cumulative exposure. Thus, Haber's Law did not adequately describe the results of our study.     

Preoperative Intrauterine Irradiation of Endometrial Carcinoma Stage I: A Clinical and Radiographic Evaluation of the Bulb Technique

In a series of 146 cases of endometrial carcinoma stage I an afterloading technique using high dose-rate cobalt-60 sources has been evaluated for preoperative intracavitary irradiation. The uterine cavities were visualized by hysterograms and the target volumes were calculated. Absorbed doses were estimated at the surface of the target volume and within the uterine cavity. Surgery was performed six weeks after radiotherapy and the operative specimens were examined by a whole-organ sectioning technique. The frequency of residual carcinoma was assessed in relation to reference doses, minimum doses in the target and the position of the treatment catheter. The dose per fraction at the reference point, the minimum absorbed dose at the anterior surface of the target, the anterior-posterior diameter of the target volume and the position of the treatment catheter within the uterine cavity were found to be significant for tumor eradication. The irradiation technique and the histopathologic findings with reference to the operative specimen were significant for the rate of vaginal metastases but not for tumor recurrences at other sites. Radiation reactions involving the urogenital organs were few (4.8%). The most serious radiation reaction was obstruction of the small bowel (5.5%). The absorbed dose per fraction was the most important single risk factor for this complication.     

Cell cycle perturbations in cisplatin-sensitive and resistant human ovarian carcinoma cells following treatment with cisplatin and low dose rate irradiation

Purpose: To investigate cell cycle pertubations in plateau-phase human ovarian carcinoma cells following treatment with cisplatin, low dose-rate irradiation (LDRI), or combined cisplatin and LDRI, in order to understand cell cycle mechanisms by which these two treatment modalities interact. Methods: Human ovarian carcinoma cells sensitive (A2780) and resistant (2780^CP) to cisplatin were grown to plateau phase and given protracted cisplatin treatments (A2780 0.7 and 2 μg/ml; 2780^CP 5 and 15 μg/ml) and/or LDRI (0.41 cGy/min). Cell cycle distribution following treatment was determined by two-parameter flow cytometry, based on bromodeoxyuridine (BrdU) uptake and DNA content using propidium iodide staining.Results: The cisplatin-sensitive A2780 cells exposed to cisplatin alone for up to 28 h showed depletion of the G1 fraction and accumulation in S-phase, although the percentage of S-phase cells actively incorporating BrdU dropped to almost zero. The cisplatin-resistant 2780^CP cells exposed to cisplatin alone showed a G1 arrest when exposed to 15 μg/ml, but not when exposed to 5 μg/ml. LDRI alone caused little cell cycle redistribution different from controls in either cell line. When LDRI was combined with cisplatin, no significant cell cycle redistribution was observed, apart from a decline in the actively incorporating S-phase fraction. Conclusions: Cisplatin caused A2780 cells to accumulate in nonincorporating S-phase, with no evidence of G1 arrest. Cisplatin-resistant 2780^CP cells showed a G1 block when exposed to a high enough cisplatin concentration. This could indicate a mechanism of cisplatin resistance in these cells. LDRI alone or in combination with cisplatin did not result in significant cell cycle redistribution. Received: 22 December 1995 / Accepted: 28 September 1996     

Pulsed reduced dose-rate radiotherapy: a novel locoregional retreatment strategy for breast cancer recurrence in the previously irradiated chest wall,axilla, or supraclavicular region

Purpose Reirradiation of breast cancer locoregional recurrence (LRR) in the setting of prior post-mastectomy radiation poses a significant clinical challenge due to the high risk for severe toxicity. In an attempt to reduce these toxicities, we have developed pulsed reduced dose-rate radiotherapy (PRDR), a reirradiation technique in which a series of 0.2 Gy pulses separated by 3-min time intervals is delivered, creating an apparent dose rate of 0.0667 Gy/min. Here we describe our early experience with PRDR. Patients and methods We reirradiated 17 patients with LRR breast cancer to the chest wall, axilla, or supraclavicular region using PRDR. The median prior radiation dose was 60 Gy. We delivered a median PRDR dose of 54 Gy (range 40–66 Gy) in 1.8–2.0 Gy per fraction. Eight patients received concomitant low dose capecitabine for radiosensitization. The median treatment volume was 2,084 cm³ (range 843–7,881 cm³). Results At a median follow-up of 18 months (range 4–75 months) only 2 patients have had tumor failure in the treatment region. Estimated 2-year local control rate is 92%. Treatment was well tolerated with 4 patients experiencing grade 3 acute skin toxicity. Despite a median cumulative dose of 110 Gy (range 80–236 Gy), there has been only one grade 3 and one grade 4 late toxicity. Conclusions With a median follow-up of 18 months, PRDR appears to be an effective method to reirradiate large volumes of previously irradiated tissue in selected patients with locoregional chest wall, axilla, and supraclavicular recurrences. Presented in part at the 2007 ASCO/ASTRO/ASBS Breast Cancer Symposium, San Francisco, CA, USA, September 7–8, 2007.     

125I籽源持续照射对人肺癌细胞凋亡及DNA-PK蛋白表达的影响

目的探讨125I籽源低剂量率持续照射诱导人肺癌细胞凋亡以及对DNA依赖蛋白激酶复合物(DNA-PK)表达的影响.方法选择A549和NCI-H446两种辐射敏感性不同的人肺癌细胞株,采用9粒125I籽源组成的平面照射装置进行持续照射,吸收剂量为2 Gy.应用流式细胞术检测细胞凋亡和细胞周期的变化,免疫组化方法检测DNA-PKcs蛋白表达.结果125I籽源照射2 Gy后,A549和NCI-H446细胞的凋亡率分别为(11.14±1.12)%和(25.27±5.65)%,分别是对照组的5倍和8倍左右,其中NCI-H446细胞的凋亡率较A549细胞显著升高(P＜0.05),显示NCI-H446细胞更敏感.两种细胞的细胞周期均出现明显的G2/M期阻滞(P＜0.05).A549细胞自身蛋白表达显著高于NCI-H446细胞(P＜0.05).结论125I籽源低剂量率持续照射诱导肺癌细胞凋亡的效果与DNA-PK修复基因的状态和受照射后的变化密切相关.     

Radiothérapie flash à très haut débit de dose : point sur les avancées récentes

In the last decade, major advances in high precision treatment delivery and multimodal imaging allowed radiotherapy to be more efficient and better tolerated. However, the technology of the accelerators used to generate X-ray beams is outdated and does not allow to explore the tolerance to novel approaches in terms of dose-rate. We have been the first to propose a completely novel modality of irradiation, named Flash radiotherapy, in which the dose per pulse and the instant dose-rate during the pulses is 10³ to 10⁴ higher than those used in conventional facilities. Flash has been shown to spare mouse lung from radio-induced fibrosis, whilst leaving unchanged the antitumor potential. Other teams have shown that the advantage of Flash in terms of reduced complications extends to normal brain and intestinal crypts. The goal of this paper is to review the progress of studies dealing with very high dose-rate “Flash” irradiation, describe the theoretical models proposed to explain the underlying mechanisms, and discuss the prospects for clinical applications of this emerging technique.