Radiotherapy Oxygen Research Articles

Singlet Dioxygen ¹O₂, its Generation, Physico-Chemical Properties and its Possible Hormetic Behavior in Cancer Therapy

Singlet dioxygen 1O2 is one excited state among the three other possible spectroscopic states of molecular oxygen. Here, we first describe the use of published spectroscopic data and thermodynamic modeling based on irreversible entropy production. Such concepts are further applied to the synthesis of singlet dioxygen and its reactions with crucial biological molecules. In a last section, we suggest that singlet dioxygen and ozone may be responsible for the success of radiation therapy, that has been used to treat cancer successfully for over 120 years. Its precise mechanism of action remains controversial. We thus aim to clarify the role of singlet oxygen in radiotherapy and chemotherapy. A partial conversion of ionizing radiation in the body into thermal photons could be assumed. The antitumor effect may involve these thermal photons, such as the one delivered by red/infrared sources. Thermal photons (wavelengths of 635 nm and 1270 nm) convert triplet dioxygen into singlet dioxygen by changing the spin of its outer electrons. Despite its short half-life, Singlet dioxygen is responsible for the activation of multiple free radicals (such as hydrogen peroxide), which may target proteins and DNA, induce either apoptosis or oxidative phosphorylation. At moderate concentrations, thermodynamic data suggests that singlet dioxygen may readily react with water to form a potent pro-apoptotic molecule (ozone), thus decreasing cancer growth. However, at high concentration cytotoxic effects against all kind of cells occurs. This strongly suggests a non-linear hormetic behavior of singlet dioxygen. It is also proposed that cytotoxic chemotherapy induces the same free radicals that singlet dioxygen does. There are also other ways to enhance the production of singlet dioxygen, such as phototherapy using Methylene Blue for instance. As a source of reactive oxygen species (ROS), singlet oxygen could thus be a common agent active both in radiotherapy and chemotherapy. It is probable that the activity of radiation therapy and chemotherapy may be mediated by the conversion of triplet to singlet oxygen. This may explain the oxygen effect such as described in radiotherapy and chemotherapy.

Clinical studies of hypoxia modification in radiotherapy

Hypoxic modification has been the subject of investigations in clinical radiation oncology since the early 60s. To date, this has not yet resulted in a treatment that has been widely accepted. Logistics and technical difficulties limit the routine use of hyperbaric oxygen in radiotherapy. The nitroimidazoles have not gained general acceptance, initially because of their toxicity and later because of doubts about the effectiveness of the newer generation of less toxic drugs. Nevertheless, there is good evidence from these studies that improving clinical outcome by hypoxic modulation is an achievable goal. Newer approaches including combinations of radiotherapy with tirapazamine, erythropoietin, and carbogen and nicotinamide (ARCON) are currently in phase III trial. For these new strategies to be successful, it is important that the proper patient categories are selected. Various methods to assess tumor oxygenation are now becoming available in the clinic. These potential predictive assays must be incorporated and validated in current and future large-scale clinical trials. Modifiers that target other aspects of tumor biology may also have indirect effects on tumor oxygenation. These aspects require further study in preclinical and early clinical settings.

What have we learnt from hyperbaric oxygen?

The 15 randomised controlled clinical trials of hyperbaric oxygen in radiotherapy yielded three with highly significant benefit and six with useful margins not reaching statistical significance. The increase in tumour control was partly negated by an increase in normal tissue effect. Now simple carbogen breathing in animal tumour models has shown high efficiency and there is the potential for its use in man as a simple means of hypoxic cell radiosensitisation.

Perfluorochemical emulsions and hyperbaric oxygen in radiotherapy

Perfluorochemical emulsions and hyperbaric oxygen in radiotherapy

Hyperbaric oxygen: the Medical Research Council trials and their clinical significance

The clinical trials of the use of hyperbaric oxygen in radiotherapy conducted by the Medical Research Council's working party have shown that local cure and survival can be improved in head and neck and cervical cancer. Evidence for benefit has been presented in carcinoma of bronchus, but none has so far been found in carcinoma of the bladder. Although hyperbaric oxygen has produced increased effect upon normal tissues as well as upon tumour, a real improvement in therapeutic ratio appears to be present. The future use of hyperbaric oxygen in radiotherapy will depend upon a comparison of effectiveness with other methods now being tested to improve radiotherapy. The trials have yielded much fundamental and clinical data of general relevance in the radiotherapy of malignant disease.

Radiation induced bowel damage in rats treated under conditions of air or hyperbaric oxygen

The use of hyperbaric oxygen in radiotherapy will only result in an improved therapeutic ratio if the tumour is hypoxic and normal tissue well oxygenated, since hypoxic normal cells, if present, will also undergo an increased radiation response. When the abdomen is irradiated, acute or chronic bowel damage may occur. If either the normal mucosa or submucosal cells were normally hypoxic, an increased incidence of damage might be expected with hyperbaric oxygen. Some reports of hyperbaric abdominal irradiation in man suggest an increase in incidence of late bowel damage. An experimental model has been designed in which abdominal irradiation has been administered to rats under either conditions of air breathing or hyperbaric oxygen. Mortality at 12 days has been used as an assessment of mucosal damage, and late mortality to assess late bowel injury. No increase in early mortality was shown following hyperbaric irradiation, but late mortality was significantly increased in the hyperbaric group of animals. The significance of these findings and their relevance to the human situation is discussed.

Hyperbaric oxygen in radiotherapy of head and neck carcinoma: Interim report of a controlled clinical trial

A prospective controlled trial of hyperbaric oxygen in the radiotherapy of head and neck tumours is described, using a regime of 10 fractions in 3 weeks. Each patient is allocated at random to treatment in either air or oxygen after prescription of the tumour dose. Identical beam direction techniques are used in air and oxygen treatments. Higher survival rates, and significantly higher local tumour control rates have so far been observed in the oxygen compared with the air series, with no difference in complications. It is concluded that under the conditions of this trial, high-pressure oxygen is an effective adjuvant to radiotherapy.

High Pressure Oxygen in Radiotherapy

High Pressure Oxygen in Radiotherapy

Radiosensitivity of the human oxygenated cervical spinal cord based on analysis of 357 cases receiving 4 MeV x rays in hyperbaric oxygen.

The incidence is recorded of radiation-induced myelitis of the cervical cord in 357 patients receiving 4 MeV fractionated irradiation in hyperbaric oxygen (HPO) at 4 ATA. Radiation myelitis is a dose-dependent phenomenon showing “multihitness” of effect. It was analysed in terms of a cell survival model, assuming a D0=130 rads and extrapolation number m=2 for this tissue. The calculated risk of patients developing myelitis in HPO in terms of the percentage of affected patients (I) is given by the equation for N fractions of D rads to the spinal cord. An attempt has been made to compare these findings with reports in the literature of CNS damage following more conventional irradiation delivered in air, with a view to estimating relative radiosensitisation of this tissue by hyperbaric oxygen in radiotherapy. The incidence appears higher in HPO, but data reported for air treatments are insufficient for a more conclusive statement to be made.

Modification of tumor microcirculation as an adjunct to hyperbaric oxygen in radiotherapy.

There is convincing evidence in the medical literature that the failure of radiation to sterilize many cancers is related to an abnormal circulation leaving some cancer cells hypoxic, but viable. In cancer of the cervix, one of the few areas where tumor vessels can be observed, large tortuous surface vessels with a diameter greater than 50 microns have frequently been recorded (10). The space between these vessels is also greater than the distance oxygen, at normal tension, can diffuse through tissue (11). Attempts to reverse this situation by administration of oxygen under pressure during irradiation have not resulted in any spectacular increase in cure rate (13). The explanation of this may be in the fall of oxygen tension along the length of the tumor capillary (4). Because oxygen diffuses rapidly from the arterial end of the capillary, a reduction in flow rate of blood to a fourth of normal will nearly equalize the oxygen tension at the venous end of the capillary bed, although the arterial oxygen tension is increased twentyfold by administration of oxygen at 4 atmospheres. A diminution of flow rate in tumor capillaries could be expected for a number of reasons, including the large tortuous configuration of these vessels, irregular vessel lining which may consist only of tumor cells, and increased tissue pressure. Slowing of the flow rate from these causes may then result in an apparent increase in blood viscosity due to red cell aggregation or “sludging” (14). The critical oxygen tension is the minimal value in viable cancer cells, not the average, since only a few cell survivors will presumably result in clinical failure. As it appears that fairly simple physiologic measures, such as correction of anemia, may improve the radiation cure rate in squamous-cell cancer (5), we are presently investigating simple means of improving blood flow through the abnormal capillary bed of tumors, to see if this might augment the oxygen effect, whether this oxygen be under pressure or at the normal content and pressure of air. Unfortunately, the methods of study of blood flow in any capillary system (hemorheology) are still very limited. We have chosen to investigate two agents, dextran and heparin, using polarographic technics to determine change in tumor-oxygen tension and variation of “cure rates” in experimental squamous-cell cancer. The only agents studied to any considerable extent which might modify tumor blood flow are vasodilators. A report on these in human cervical cancer will be published elsewhere (1). Dextran, although designed as a blood volume expander, is proving useful in many conditions characterized by decreased blood flow and red cell aggregation.2 The pharmacological action depends on the molecular weight, and clinical dextran, with an average weight of 75,000 was used in this study. Lower molecular weights of 20 to 40,000 might be even more efficacious (2).

Radiation dose fractionation and high pressure oxygen in radiotherapy of the DBA mouse mammary carcinoma.

Radiobiological studies of the DBA mouse mammary carcinoma have shown that for single dose irradiation of 8 mm. diameter tumors the response is essentially the same for irradiations given under anoxia, air, O2 30 psi conditions. If, however, the irradiations are administered at 10 equal doses at 24 hour intervals, the ratio TCD50 anoxia/TCD50 O2 30 psi is 1.77, instead of approximately 1.08 for the single dose irradiation. This is further increased to approximately 2.7, when the radiation is administered at twice weekly instead of daily intervals. These results suggest that the effectiveness of high pressure oxygen in improving results of radiation therapy may be highly dependent on the dose fractionation schedule employed.

Beam direction in hyperbaric oxygen therapy.

In any trial designed to assess the value of high pressure oxygen in radiotherapy it is essential that overall treatment time, fractionation and the quality of field planning and treatment are as nearly as possible identical for both the hyperbaric and the control series. Therefore, we must strive to achieve a standard of beam direction inside the tank fully comparable in accuracy with present methods outside the tank, since it would be wrong to lower the standard of treatment for those patients treated as controls at atmospheric pressure. This paper describes preliminary attempts to develop a system of beam direction that fills these requirements when used in conjunction with any transparent high pressure oxygen tank, such as the Vickers tank shown in Fig. 5. The restrictions imposed by the presence of the pressure tank largely determine the general form of the beam direction system: (1) Early experience showed that most hyperbaric therapy patients tolerate full immobilisation by conventional plastic she...

Increased radiosensitivity of skin and normal tissues in high pressure oxygen.

INCREASED RADIOSENSITIVITY OF SKIN AND NORMAL TISSUES IN HIGH PRESSURE OXYGENH. A. S. VAN DEN BRENK, M.S., F.R.C.S., D.T.R.Audio Available | Share

The Place of Oxygen in Radiotherapy

Our experience following the treatment of 235 patients in high pressure oxygen, extending over ten years, are presented. The indications, technique and results are outlined. Considering the criteria of selection we feel confident that the use of high pressure oxygen has improved the results.

An experimental method for comparing treatments of intact malignant tumours in animals and its application to the use of oxygen in radiotherapy.

A technique was developed for growing transplantable malignant tumors in the subcutaneous tissue of the rat in such a way that they remain localized until they have grown to a suitable size for testing the effects of different treatments. The course of the tumors was followed in situ by daily measurement. Comparisons were made of the effects of single doses of 2000 rads and 4000 rads of 250-kv x rays under three different conditions of oxygenation of the tumor: with the tumor made anoxic by clamping the circulation; with the tumor aerated with its circulation intact and the rat breathing air at atmospheric pressure; and with the tumor oxygenated with the animal breathing oxygen at 4 atm pressure. The effect of 2000 rads given in air approximately equals that of 4000 rads to the anoxic tumor and the effect of 2000 rads in oxygen approximately equals that of 4000 rads in air. These results indicate that when the rat breathes air there are cells in the tumor protected from radiation injury by hypoxia and that after radiation in air such cells can regenerate the tumor and their radiosensitivity can be enhanced by the breathing of oxygen at high pressures. Themore » pathological basis of these conclusions suggests that they apply equally to many forms of human cancer. (auth)« less