Search

The breathing of gas mixtures containing 8-9% O2 during irradiation of tumors has been tested at several cancer clinics (in Russia and abroad) with the purpose of decreasing the morbidity of normal issues, thus providing the possibility to increase the dose of radiation. Previous experiments have demonstrated a broad spectrum of dose modification factors (DMF) for different normal tissues as well as for different transplanted tumors, with in general larger protection of normal tissues. The present study was designed to assess the radioprotective effect for mouse kidney of breathing a gas mixture containing 8% O2 by morphometry of histological specimens. Both kidneys were locally irradiated using single fractions (11-19 Gy in air and 13-19 Gy in hypoxia) or 5 fractions separated by 24 h intervals (25-35 Gy in air and 30-40 Gy in hypoxia). Histological examination was performed 8 and 10 months after treatment. The DMF for glomeruli damage (glomerulosclerosis, ecstatic capillaries, hemorrhage) was in the range 1.25-1.29. Tubular damage showed a DMF of 1.28-1.37. Using the endpoint of development of interstitial tissue in the cortex a DMF of 1.32-1.37 was found after a single treatment, and 1.48 after fractionated irradiation. The radioprotective effect for arteriolar lesions was lower than measured using the above endpoints, namely 1.13-1.15 after single and 1.16-1.18 after fractionated irradiation. It was shown previously on groups of animals treated in the same manner that the DMF was between 1.24-1.26 when renal damage was assessed by hematocrit measurements, between 1.32-1.28 when it was evaluated by urination frequency, and 1.23-1.27 when kidney wet and dry weights were used as end-points. All these data witness that breathing 8% oxygen increases the tolerance of kidney function with a DMF above 1.2. The impact of low protection of arterioli on renal function in the late period after radiotherapy needs additional study.

In experiments with Chinese hamster cells and Ehrlich ascites tumor cells it has been shown that a decrease in intracellular pH from 7.0 to 6.0, produced by 0.1 M phosphate buffer, ameliorates the radiation injury to cells (DMF = 1.35) with respect to their clonogenic capacity and induction of chromosome aberrations. The rate of repair of DNA single-strand breaks, within the pH range under study, is invariable.

The effect of gas hypoxic mixture, containing 8% of O2 (GHM-8), on the ability of cell precursors of haemopoietic stroma (which form colonies (clones) of fibroblasts (CFU-F) in a culture, and are present in the bone marrow of adult rats) to repair potentially lethal and sublethal radiation damages has been investigated. The recovery of CFU-F from potentially lethal damages, that was studied after their delayed survival in a culture following irradiation of animals, proceeds at nearly the same rate in cells irradiated both in the air and in hypoxic conditions (GHM-8). Fractionated irradiation reduces the radioprotective effect of GHM-8 for CFU-F, particularly for the radioresistant subpopulation; the ability of CFU-F to recover from sublethal radiation damages decreases.

The ability of cell precursors of the haemopoietic stroma (CFU-F), that are present in the bone marrow of adult rats, to recover from potentially lethal and sublethal radiation damages has been investigated. The highest reparability, with respect to potentially lethal damages, is displayed by the most radioresistant CFU-F population, that forms loose colonies (clones) in a culture; the slope of the dose-response curve, not the extrapolation number, changes, and heterogeneity of the CFU-F population is observed. The results obtained confirm the presence of heterogeneity in the population of CFU-F, that was revealed in studying their radiosensitivity by the formation of dense and loose fibroblast colonies in a culture.

A radioprotective effect of hypoxia was studied in kidney radiation. The use of hypoxic respiratory mixture containing 8% oxygen (the normal content is 21%) enhances kidney resistance to local single and fractionated irradiation. Determination of renal activity of succinate dehydrogenase, lactate dehydrogenase, acid and alkaline phosphatase and urinary N-acetyl-beta-D-glucosaminidase, gamma-glutamyl transferase, alkaline phosphatase, lactate dehydrogenase is recommended as tests for kidney radiation damage.

A comparative study was made on the survival rate of cell-precursors of haemopoietic stroma, that form, in a rat bone marrow culture, colonies (clones) of fibroblasts (CFU-F) after gamma-irradiation of animals in the air or in a gas hypoxic mixture, containing 8% of O2 (GHM-8). Irradiation in GHM-8 was shown to increase the survival rate of CFU-F by 1.7 times (as compared to exposure in the air) as estimated by the total number of colonies that are formed in a culture; the radioprotective effect of GHM-8 was more pronounced for CFU-F which form dense colonies: DMF for dense and loose clones was 2.4 and 1.6 respectively.

The radioprotective action of hypoxia in local irradiation of kidneys was studied. The experiments were carried out on hybrid mice (CBA x C57Bl) exposed to local X-ray irradiation through a lead diaphragm matched to the kidneys. In the experimental group the animals breathed in gaseous mixture with 8% of oxygen prior to and during irradiation. 20-36 weeks after irradiation the functions of glomerular and juxtaglomerular systems, as well as mass of native and dried kidneys were studied in the animals. It is shown that hypoxia efficiently protects kidneys against irradiation and permits increasing the supplied dose of radiation at least by 25%. High-efficient protection is retained when passing from single to fractionated irradiation.

The protective effect of hypoxic gas mixture containing 8% of oxygen (HGM-8) has been studied in long terms after local single and fractional X-ray irradiation of the kidney in mice. Some criteria of injury shown that hypoxia protects the kidneys against irradiation, changes in irradiation dose constituting 1.25-1.33. When passing from single irradiation to five-fold daily one, the protective effect of hypoxia does not fall significantly.

Combined radiotherapy of patients with cervical carcinoma of stages IIb and IIIb was conducted. Hypoxia (8.0-8.5% of O2 in the respiratory mixture) was used in microfractionated (2 Gy) irradiation of metastatic spreading zones. When irradiating under conditions of hypoxia, the number of fractions was brought up to 28 as compared to 20 in control. Despite a 40%-increase of the dose, seriousness of radiation reactions and remote injuries remained at the same level. It is found that patients endure well the respiratory mixture for 6 min. necessary for irradiation.

The method of intestinal "microcolonies" was used to study the radioprotective effect of a gas mixture, containing 8% of O2, on mice subjected to single and fractionated (5 fractions for 30 min) irradiation. The protective effect was indicated by a decreased slope of dose curves of the stem cell injury; the extrapolation number decreased simultaneously. So the values of dose modifying factors (DMF) were higher, when calculated by D0 ratio (where they amounted to 1.76 and 1.39 for single and fractionated exposure respectively), than those determined by equally effective doses (1.19 and 1.26 for single and fractionated effects respectively, which corresponded to LD50/4 when calculated at lg N = 1.9). It is suggested that the radiation response of certain stem cell populations of intestinal epithelium are different: this is attributed to different degrees of hypoxia in cells and to different directions of the hypoxia effects on the injury and the ability of postirradiation repair.

The protective action of a hypoxic gaseous mixture, containing 8% of oxygen was studied in a long term after local single and fractionated irradiation. A degree of protection of all morphofunctional structures of the kidney, evaluated by different criteria, was approximately the same (1.25-1.33). Dose fractionation into 5 fractions caused no considerable changes in DMF of hypoxia.

Radiation therapy is widely used in pediatric oncology. Its use emphasizes the problems of the protection of growing tissues and organs. The paper is concerned with the problem of effective distribution of an ionizing radiation dose delivered to a locally advanced tumor in children. Analysis of the literature and authors' data show that the growing organs of a child are 2-2.5-fold more sensitive than the same organs of an adult. Besides some organs and tissues at various ages of a child possess a various degree of maturity. Therefore it is proposed that small single doses (0.6-1 Gy) that can be delivered 2-3 times a day, should be used in pediatric oncology. A scheme of dynamic irradiation of radiosensitive and resistant tumors of children was prepared and tested under clinical conditions.

The biological effect of 211At alpha-particles has been investigated using the Chinese hamster fibroblasts and Ehrlich carcinoma cells growth in vitro. The mean energy of 211At alpha-particles is 6.8 MeV, LET in tissue is 70-160 keV/microns; the half-life period of decomposition of 211At is 7.2 h. The end-points used were a decrease in the mitotic activity, an elevation of the number of degenerating cells, cell with chromosome aberrations and the cell survival. The RBE of alpha-particles in comparison with 60Co gamma-rays is close to 3.

It is shown that such substances as gutimine, antizol and mexamine increases the resistance of animals to short-term breathing of gas mixtures containing 6 and 5% oxygen. Even if some of them decrease the degree of radioprotective effect of hypoxia, they afford the possibility to safe use of breathing mixtures with lower oxygen content than endured by intact animals, with the resulting increase in radioprotection. Thus the antihypoxic substances can be tested during hypoxiradiotherapy of human tumors.

A clinical investigation of the tolerance of a short-term (15-30 min) normobaric gaseous hypoxia caused by the inhalation of mixtures containing 7.4-8.2% O2 was conducted. Cerebral and liver hemodynamics, function of the cardiovascular system, some biochemical and hematological indicators were studied in 20 healthy volunteers and 18 cancer patients. It was noted that breathing with this mixture was worse tolerated than with that containing 10% O2, however no stable functional changes in the human body were observed. In the authors' opinion, the gaseous mixture containing 8% O2 can be used in radiation therapy of cancer patients for the protection of normal tissues.

Breathing with gas mixture containing 6-8% of oxygen during whole-body and large-field irradiation of mice diminishes the radiation-induced life-span shortening (DMF = 2.2) and decreases the degree of canescence (DMF = 1.5), the frequency and severity of nephro- and cardiosclerosis (DMF = 1.5), and the probability of occurrence of pleura and pericardium edemas provoked by cardiopulmonary insufficiency (DMF = 1.4). The fact that hypoxic hypoxia retains its high radioprotective efficiency in relation to the delayed effects of radiation is important for radiotherapy of tumors.

The paper represents a comparative analysis of hypoxiradiotherapy of 202 patients with malignant tumors of different sites. A significant decrease (a 3.5-fold) in the number of severe local radiation reactions was noted in hypoxiradiotherapy of cancer of the esophagus, pancreas and metastases of seminoma to the retroperitoneal lymph nodes. A decrease in the number and intensity of general radiation reactions and the absence of pyo-inflammatory complications after radical operations were noted in preoperative large fractionated hypoxiradiotherapy of colon and lung cancer. The general number of radiation reactions was 12% less in hypoxiradiotherapy. Tumor regression after hypoxiradiotherapy did not slow down. Complete or considerable tumor resorption after irradiation against a background of gaseous hypoxia was noted in 74 +/- 7% of the patients and in 65 +/- 7% after radiotherapy alone. Hypoxiradiotherapy alone or before operation should be widely introduced into clinical practice of cancer dispensaries or radiological departments.