Short-term systemic effects of head and neck irradiation.

BACKGROUND: Various localized side effects which accompany head and neck irradiation [IR] have been widely reported. However, systemic side effects/have been only sparsely reported in the short-term period post-IR in an animal model. The potential modulatory role of zinc-desferrioxamine [Zn-DFO] on IR effects was examined because of its known ability to protect against the damage induced by free radicals which are mediated by redox-active metal ions. MATERIALS AND METHODS: We used three groups of male Wistar rats: a] sham irradiated controls b] irradiated [15 Gy]; c] irradiated and treated with Zn-DFO [20 mg/k] one hour prior to IR. During the first two weeks post-IR, body weight and food and water intake were monitored daily, while lymphocytes, segmented neutrophils and white blood cells [WBC] were counted at 10 minutes 4 and 16 hours and 1, 3, 7 and 14 days. Serum TNF-a and IL-6 were obtained at 10 minutes and 7 days. RESULTS: On day 7 post-IR, body weight and food and water intake were reduced by 84% 96% and 85% [p < 0.01], respectively in the above mentioned three groups of rats. This resulted in the death of 22% of the animals and was followed by recovery towards the end of the second week. At all time points examined between 10 minutes and 14 days, WBC were reduced by 52-74%. On the 7th day, Zn-DFO demonstrated a 33% protective effect against the WBC reduction. At 10 mins post-IR, a 84.8-fold [p < 0.01] increase of TNF-alpha, but not IL-6, was noted. However, on the 7th day post-IR, both TNF-alpha and IL-6 levels were increased by 48.5-fold and 102.5-fold [0.01], respectively. CONCLUSION: The data presented delineate the severe short-term systemic effects of head and neck IR in a rat model. We suggest considering the severe cachectic and immunocompromised status of the animals when performing various short-term studies with this model. During this period nutritional and immunological support for the examined animals is recommended. Further evaluation of the underlying mechanisms of IR-induced leukopenia and cachexia in animals and the possible implications for humans is warranted.

Investigation of the comparative toxicity of 5-FU bolus versus 5-FU continuous infusion circadian chemotherapy with concurrent radiation therapy in locally advanced rectal cancer.

PURPOSE: To compare the relative toxicities of bolus versus infusional 5-FU chemotherapy administrated concurrently during external beam irradiation in patients with locally advanced rectal cancer following surgical extirpation. METHODS: A total of 26 eligible patients were retrospectively identified as having been treated for rectal adenocarcinoma at the Stratton VAMC between 1989 and 1997. A comparative analysis of treatment dose intensities, treatment delays and toxicities in these patients was performed. RESULTS: Significantly less WBC toxicity was observed in the patients receiving infusional 5-FU chemotherapy. The other toxicities, with the exception of skin toxicity, were generally less frequent in the 5-FU infusional group. When the toxicities were corrected for 5-FU dose intensity, to yield toxicity per mg of 5-FU, statistically significant differences were found for hematological toxicity (WBC and platelets), and for gastrointestinal toxicity (frequency and severity of diarrhea and weight loss). The majority of patients receiving infusional 5-FU therapy were treated using a circadian pattern of treatment peaking around the time of the radiation therapy. Patients receiving infusional 5-FU were able to tolerate over twice the dose intensity as those receiving bolus administration. Local recurrence rate in all patients was 3.8% comparing favorably to other reported studies. Distant recurrence frequency was also acceptable at 34.6% for the group. CONCLUSION: Infusional 5-FU chemotherapy compared with bolus therapy during pelvic radiation minimizes toxicity to the patient while maximizing the dose of 5-FU that can be delivered. As infusional 5-FU therapy during radiation has previously been shown to increase disease free duration and survival, infusional 5-FU should be considered as an acceptable standard of care to prevent local recurrence of rectal adenocarcinoma following its resection. Shaping this infusional 5-FU chemotherapy within the day so that most of the daily dose is delivered around the time of the radiation therapy may further modify the toxic therapeutic ratio of combined modality therapy.

Reduced hematopoietic function and enhanced radiosensitivity of transforming growth factor-beta1 transgenic mice.

The cytokine transforming growth factor-beta1 (TGF-beta1) has been implicated in some tissue responses to radiation. Previous studies have demonstrated that exogenous TGF-beta1 increased the lethality of radiation in mice, but the effects of endogenous TGF-beta1 have not been investigated. To this end, we examined mice that are transgenic for active TGF-beta1 (Alb/TGF-beta1), over-expressed via an albumin promoter in the liver with resultant elevation of circulating levels of this cytokine. Alb/TGF-beta1 mice subjected to 8 Gy of total body irradiation at 3 or 5 weeks of age experienced significantly higher mortality than wild type age- and sex-matched controls by 1 to 2 weeks after irradiation. Alb/TGF-beta1 3 weeks of age also succumbed to 2 and 4 Gy of whole-body irradiation, while no mortality was observed in wild type mice. Four-week-old Alb/TGF-beta1 mice exhibited mild anemia and mild uremia. At one week after whole body irradiation with 2 Gy, 4-week-old Alb/TGF-beta1 mice had significantly reduced white blood cell counts, hematocrit, and platelet counts. Histopathologically, irradiated Alb/TGF-beta1 mice exhibited decreased bone marrow cellularity and decreased splenic extramedullary hematopoiesis. These results suggest that chronic over-expression of active TGF-beta1 is associated with increased radiosensitivity and that this effect may be mediated by increased sensitivity of bone marrow to the suppressive effects of radiation. Since TGF-beta1 levels can be greatly elevated in patients with certain tumors, these findings may be significant for radiotherapy. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 13-21 (2000). Published 2000 Wiley-Liss, Inc.

Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large-animal model.

Bone marrow transplantation (BMT) has considerable potential for the treatment of malignancies, hemoglobinopathies, and autoimmune diseases, as well as the induction of transplantation allograft tolerance. Toxicities associated with standard preparative regimens for bone marrow transplantation, however, make this approach unacceptable for all but the most severe of these clinical situations. Here, we demonstrate that stable mixed hematopoietic cell chimerism and donor-specific tolerance can be established in miniature swine, using a relatively mild, non-myeloablative preparative regimen. We conditioned recipient swine with whole-body and thymic irradiation, and we depleted their T-cells by CD3 immunotoxin-treatment. Infusion of either bone marrow cells or cytokine-mobilized peripheral blood stem cells from leukocyte antigen-matched animals resulted in stable mixed chimerism, as detected by flow cytometry in the peripheral blood, thymus, and bone marrow, without any clinical evidence of graft-versus-host disease (GvHD). Long-term acceptance of donor skin and consistent rejection of third-party skin indicated that the recipients had developed donor-specific tolerance.

Occupational exposure to high frequency electromagnetic fields and its effect on human immune parameters.

The present study recorded a considerable excess of recommended exposure limits in the vicinity of shortwave diathermy devices used for medical treatment of patients. Different kinds of field probes were used to measure electric and magnetic field strength and the whole body exposure of medical personnel operating shortwave, decimeter wave and microwave units was calculated. To investigate the influence of chronic exposure on the immune system of operators, blood was sampled from physiotherapists working at the above mentioned devices. Eighteen exposed and thirteen control persons, matched by sex and age, were examined. Total leucocyte and lymphocyte counts were performed and leucocytic subpopulations determined by flow cytometry and monoclonal antibodies against surface antigens. In addition, to quantify subpopulations of immunocompetent cells, the activity of lymphocytes was measured. Lymphocytes were stimulated by mitogen phytohemagglutinin and their proliferation measured by a flow cytometric method. No statistically significant differences between the control and exposed persons were found. In both study groups all immune parameters were within normal ranges.

Effects of glycyrrhizae and glycyrrhizic acid on cellular immunocompetence in low-dose gamma-ray irradiated mice.

BACKGROUND: For both animals and human beings, it is important to prevent damage from ionizing radiation and to restore immunocompetence following irradiation. The present study was conducted to investigate the effects of glycyrrhizae (GL) and glycyrrhetinic acid (GA) on cellular immunocompetence in low dose gamma-ray-irradiated mice. METHODS: Six- to 8-week-old ICR strain' Crl:CD-1-ICR (BR) strain male mice, bred in the Institute of Cancer Research, U.S.A., were chosen and divided into four groups. Group A was the normal control. Group B, the experimental control, received 1 Gy of whole body gamma-ray irradiation. Groups C and D, the experimental groups, were treated with 500 mg/kg of GL (orally) and 5 mg/kg body weight of GA (i.p.), respectively, once a day, 5 days a week for 2 weeks after gamma-irradiation. The tested mice were killed, at 6 different intervals to measure their leukocyte and differential counts. Cellular immunocompetence was measured by the 3H-thymidine uptake in each group. RESULTS: One gray of gamma-ray irradiation had evident inhibition on the leukocyte and differential counts and the cellular immunity of mice. GL and GA could help to restore the decreased leukocyte counts and the cellular immunocompetence in low dose gamma-irradiated mice. CONCLUSION: GL and GA could help to restore decreased leukocyte counts and the cellular immunocompetence in low-dose gamma-ray-irradiated mice.

Tolerance of half-body irradiation as systemic therapy for patients with locally advanced breast cancer.

BACKGROUND: Locally advanced breast cancer (LABC) is one of the main causes of cancer death among women in Bulgaria. In 1988, when this study started, there was still controversy about the role of chemotherapy in controlling systemic disease. There were encouraging results from the Radiation Therapy Oncology Group (RTOG) 82-06 study suggesting that half-body irradiation (HBI) should be used earlier in the disease course to prevent the development of metastases. There were many patients with LABC requiring treatment, but there was a problem with obtaining the drugs needed; they were expensive and not consistently available. PROCEDURE: Taking into account the medical contraindications to chemo-therapy treatment, its toxicity, and the possibility of chemoresistance, we initiated this study to look at the effects of HBI given as two fractions of 4 Gy to the upper and then lower parts of the body, after surgery and before local radiotherapy. RESULTS: The acute tolerance of this regimen in 36 patients with LABC was as good as it was in 4 additional LABC patients with M1 disease, and hematologic recovery was satisfactory. CONCLUSIONS: We conclude that systemic treatment with HBI is tolerable. It therefore may be a convenient and cost-effective treatment for LABC, although better treatments are still needed.

On the inhibitory activities of a new boron compound and ultrasound against the mouse ascites tumour.

The inhibitory effects of a new boron compound, dihydroxy (oxybiguanido) boron (III) hydrochloride monohydrate (HB), and ultrasound (US) of a frequency 25 kHz on the growth of ascites tumour in female Swiss mice were studied by monitoring the survival, weight of tumour-associated material, tumour cell count, serum alkaline phosphatase activity and the haematological parameters of the treated animals. 5-Fluorouracil (5-FU), a well-known anticancer agent, was used as positive control. While HB exhibited a very significant antitumour action, US alone produced a small but significant inhibitory effect. The combination of US with HB or 5-FU produced an extra antitumour action as compared to the actions of these chemicals used singly. The mechanisms of action of the new boron compound (HB) and US are discussed.

[The indices of the peripheral blood leukocytes in subjects working within a 30-kilometer area of the Chernobyl Atomic Electric Power Station and in the workers of a chemical plant]. / Pokazateli leikotsitov perifericheskoi krovi u lits, rabotaiushchikh v 30-kilometrovoi zone ChAES, i rabotnikov khimicheskogo predpriiatiia.

Changes in leukocytes are analyzed together with the pattern of leukogrammes, morphological and cytochemical parameters characterizing leukocytes of the peripheral blood in those persons working within the zone of radiation control and in workers of chemical plants. Criteria of high informative value have been established for identification of those groups of individuals running a risk for development of hematological pathology.

[Therapeutic effect of ultraviolet irradiation of autologous blood in early period of acute radiation sickness]. / Lechebnoe deistvie ul'ytafioletovogo oblucheniia autokrovi v rannie sroko ostroi luchevoi bolezni.

In experiments with dogs the acute radiation sickness was caused by common relatively uniform 3.5 Gy dose gamma-irradiation. Reinfusion of UV-irradiated autologous blood induced undoubted curative effect, which manifested itself in increased mean life, reduced mortality, more full restoring of blood-formation.

[Evaluation of radioprotective properties of a lipocarotenoid extract from mycelium of basidiomycetes during external irradiation]. / Otsenka radiozashchitnykh svoistv lipokarotinoidnogo ékstrakta iz mitseliia bazodial'nogo griba v usloviiakh vneshnego oblucheniia.

Radioprotective properties of LPC extract from mycelium of Basidiomycetes fungus at doses 12.0; 3.0 and 1.0 Gy of external irradiation were investigated. The extract of LPC at 2.5 mkg/ml concentration promoted the survival of animals (to 40%) and increased the average life at the lethal dose. At 1.0 Gy dose the use of extract resulted in restoration of radiosensitive organs weights, the number of blood leucocytes and some indexes of lipid peroxidation in blood plasma. The extract has produced some effect on the amount of spermatogenic cells in the testis.

Protective effect of swerchirin on hematopoiesis in 60Co-irradiated mice.

The protective effect of swerchirin, a purified xanthone isolated from whole herb of Swertia calycina Franch. on hematopoiesis was investigated. A significant increase of colony formation in the spleen (colony forming unit in spleen = CFU-S) of mice irradiated with 550 rad 60Co gamma-rays and an enhancement of proliferative response of BMC to rmGM-CSF treated with swerchirin [10 mg/kg, 3 time/wk, i.p.] was observed. After introduction of swerchirin [10 mg/kg, i.p. once] a significant increase in the number of peripheral blood leukocytes and a rise in the serum of colony stimulating factor (CSF) were also confirmed. The types of CSF in serum were M-CSF and other hematopoietic growth factors, which were confirmed using McAb of IL-3, GM-CSF and PcAb of M-CSF. These beneficial effects of swerchirin on hematopoiesis may be related to its activity inducing CSFs and other hematopoietic growth factors, and warrant further evaluation of its usefulness.

Difference in the effects of radioprotection between aerial and root parts of Lycium chinense.

Radiation protection from bone marrow death by consecutive injections of crude extracts from different parts of Lycium chinense (LC), root (LCR) and aerial part (LCA), before whole body X-irradiation was confirmed by tests with ICR strain mice. Both extracts were effective after intraperitoneal injection of a high dose, once a day, for seven consecutive days before irradiation. Based on the studies of endogenous hematopoietic spleen colony formation (CFUs), and the postirradiation behavior of hematograms and hematocrits, it was demonstrated that the LCR protects mice more effective when given in a dose of 500 mg/kg. Enhanced CFUs was found in the irradiation range of 4-8 Gy by various treatments. Recovery of leukocyte, erythrocyte and thrombocyte counts was significantly stimulated by the extract of LCR with 500 mg/kg administration. Stimulated recovery by the extract from the LCR was also observed in hematocrit. On the contrary, the extracts of both LCA and LCR did not markedly affect recovery of leukocyte, erythrocyte, thrombocyte counts and hematocrits by 250 mg/kg administration. It could be deduced that the uncertainly radioprotective action is induced by a possible process of enhanced regeneration of the hematopoietic stem cells due to either enhanced postirradiation repair or an increased proliferation of the hematopoietic stem cells under the suitable extract administration.

Metallothionein-I transgenic mice are not protected from gamma-radiation.

Metallothionein (MT) has been proposed to play a protective role against the toxic effects of free radicals and electrophiles, such as those produced by gamma-radiation. Therefore, this study was designed to determine whether MT-transgenic mice, which carry 56 copies of the MT-I transgene and have higher tissue MT concentrations, are resistant to the toxic effects of gamma-radiation. Mice were exposed to 137cesium radiation, and survival was followed for 30 days. At all doses (7-12 Gy) examined, no difference in the survival was observed between control and MT-transgenic mice. The average survival times between control and MT-transgenic mice were also similar. Leukocytes were decreased 78 +/- 7% and 75 +/- 11% in control and MT-transgenic mice respectively 5 days after radiation. Furthermore, MT-transgenic mice were also equally susceptible as control mice to the lethal toxic effects produced by cyclophosphamide (1.75 mmol/kg, i.p.). In summary, MT-I transgenic mice are not protected against the toxic effects produced by gamma-radiation or cyclophosphamide.

The utility of serial complete blood count monitoring in patients receiving radiation therapy for localized prostate cancer.

PURPOSE: It is standard practice in our department to monitor weekly complete blood counts (CBCs) in patients receiving definitive radiation therapy for prostate cancer. The clinical utility and cost effectiveness of this practice has not been analyzed. METHODS AND MATERIALS: The charts of all prostate cancer patients treated with radiation therapy between January 1994 and July 1996 at the Veterans Administration Hospital, Philadelphia, PA were reviewed. CBC values were available for 89 patients. Patients received a median dose of 68 Gy using a four-field box technique and megavoltage photons. Whole-pelvic radiotherapy followed by a conedown to the prostate was administered to 29 patients. Fifty-nine patients received radiation to the prostate alone or prostate and seminal vesicles. Fifty-seven patients received concurrent hormonal therapy which included luteinizing hormone-releasing hormone (LHRH) agonist, antiandrogens, or both. RESULTS: No patient experienced a drop in their hemoglobin, white blood cells (WBCs), or platelets below critical nadirs (defined as WBC < 2 counts x 1000/mm(3), hemoglobin < 8 g/dl, platelet < 50 counts x 1000/mm(3) 2 in WBCs. In the urban area surrounding the Philadelphia Veterans Administration Medical Center, the cost of obtaining a CBC is approximately $30. However, if staff time is considered, the cost of obtaining a weekly CBC during prostate cancer radiotherapy approached $400 per patient. CONCLUSION: These results suggest that weekly monitoring of CBCs in prostate cancer patients undergoing definitive radiotherapy may not be necessary. We recommend a baseline CBC be performed, and if normal, no other monitoring unless clinically indicated. This strategy would result in a cost savings approaching $30,000 per 100 treated patients. Further research on the cost effectiveness and utility of serial blood tests in patients receiving partial body radiation therapy is needed.

Radiotherapy, toxicity and dosimetry of copper-64-TETA-octreotide in tumor-bearing rats.

UNLABELLED: The efficacy of 64Cu [T1/2 = 12.7 hr; beta+ (0.655 MeV; 19%); beta- (0.573 MeV; 40%)] as a radioisotope for radiotherapy has been recently established. Here we demonstrate that 64Cu-1,4,8,11 -tetraazacyclotetradecane-N,N',N",N'''-tetraacetic acid (TETA)-octreotide, a somatostatin receptor ligand, inhibits the growth of CA20948 rat pancreatic tumors in Lewis rats at doses that cause minimal toxicity. METHODS: Tumor-bearing rats were administered a single 15 mCi (555 MBq) dose, a fractionated dose of 15 mCi given in 2-3 doses over 2-8 days, or control agents of buffer, unlabeled octreotide or 64Cu-labeled TETA. In certain experiments, blood was removed at times from 4-23 days post-treatment, and a complete blood count along with blood chemistry analyses were obtained. RESULTS: Tumor-growth inhibition was significantly greater in rats injected with a single 15 mCi dose than in rats injected with control agents (p < 0.05). Dose fractionation in two doses, either 1 or 2 days apart, induced significantly increased tumor-growth inhibition compared with rats given a single dose (p < 0.05). The only toxicity observed in treated rats was a decrease in the white blood cell count. This drop was more pronounced in rats treated with a single dose compared with those treated with a fractionated dose. Human absorbed doses of 64Cu-TETA-octreotide to normal organs were estimated from biodistribution data in Lewis rats, and these data indicate that radiotherapy with 64Cu-TETA-octreotide in humans would be feasible. CONCLUSION: Copper-64-TETA-octreotide is a promising radiopharmaceutical for targeted radiotherapy of somatostatin receptor-positive tumors.

[The natural resistance of the inhabitants of Kiev 10 years after the accident at the Chernobyl Atomic Electric Power Station]. / Sostoianie estestvennoi rezistentnosti zhitelei Kieva spustia desiat' let posle avarii na ChAES.

A study was made of the natural resistance status in inhabitants of Kiev over ten years after the Chernobyl power plant accident. The results obtained showed that small doses of ionizing radiation exert a negative effect on the body inducing morphological changes in leucocytes, lowering the blood absolute content of large granule-containing lymphocytes, causing decline in the level of natural killer activity, changes in leucocyte as well as lymphocyte counts. In inhabitants of Kiev, post-Chernobyl changes in the studied parameters-tend to get more pronounced with time.

Myelosuppressive changes from single or repeated doses of radioantibody therapy: effect of bone marrow transplantation, cytokines, and hematopoietic suppression.

Myelosuppression is the dose-limiting side effect of most forms of radioimmunotherapy (RAIT). Long-term leukopenia (4-8 weeks) has been documented from a single maximum tolerated dose (MTD) in experimental mice. Several methods for alleviating RAIT-induced marrow toxicity have been evaluated preclinically, including cytokine intervention, bone marrow transplantation (BMT), and hemoregulatory peptide administration. To improve the therapeutic potential of RAIT, multiple doses of radioantibody must be delivered. Maximizing the frequency of radioantibody administration is desirable. However, little is known about the myelotoxic effects of multiple cycles of RAIT. In the studies presented here we compared the magnitude of myelosuppression, the time of nadir, and the duration of toxicity associated with one or two MTDs of 1-131-MN-14 anti-carcinoembryonic antigen immunoglobulin G (250 microCi) administered to BALB/c mice 49 days apart, the shortest interval possible without producing lethality. Studies were conducted with radioantibody alone or with cytokines (interleukin-1/granulocyte-macrophage colony-stimulating factor), BMT, or Hp5b to determine whether bone marrow became more "brittle" after the first dose. Profiles of myelosuppression and recovery were monitored weekly for 7 weeks after each dose in both granulocyte and lymphocyte populations. The results demonstrated that granulocyte suppression was greater and of longer duration after the second dose of RAIT administered alone, with cytokines, or with BMT, but less severe with Hp5b. For example, in the RAIT + BMT treatment, the second dose resulted in an 87% loss of granulocytes, whereas a 30% loss occurred after the first dose. The nadir of toxicity lasted until days 21 to 28 after the second dose and until day 14 after the first dose. Lymphocyte suppression was of greater duration after the second cycle of RAIT alone or RAIT with BMT, plateauing at <50% of untreated levels between days 28 and 49, but was of shorter duration when RAIT was given with cytokines or Hp5b. The results are discussed in terms of 1) the radiosensitivity of each subpopulation, 2) the effects on progenitors and on stromal cells, 3) the benefits of increasing dose frequency vs. increasing dose intensity, and 4) the possibility of using preclinical data to optimize the frequency of dosing in patient trials.

Study of human neurovegetative and hematologic effects of environmental low-frequency (50-Hz) electromagnetic fields produced by transformers.

A survey of neurovegetative and hematologic disorders was conducted in a population (n = 13) exposed occupationally to environmental electromagnetic fields; the population was matched with 13 control subjects. The exposed subjects worked at least 8 h/d for 1-5 y in premises located above transformers and high-tension cables, and the subjects were submitted to low-frequency electromagnetic fields (i.e., 50 Hz) of 0.2 microT-6.6 microT. The subjects were matched with respect to socioeconomic category, sex, and age with a control population of subjects that worked in premises outside of the immediate vicinity of transformers or high-tension cables. The exposed population had a significant increase in degree of certain neurovegetative disorders (i.e., physical fatigue, psychical asthenia, lipothymia, decreased libido, melancholy, depressive tendency, and irritability). In addition, the population experienced a significant fall in total lymphocytes and CD4, CD3, and CD2 lymphocytes, as well as a rise in NK cells. Leukopenia and neutropenia were also observed in two persons permanently exposed to doses of 1.2-6.6 microT. The disorders disappeared when exposure stopped, and they reappeared on reexposure.