Tyrphostin AG 1024 modulates radiosensitivity in human breast cancer cells

Insulin-like growth factor-1 (IGF-1) plays an important growth-promoting effect by activating the PI3K/Akt signalling pathway, inhibiting apoptotic pathways and mediating mitogenic actions. Tyrphostin AG 1024, one selective inhibitor of IGF-1R, was used to evaluate effects on proliferation, radiosensitivity, and radiation-induced cell apoptosis in a human breast cancer cell line MCF-7. Exposure to Tyrphostin AG 1024 inhibited proliferation and induced apoptosis in a time-dependent manner, and the degree of growth inhibition for IC20 plus irradiation (4 Gy) was up to 50% compared to the control. Examination of Tyrphostin AG 1024 effects on radiation response demonstrated a marked enhancement in radiosensitivity and amplification of radiation-induced apoptosis. Western blot analysis indicated that Tyrphostin AG 1024-induced apoptosis was associated with a downregulation of expression of phospho-Akt1, increased expression of Bax, p53 and p21, and a decreased expression of bcl-2 expression, especially when combined with irradiation. To our knowledge, this is the first report showing that an IGF-1 inhibitor was able to markedly increase the response of tumour cells to ionizing radiation. These results suggest that Tyrphostin AG 1024 could be used as a potential therapeutic agent in combination with irradiation.   http://www.bjcancer.com © 2001 Cancer Research Campaig

Introducing a new ICRU report: Prescribing, recording and reporting electron beam therapy

The ICRU published several Reports about volumes and doses specifications for radiotherapy, such as the Report 29 (1978), devoted to photon and electron beam therapy. This report 29 becoming absolete, a new Report was published in 1993 for external photon beam radiotherapy, the Report 50, recommending new definitions and more accurate specifications. With electran beams specific problems are raised, and the ICRU considered suitable to prepare a special Report for them, to be published in the near future.The main features of the present draft are as follows:1.Volumes specifications in agreement with the ICRU Report 50,•Volumes to be determined before treatment planning: gross tumour volume (GTV), c1inical target volume (CTV), organs at risk volumes (OR).•Volume to be determined during treatment planning: Planning target volume (PTV).•Volumes resulting fram the treatment plan chosen: treatment volume (TV), irradiated volume (IV).In the future Report on electron beams, an additional volume is defined, the internal target volume (ITV) geometrical concept representing the volume en-compassing the c1inical target volume, taking into consideration margins due to the variations of the clinical target volume in position, shape an size. A similar concept has been extended to organs at risk, the planning organ at risk volume.2.Dose specificationThe general statements for photon beams apply:•dose at a reference point (ICRU point) situated at or near the center of the planning target volume and, when possible, near or on the central axis of the electron beam at the depth of the peak dose.•Minimal and maximal doses in the planning target volume•Dose delivered to the organs at risk•Additional information is recommended, when possible (e.g. DVH).With electron beams, the dose homogeneity expected within the PTV (± 5 to ± 10 %) requires an adaptation of the terapeutic range concept, such that the value of the isodose surface encompassing the PTV be situated between 85 % and 95 % of the reference dose. The peak absorbed dose on the beam axis should always been specified, even if it is different fram the reference dose.At last, as in Report 50, three levels of dose evaluation for reporting are considered, depending on the aim of the treatment and the data available

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer. © 1999 Cancer Research Campaig

Radiation doses to normal tissues and organs outside the target volume during radiotherapy

Public Health Codes more and more require that any information relevant to the estimation of the high doses delivered within the target volumes and low doses delivered outside should be recorded. In this context, the availability for each radiotherapy patient of the magnitude of the unavoidable low doses delivered outside the target-volumes becomes an important issue. However, to date, Treatment Planning Systems (TPS) are not designed for this issue. Therefore, we have developed a new version of the ISOgray TPS which can provide, in addition to the doses distributions in the fields, the magnitude of the doses to distant healthy tissues in the course of common radiotherapeutic procedures. Our strategy involves 3 modules: A library of adjustable whole-body patient models in treatment position which allows different patient anatomies to be simulated; A multi-sources beam model, which allows the description of the irradiation field to be extended to the whole body; A dose calculation engine producing the distributions of doses in the fields and in any organ outside. This paper describes the principles of the system and provides data on doses distributions to distant organs for various common radiotherapeutic procedures. At this stage of development, the agreement of measured and calculated doses reaches ±3% in the radiation field and is better than ±15% outside. In the case of a 17 years aged girl treated for Hodgkin's disease using two 6MV opposite photon beams, when a dose of 20 Gy was delivered to the target volume, outside the beam, the dose to the brain was 0.37 Gy (1.85% of the tumor dose), the kidney 0.06 Gy (0.30%) and the ovaries below 0.02 Gy (<0.1%). Although the development of our system is still in progress, these preliminary results are encouraging. Allowing the realization of whole-body dose evaluations for each patient in the course of radiation therapy treatment planning, our approach must provide relevant information required to meet the current requirements of patient radiation protection and radiation therapy benefit-risk management purposes. The systematic evaluation of low doses outside the radiation therapy fields creates new opportunities in quality assurance of radiation therapy and prospective studies of long-term risks of radiation modern radiotherapeutic procedures