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Current and potential shortfalls in the number of radiation scientists stand in sharp contrast to the emerging scientific opportunities and the need for new knowledge to address issues of cancer survivorship and radiological and nuclear terrorism. In response to these challenges, workshops organized by the Radiation Research Program (RRP), National Cancer Institute (NCI) (Radiat. Res. 157, 204-223, 2002; Radiat. Res. 159, 812-834, 2003), and National Institute of Allergy and Infectious Diseases (NIAID) (Nature, 421, 787, 2003) have engaged experts from a range of federal agencies, academia and industry. This workshop, Education and Training for Radiation Scientists, addressed the need to establish a sustainable pool of expertise and talent for a wide range of activities and careers related to radiation biology, oncology and epidemiology. Although fundamental radiation chemistry and physics are also critical to radiation sciences, this workshop did not address workforce needs in these areas. The recommendations include: (1) Establish a National Council of Radiation Sciences to develop a strategy for increasing the number of radiation scientists. The strategy includes NIH training grants, interagency cooperation, interinstitutional collaboration among universities, and active involvement of all stakeholders. (2) Create new and expanded training programs with sustained funding. These may take the form of regional Centers of Excellence for Radiation Sciences. (3) Continue and broaden educational efforts of the American Society for Therapeutic Radiology and Oncology (ASTRO), the American Association for Cancer Research (AACR), the Radiological Society of North America (RSNA), and the Radiation Research Society (RRS). (4) Foster education and training in the radiation sciences for the range of career opportunities including radiation oncology, radiation biology, radiation epidemiology, radiation safety, health/government policy, and industrial research. (5) Educate other scientists and the general public on the quantitative, basic, molecular, translational and applied aspects of radiation sciences.

The interaction between 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and radiation was investigated in two different mouse tumor models and a normal mouse tissue. C3H mouse mammary carcinomas transplanted in the feet of CDF1 mice and KHT mouse sarcomas growing in the leg muscles of C3H/HeJ mice were used. DMXAA was dissolved in saline and injected intraperitoneally. Tumors were irradiated locally in nonanesthetized mice, and response was assessed using tumor growth for the C3H mammary carcinoma and in vivo/in vitro clonogenic cell survival for the KHT sarcoma. DMXAA alone had an antitumor effect in both tumor types, but only at doses above 15 mg/kg. DMXAA also enhanced radiation damage, and again there was a threshold dose. No enhancement was seen in the C3H mammary carcinoma at 10 mg/kg and below, while in the KHT sarcoma, doses above 15 mg/kg were necessary. This enhancement of radiation damage was also dependent on the sequence of and interval between the treatments with DMXAA and radiation. Combining radiation with DMXAA at the maximum tolerated dose (i.e., the highest dose that could be injected without causing any lethality) of either 20 mg/kg (CDF1 mice) or 17.5 mg/kg (C3H/HeJ mice) gave an additive response when the two agents were administered simultaneously. Even greater antitumor effects were achieved when DMXAA was administered 1-3 h after irradiation. However, when administration of DMXAA preceded irradiation, the effect was similar to that seen for radiation alone, suggesting that appropriate timing is essential to maximize the utility of this agent. When such conditions were met, DMXAA was found to increase the tumor response significantly in the absence of an enhancement of radiation damage in normal skin, thus giving rise to therapeutic gain.

Combinations of single and multiple doses of adriamycin and radiation were studied in EMT-6/Ro tumor-bearing BALB/cKa mice. The response to these chemotherapy-radiotherapy treatments was determined using a tumor growth delay assay. The single-dose interaction between adriamycin and radiation was assessed using an isoeffect analysis and was found to be additive for both a 2- and 120-hr interval between agents when changes in tumor size were accounted for. When a single dose, two equal doses, or multiple daily doses of adriamycin (all to the same total dose) were combined with a course of ten 200-rad fractions given in 12 days, the resultant tumor growth delays also were in keeping with an additive response between the two treatment modalities. However, in combination with fractionated radiotherapy, a large single dose of adriamycin was more effective than concurrent small daily adriamycin exposures.

The lungs of 2 to 3-month-old female C3H/HeJ and 6-month-old male LAF1 mice were locally irradiated with graded doses of radiation ranging from 900 to 1800 rad. The patterns of animal details for times up to 60 weeks after irradiation were recorded. Over this period mice in all the irradiated groups continued to die. However, the onset of animal deaths was dose dependent such that lethality occurred earlier after the higher radiation doses. Whereas mice receiving large radiation doses started to die by 75-100 days post-treatment, few or no animal deaths occurred in those groups receiving the lowest doses until 200-300 days after irradiation. At 180 and 420 days postirradiation animal lethality dose-response curves were constructed; these were found to be similar in shape (sigmoid), but at the later time the calculated LD/sub 50/ values were approx.300-400 rad lower than those determined using the 180-day post-treatment end point. Histological examination of the irradiated lungs indicated that the animal deaths occurring by 180 days were associated with radiation pneumonitis while the late deaths were associated with pulmonary fibrosis. The addition of the radiation sensitizer misonidazole prior to lung irradiation did not significantly enhance pulmonary toxicity at either end point.

The response of KHT sarcoma cells growing as microscopic lung colonies to radiation treatments given with or without the hypoxic cell sensitizer misonidazole was evaluated using an in vivo to in vitro clonogenic cell survival assay. For comparison the survival curve for well-oxygenated KHT sarcoma cells was obtained by excising the colony-containing lungs from their hosts, dispersing the lung colonies to a single-cell suspension, and irradiating the cells in vitro. By increasing the time between excision and irradiation from 2 to 24 hr it was possible to demonstrate for these lung colony-derived cells an intercellular contact effect denoted by a reduction in the shoulder of the cell survival curve over this period. In vivo radiation treatments were given at two different lung colony volumes, 0.7 and 1.8 mm/sup 3/. The addition of misonidazole prior to irradiation sensitized the hypoxic cell compartment at both colony sizes and reduced the final slope in each case to the same degree (factor of approx. 1.8). At a cell survival level of 10/sup -3/ this resulted in an enhancement ratio of approx. 1.2 to approx. 1.5. By comparison this dose of misonidazole did not enhance the radiation-induced pulmonary toxicity determined using a LD/sub 50/180/ assay.

The arterial pH and partial pressures of oxygen (PaO/sub 2/) and carbon dioxide (PaCO/sub 2/) were evaluated in LAF1 mice 15 and 38 weeks after localized irradiation of the animals' thoraxes. Graded radiation doses of 900 to 1200 rad were administered. These doses resulted in 0 to 100% lethality by 26 weeks (180 days) after irradiation. At 15 weeks after treatment mice receiving radiation doses which would subsequently result in lethality (by 180 days) exhibited significant reductions in their PaO/sub 2/ and elevations in their PaCO/sub 2/ values, respectively. However, there was no clear dose-response relationship between blood gas values and radiation dose, which may reflect the animals' ability to compensate for their poor blood gas exchange by an increased breathing frequency. At 38 weeks after irradiation the blood gas values were abnormal in mice from groups which had normal blood gas values at Week 15 (and no fatalities by Week 26) but in which animal deaths had occurred between Weeks 26 and 38. These data therfore indicated (i) that abnormal blood gas values occurred in the mice prior to fatalities resulting from the acute radiation pneumonitis syndrome and (ii) that mice surviving the initial radiation pneumonitis phase could still more » succumb to progressive pulmonary toxicity which was reflected by the increasing levels of animal lethality and altered blood gas tensions at the later times. « less