A five-field conformal technique with three-dimensional radiation therapy treatment planning (3-DRTP) has been shown to permit better definition of the target volume for lung cancer, while minimizing the normal tissue volume receiving greater than 50% of the target dose. In an initial study to confirm the safety of conventional doses, we used the five-field conformal 3-DRTP technique. We then used the technique in a second study, enhancing the therapeutic index in a series of 42 patients, as well as to evaluate feasibility, survival outcome, and treatment toxicity. Forty-two consecutive patients with nonsmall-cell lung carcinoma (NSCLC) were evaluated during the years 1993-1997. The median age was 60 years (range 34-80). The median radiation therapy (RT) dose to the gross tumor volume was 6,300 cGy (range 5,000-6,840 cGy) delivered over 6 to 6.5 weeks in 180-275 cGy daily fractions, 5 days per week. There were three patients who received a split course treatment of 5,500 cGy in 20 fractions, delivering 275 cGy daily with a 2-week break built into the treatment course after 10 fractions. The stages of disease were II in 2%, IIIA in 40%, IIIB in 42.9%, and recurrent disease in 14.3% of the patients. The mean tumor volume was 324.14 cc (range 88.3-773.7 cc); 57.1% of the patients received combined chemoradiotherapy, while the others were treated with radiation therapy alone. Of the 42 patients, 7 were excluded from the final analysis because of diagnosis of distant metastasis during treatment. Two of the patients had their histology reinterpreted as being other than NSCLC, 2 patients did not complete RT at the time of analysis, and 1 patient voluntarily discontinued treatment because of progressive deterioration. Median follow-up was 11.2 months (range 3-32.5 months). Survival for patients with Stage III disease was 70.2% at 1 year and 51.5% at 2 years, with median survival not yet reached. Local control for the entire series was 23.3+/-11.4% at 2 years. However, for Stage III patients, local control was 50% at 1 year and 30% at 2 years. Patients who received concurrent chemotherapy had significantly improved survival (P = 0.002) and local control (P = 0.004), compared with RT alone. Late esophageal toxicity of > or =Grade 3 occurred in 14.1+/-9.3% of patients (3 of 20) receiving combined chemoradiotherapy, but in none of the 15 patients treated with RT alone. Pulmonary toxicity limited to Grades 1-2 occurred in 6.8% of the patients, and none developed > or =Grade 3 pulmonary toxicity. Patients with locally advanced NSCLC, who commonly have tumor volumes in excess of 200 cc, presenta challenge for adequate dose delivery without significant toxicity. Our five-field conformal 3-DRTP technique, which incorporates treatment planning by dose/volume histogram (DVH) was associated with minimal toxicity and may facilitate dose escalation to the gross tumor.
Optimal treatment for Hodgkin's disease during childhood is unknown. We report the treatment outcome of patients with Hodgkin's disease <13 years of age seen at the American University of Beirut Medical Center (AUBMC) between 1980 and 1996. A retrospective review of the medical records of 24 children treated for HD at AUBMC was performed. Treatment consisted of chemotherapy alone (n = 15) or chemotherapy plus involved field radiotherapy (n = 9). Chemotherapy consisted of COPP, ABVD, or alternating cycles of each for a total of 6 to 12 cycles, depending on clinical and radiological response; three patients received MOPP. Five patients in the chemotherapy group had clinical stage (CS) I and II and 10 had CS III disease. In the combined modality group, eight patients had CS I and II and one had CS IV disease. At a median follow-up of 5 years, the event-free survival (EFS) for the combined modality group was 100% and the overall survival (OS) 100%. For the chemotherapy alone group, the EFS was 56% and the OS was 79%. Four patients (27%) in the chemotherapy alone group who had Stage IIIB disease relapsed. Mean time to relapse was 4.3 years. In our experience, six cycles of COPP or (COPP plus ABVD) alone were suboptimal for the treatment of Stage IIIB Hodgkin's disease patients, especially those with involvement of lower abdominal nodes (III2B), extensive pulmonary disease, or mixed cellularity histology. Radiation therapy or additional chemotherapy courses are required for these patients.
Paraaortic nodal irradiation (PAI) was thought to be useful in the treatment of cervical cancer, but its clinical application has been limited by a relatively high morbidity. To reduce this morbidity, we routinely applied the four-field technique in PAI. To clarify its efficacy, clinical data were retrospectively analyzed. Ninety-seven patients with cervical cancer, who received a minimum 40 Gy of paraaortic irradiation between 1976 and 1994, were enrolled in the analysis. The patients were prescribed PAI using four-field portals with 10 MV photons (mean 50.4 Gy, range 40-70 Gy). The 5-year cause-specific survival rate was 32.2%. As for sequelae determined using the French-Italian glossary, G1a/G2a of stomach and duodenum developed in 26.8/1.0%, G2b of small bowel in 3.1%, G1b of nonspecific abdominal symptoms and/or signs in 12.4%, and G2 of bone in 3.1%. The operative history group had a slightly larger incidence of gastrointestinal complications than those without operative history, but the difference was not statistically significant. Application of four-field portals in PAI was useful, with acceptably low toxicity and successful compliance for moderate-to-high dose irradiation. This suggests that PAI may greatly contribute to the improvement of the therapeutic outcome of cervical carcinoma.
The goal of this study was to compare, with a human tumor xenograft, two different strategies for increasing tumor response to fractionated irradiation, namely, oxygenating the hypoxic tumor cells with carbogen and nicotinamide, or killing these cells with the hypoxic cytotoxin, tirapazamine (TPZ). We used the human hypopharyngeal squamous cell carcinoma cell line FaDu implanted in immune-deficient SCID mice and assessed its response to radiation by cell survival and by growth delay. The tumors were irradiated either once or twice daily with 2 or 2.5 Gy/fraction with either TPZ (0.08 mmol/kg) or nicotinamide (1,000 mg/kg) with carbogen breathing. We also tested the effect of giving TPZ on alternate days, or daily during the first half of the course, the second half, or for the whole course of radiation. We found that adding TPZ or nicotinamide with carbogen to the fractionated radiation regimen enhanced the response of the human xenograft. The enhancement was somewhat greater (though not significantly so) for TPZ, especially when given with each radiation dose. In conclusion, adding TPZ, or nicotinamide plus carbogen, to fractionated irradiation enhanced the response of this human tumor xenograft to fractionated irradiation. Consistent with theoretical modeling, there was a greater enhancement of the radiation response of the tumor when TPZ was given with each radiation dose than when given with only half of the radiation doses.
The genetic determinants for most breast cancer cases remain elusive. However, a mutation in a tumor suppressor gene, such as p53, BRCA1, BRCA2, or ATM, has been determined to be one mechanism of breast carcinogenesis. It has been established that inherited mutations in p53, BRCA1, and BRCA2 significantly contribute to breast cancer risk, although the importance of an inherited ATM mutation is controversial. Sporadic mutations in p53 are also common in breast cancer cells. The precise deficiencies that result from these genetic mutations have yet to be fully described. Although the functions of these genes are different, they are all involved in the maintenance of genomic stability after DNA damage. Mutations that impair the function of these four genes may adversely affect the manner in which DNA damage is processed. It is likely that the risk of breast cancer development is increased through this mechanism. In this article, we review the relevancy of p53, BRCA1, BRCA2, and ATM mutations to breast cancer development, and review the in vitro, in vivo, and clinical data exploring the mechanisms by which these mutations affect genomic integrity and DNA damage repair.
Advanced squamous cell carcinomas of the head and neck are difficult to control despite optimal surgery, radiotherapy and/or chemotherapy, and the tumors are usually not immunogenic. Because of the anatomic accessibility of the tumors, local adoptive immunotherapy of these tumors is feasible and may interact with radiotherapy to retard tumor growth. It is hypothesized that antigens released from tumor cells injured by radiation may stimulate, in the presence of interleukin-2, an enhanced immunocytodestruction of live tumor cells by adoptively transferred lymphokine activated killer cells and recruited tumor cytotoxic cells. DBA/2 mice were injected subcutaneously with 5 x 10(5) syngeneic squamous cell carcinoma cells in the thigh and the resulting tumors were treated for two weeks with daily peritumoral injections of interleukin-2 (1,000 International Units) or saline, four radiation treatments of 625 cGy each, and four peritumoral injections of 10(7) lymphokine activated killer cells. The results suggested that radiotherapy combined with peritumoral injection of lymphokine activated killer cells and interleukin-2 resulted in a significant reduction (P < 0.01) of tumor size whereas radiation alone, at the same dose, failed to produce a significant effect. Such results may have direct clinical application in enhancing the response of tumors to radiotherapy and in reducing the incidence of tumor recurrence.
The endothelial cell glycoprotein, thrombomodulin (TM), is an important physiological anticoagulant. TM is downregulated and released from the cell membrane into the circulation by ionizing radiation and during inflammation. The present study measured plasma TM in 17 patients before, during, and after radiation therapy of lung cancer: nine patients developed radiation pneumonitis, whereas eight matched patients did not. Plasma TM did not change significantly in patients who developed radiation pneumonitis. In contrast, patients who did not develop pneumonitis exhibited a moderate, but statistically significant, decrease in plasma TM antigen during the initial 1-2 weeks, with complete normalization towards the end of treatment. Our study suggests that decreased release of TM during the early phase of radiation therapy may be associated with reduced pulmonary toxicity. The use of plasma TM as a marker of pulmonary toxicity needs further study.
The purpose of this study was to evaluate the probability and extent of response to radiation therapy in patients with chemotherapy-resistant intermediate grade non-Hodgkin's lymphoma. Thirty-five patients with chemotherapy-resistant non-Hodgkin's lymphoma received local radiation therapy after initial treatment with at least six cycles of systemic chemotherapy. There were 17 men and 18 women in our study. Ages ranged from 15 to 68 years, median age was 42 years. Chemotherapy resistance was defined as relapse after initial chemotherapy (11 patients) or failure to achieve complete remission (partial response in 18 patients, stable disease in 1 patient, and disease progression in 5 patients). Radiation doses were between 1,980–5,040 cGy (median dose of 3,200 cGy). Treatment outcome was evaluated with respect to any subsequent relapse either within or outside the irradiated region. The 2-year actuarial survival was 65%. The cumulative incidence of isolated local failure and any local failure at 2 years were 33% and 54%, respectively. Tumors that responded to initial chemotherapy had a better local control probability than tumors that did not respond. The 2-year actuarial local failure rates for these two groups were 51% and 83%, respectively (P = 0.01). There was a trend for improved local control with radiation doses ≥3,960 cGy, suggesting the presence of a dose–control relationship. The rate of disease progression within an irradiated region in patients with intermediate grade non-Hodgkin's lymphoma that relapsed after or failed to respond completely to full course chemotherapy was substantially higher than the historical in-field failure rates when radiation therapy was used as the sole modality of treatment. Prior response to initial chemotherapy was a predicting factor for local control following radiation therapy. Radiat. Oncol. Invest. 7:186–191, 1999. © 1999 Wiley-Liss, Inc.
To determine if there is a subgroup of patients with pretreatment PSA ≥ 20 ng/ml with a favorable outcome after external beam radiation therapy. We analyzed retrospectively treatment outcomes of 129 patients with pretreatment PSA ≥ 20ng/ml treated in our department from 2/88–8/94. Median patient age was 70 years (range 51–89 years). Tumor stage was T1/T2ab in 68, T2c/T3 in 61 patients. Initial Gleason grade was < 7 in 82 and ≥ 7 in 47 patients. Median PSA was 35 ng/ml (mean 45 ng/ml, range 20–191 ng/ml). Ninety-seven patients received four-field conformal external beam radiation therapy. No patient received surgery or hormonal therapy prior to treatment. Median central axis dose was 73 Gy (range 68–79 Gy). Covariates considered in univariate and multivariate analyses included central axis dose, pretreatment PSA, presence of perineural invasion, Gleason score, palpable tumor stage and patient age. bNED failure was defined as a PSA ≥ 1.5 and rising on two consecutive determinations. Median follow up was 50 months (range 3–100 months). Overall bNED control for the entire patient population was 22% at five years. Of the covariates analyzed, dose (P < 0.01), stage (P < 0.01), Gleason Score (P < 0.01), and the presence of PNI (P = 0.01) were significant on multivariate analysis. Based on these results, patients could be stratified into two distinct groups. Group I consisted of 19 patients with favorable features including T1/T2ab disease, Gleason Score 2–6, no perineural invasion treated to a dose > 73 Gy to the central axis. Patients in Group II had at least one of the above poor prognostic features or were treated to central axis doses < 73 Gy. The bNED control was significantly higher for patients in Group I than those in Group II (58% vs. 23%, P = 0.0027). There appears to be a favorable subgroup of patients with PSA ≥ 20 ng/ml where treating to doses over 73 Gy to the central axis is warranted (four-year bNED rate of 58%). However, because of the small patient numbers, these results will need to be validated with longer follow up. Radiat. Oncol. Invest. 7:106–110, 1999. © 1999 Wiley-Liss, Inc.
Sarcoidosis is a chronic, multisystemic disorder of unknown etiology. The incidence of central nervous system involvement is as high as 5%. Although steroids have been the cardinal treatment for sarcoidosis, many patients become symptomatically unresponsive to them. Other patients may suffer from glucose intolerance, cataracts, and obesity, which are adverse effects of high-dose steroids. Various reports in the literature suggest that some chemotherapeutic agents and/or radiation may be useful in these situations. We present three patients with neurosarcoidosis who were treated with radiation at a single institution. We also review previous reports on radiation-treated neurosarcoid patients. While the results vary, some patients clearly derive symptomatic benefits from low-dose radiation. Since the side effects of low-dose cranial irradiation are minimal, it may be prudent to use radiation therapy for patients who are refractory to steroids or who suffer adversely from high-dose steroids.
Malignant gliomas remain refractory to intensive radiotherapy and cellular hypoxia enhances clinical radioresistance. Under hypoxic conditions, the benzotriazine di-N-oxide (3-amino-1,2,4-benzotriazine 1,4-dioxide) (tirapazamine) is reduced to yield a free-radical intermediate that results in DNA damage and cellular death. For extracranial xenografts, tirapazamine treatments have shown promise. We therefore incorporated tirapazamine into the synthetic, biodegradable polymer, measured the release, and tested the efficacy both alone and in combination with external beam radiotherapy in the treatment of experimental intracranial human malignant glioma xenografts. The [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) (PCPP:SA ratio 20:80)] polymer was synthesized. The PCPP:SA polymer and solid tirapazamine were combined to yield proportions of 20% or 30% (wt/wt). Polymer discs (3 × 2 mm) (10 mg) were incubated (PBS, 37°C), and the proportion of the drug released vs. time was recorded. Male nu/nu nude mice were anesthetized and received intracranial injections of 2 × 105 U251 human malignant glioma cells. For single intraperitoneal (i.p.) drug and/or external radiation treatments, groups of mice had i.p. 0.3 mmol/kg tirapazamine, 5 Gy cranial irradiation, or combined treatments on day 8 after inoculation. For fractionated drug and radiation treatments, mice had i.p. 0.15 mmol/kg tirapazamine, 5 Gy radiation, or combined treatments on days 8 and 9 after inoculation. For intracranial (i.c.) polymer treatments, mice had craniectomies and intracranial placement of polymer discs at the site of cellular inoculation. The maximally tolerated percentage loading of tirapazamine in the polymer disc was determined. On day 7 after inoculation, groups of mice had i.c. empty or 3% tirapazamine alone or combined with radiation (5 Gy × 2 doses) or combined with i.p. drug (0.15 mmol/kg × 2 doses on days 8 and 9). Survival was recorded. Polymers showed controlled, protracted in vitro release for over 100 days. The 5 Gy × 1 treatment resulted in improved survival; 28.5 ± 3.7 days (P = 0.01 vs. controls), while the single i.p. 0.3 mmol/kg tirapazamine treatment, 17.5 ± 1.9 days (P = NS) and combined treatments; 21.5 ± 5.0 days (P = NS) were not different. The fractionated treatments: 5 Gy × 2, i.p. 0.15 mmol/kg tirapazamine × 2 and the combined treatments resulted in improved survival: 44.5 ± 3.9 (P < 0.001), 24.5 ± 2.3 (P = 0.05) and 50.0 ± 6.0 (P < 0.001), respectively. Survival after intracranial empty polymer was 16.5 ± 3.0 days and increased to 31.0 ± 3.0 (P = 0.003) days when combined with the 5 Gy × 2 treatment. The survival after the polymer bearing 3% tirapazamine alone vs. combined with radiation was not different. The combined 3% tirapazamine polymer, i.p. tirapazamine, and radiation treatments resulted in both early deaths and the highest long-term survivorship. The basis for potential toxicity is discussed. We conclude that implantable biodegradable polymers provide controlled intracranial release for treatment of experimental glioma. For treatment of malignant gliomas, the combination of continuous polymer-mediated delivery and fractionated systemic delivery of tirapazamine with external beam radiotherapy warrants further exploration. Radiat. Oncol. Invest. 7:218–230, 1999. © 1999 Wiley-Liss, Inc.
This article discusses recent advances in basic research that alter the view of the pathogenesis of radiation myelopathy and summarizes the available data from developmental neurobiology and preclinical studies on demyelinating diseases. These studies have produced interesting insights into oligodendrocyte development, intercellular signaling pathways, and myelination processes. Current findings suggest that administration of cytokines as platelet-derived growth factor and basic fibroblast growth factor could increase proliferation of oligodendrocyte progenitors, enhance their differentiation, upregulate synthesis of myelin constituents, and promote myelin regeneration in the adult central nervous system (CNS). Other compounds might also be able to modulate the progression of pathogenic processes that lead to myelopathy. In addition, several possible biological prevention or treatment strategies, for example stimulation of endogenous cellular regeneration and glial cell transplantation, are discussed. Rationally designed animal experiments pursuing such strategies could further elucidate the pathogenesis of radiation-induced CNS damage. Radiat. Oncol. Invest. 7:193–203, 1999. © 1999 Wiley-Liss, Inc.
This study was designed to evaluate the combination of docetaxel (Taxotere) and carboplatin for radiopotentiation in vitro. H460 human lung carcinoma cells were treated with docetaxel (or paclitaxel) for 1 h and rinsed. After 24 h, the cells were treated with carboplatin for 1 h, irradiated, and colony forming ability was assesed. Using various doses of docetaxel with 100 microM carboplatin, the dose enhancement ratio (D.E.R.) for drugs only was 1.26. When 25 nM docetaxel was used with various doses of radiation, the radiation D.E.R. was 1.41. With all three agents combined, and after normalization for combined drug effects, the radiation D.E.R. was 1.55. Similar values were obtained using paclitaxel with these agents. Significant redistribution of cells into the radiosensitive G2/M phase was observed using a dose of paclitaxel (750 nM), which also caused radiation enhancement. However, an equally cytotoxic dose of docetaxel (25 nM) did not result in any cell cycle redistribution; this phenomenon was only observed at higher doses. This study shows that the combination of docetaxel and carboplatin enhance the effects of radiation in vitro more effectively than either drug seperately. In addition, our data show that the mechanism of radiopotentiation by docetaxel probably does not involve a G2/M block in H460 cells.
This phase II study was designed to utilize conformal radiation therapy with cisplatin and oral etoposide in patients with stage III or locally recurrent non-small-cell lung cancer to determine tolerance and toxicity of therapy. From April 1992-February 1996, 18 patients with pathologically confirmed stage IIIA, IIIB, or locally recurrent non-small-cell lung cancer (NSCLC) were entered on study. Metastatic workup included a CT scan of the thorax and upper abdomen as well as a bone scan. Chemotherapy consisted of IV cisplatin (100 mg/m2) with IV etoposide (25 mg/m2) on day 1; oral etoposide was given (50 mg/m2) days 2-14. Using three-dimensional planning, 40-45 Gy were delivered to the clinical target volume, followed by a boost to the gross tumor volume for a total of 70 Gy. Patients with recurrent disease received 40-50 Gy in total. Eighteen patients were enrolled: 16 patients were treated with curative intent and were evaluable for outcome. Two patients were treated for locally recurrent NSCLC and were not included in the outcome analysis. Stages included IIIA (44%) and stage IIIB (54%). Forty-four percent had T3/4 tumors, and 69% had N2/3 disease. Overall survival at 1 year was 64%, while 2-year overall survival was 50%. Distant metastasis-free survival at 1 year was 67%, and at 2 years 60%. The 1-year chest progression-free survival was 57%, and at 2 years 50%. Sixty-three percent required hospitalization for dehydration or neutropenia. Fifty-six percent developed leukopenia (<1,000 cells/microl) sometime during the therapy. We conclude that concurrent cisplatin and oral etoposide with conformal radiation therapy provide encouraging results in stage III lung cancer. The major toxicities of this therapy included leukopenia, thrombocytopenia, and mucosal esophagitis. Local progression of disease continues to be a problem with the current doses given. Future studies should evaluate dose escalation of radiation therapy with limited volumes, utilizing conformal radiation and chemotherapy to improve local control and potentially impact upon distant metastases.
Using a series of human bladder cancer cell lines and an immortalised normal ureteral cell line, radiosensitivities measured by three different methods after a single dose of X-radiation are compared. Clear differences between cell survival curves obtained using the clonogenic, microtetrazoline (MTT) and sulforhodamine B (SRB) assays are shown. The most sensitive of the assays investigated was the clonogenic assay. The MTT and SRB assays were found to be relatively insensitive especially at lower radiation levels, suggesting that these assays may not be suitable for predicting therapeutic dose schedules in vivo, but will be important for investigating radio-sensitivity in cell lines with very low plating efficiences. Each assay discriminated between a range of sensitivities in the cell lines examined, and with some minor differences, the ordering of sensitivities using the three assays was similar. Possible explanations for the differences between results obtained with the three assays are discussed. Radiat. Oncol. Invest. 7:77–85, 1999. © 1999 Wiley-Liss, Inc.
To study the efficacy and safety of relatively low-dosed reactor fission neutron therapy (RENT) at the research reactor of the Technical University Munich, we treated 33 superficial lesions of 20 patients with advanced malignant melanoma by neutron beam alone (n = 22), mixed neutron/electron beam (n = 5), or by neutron beam after incomplete surgery (n = 6). Median tumor volume was 17.0 cm3. Median dose for neutron beam alone was 8.0 Gy and for mixed beam 3.0 Gy n + 45.3 Gy e-. Local tumor response, local control time, survival and treatment related toxicity were followed prospectively over a time period of 52 months. Overall response rate (CR;PR) after neutron beam alone and mixed beam therapy was 64% (CR: 36%) and 100% (CR: 60%), respectively. Observed differences between complete (CR) and incomplete (PR, NC) responding lesions were as follows: median tumor volume: 2.0 vs. 51.5 cm3, local control time: 13.3 vs. 3.7 months, median survival: 19.8 vs. 9.0 months. No severe acute or late sequelae could be observed. In conclusion, low-dosed RENT is an effective and well tolerated palliative treatment of superficial malignant melanoma utilizing the biologic advantage of diminished cellular repair capacity. Because melanoma lesions of small size (< or = 6 cm3) tend to respond completely, neutron beam should be performed at an early stage.
Prognostic relevance of cell proliferation markers was evaluated in 27 glioma patients. By 1) flow cytometry (FCM), i.e., S-phase fraction (SPF), and BrdUrd-labeling index (LIfcm); 2) immunohistochemistry (IHC), i.e., BrdUrd-labeling index (LIihc) and MIB-1 immunoreactivity (MIB-1 LIihc); and 3) histologic examination, i.e., the presence or absence of cells in mitoses, were assessed. A longer local progression free survival (LPFS) was significantly associated with low SPF, low LIfcm, and low MIB-1 LIihc. For LIihc, no significant association was found. LIfcm appeared to be a more promising prognosticator than MIB-1 LIihc. In comparison with this marker, the presence or absence of mitotic figures appeared to be an even stronger prognosticator. Prognostic significance of LIfcm appeared to be of importance in low-grade gliomas. The number of patients in our study is limited. Our findings were: 1) the presence or absence of cells in mitoses (M-phase activity) appeared to be of more prognostic significance than LIfcm (S-phase activity) and MIB-1 LIihc (non-G0-phase activity); 2) of the tested experimental cell proliferation markers, LIfcm appeared to be of more prognostic significance than MIB-1 LIihc, SPF, and LIihc; and 3) LIfcm is likely to be an important prognosticator in low-grade gliomas and is, therefore, not definitive and only of potential interest.
The central nervous system injury that can result after radiotherapy has been suggested to involve induced gene expression and cytokine production. We have previously shown that irradiation of primary cultures of rat astrocytes results in the activation of NF kappa B. To determine whether such an effect also occurs in vivo, NF kappa B activity was analyzed in the cerebral cortex of the rat brain after whole body irradiation. After a single dose of 15 Gy, NF kappa B activity was increased by 2 h postirradiation, returning to unirradiated levels by 8 hours. The increase was dose-dependent beginning at 2 Gy and continuing to at least 22.5 Gy. NF kappa B activity in the irradiated cortex was not accompanied by I kappa B alpha degradation. When 7.5 Gy was delivered 24 h before the 15 Gy, the increase in NF kappa B activity after 15 Gy was significantly reduced. These results suggest that an initial exposure to radiation induced a refractory period in the brain during which the susceptibility of NF kappa B to activation by subsequent irradiation was significantly reduced. This period of reduced sensitivity to radiation was also apparent for the induction of the NF kappa B-regulated cytokines IL-1 beta, IL-6, and TNF alpha.
Intermediate grade non-Hodgkin's lymphoma (IGNHL) is generally considered a radiosensitive tumor that can be controlled with moderate radiation doses. Cell-survival curves of cell lines derived from IGNHL have been typically described to exhibit small or no shoulder, implying inability to accumulate or repair sublethal radiation damage. We characterize in this report the clonogenic radiation survival curves of two human IGNHL cell lines, WSU-DLCL2 and SK-DHL2B, established from patients who expired after having exhibited chemotherapy resistance of their tumors. The cells were irradiated with 60Co radiation at a dose rate of 85-100 cGy/min and cell survival data were analyzed according to the linear quadratic model. The alpha/beta values for WSU-DLCL2 and SK-DHL2B cells are 2 and 8.6, respectively. The corresponding SF2 are 0.42 and 0.35, respectively. Both cell lines are able to repair radiation-induced sublethal damage. These data indicate that these cells are only moderately radiosensitive.
