Radiotherapy and the potential exploitation of bystander effects.

Radiation-induced bystander effects are the subject of intense investigation in radiation protection. The effects predominate at low doses and have been discussed mainly in terms of the impact on low-dose risk assessment. Possible therapeutic implications have been alluded to, but not discussed in any detail. The purpose of this review was to consider bystander biology in areas of major importance or interest in radiotherapy. These include consideration of radiation-induced bystander effects during the cell cycle, under hypoxic conditions, when fractionated therapy modalities are used, or when combined radiochemotherapy is given. Also discussed are individual variations in toxicity of bystander factors and normal tissue "collateral" damage. The importance of considering the tumor in the context of the organ, and even the organism that supports it, is also discussed. Direct clinical radiotherapy studies that consider bystander effects are not in the public domain at the time of writing, but many in vitro studies are available that are relevant; some preliminary animal data have also been published. Because radiation-induced bystander effects appear to challenge many of the central assumptions that underlie radiotherapy practice, it is important to consider what unexplored treatment avenues might result from a consideration of these effects. The final part of this paper is devoted to this point.

A comparison of actions of neuropeptide Y (NPY) agonists and antagonists at NPY Y1 and Y2 receptors in anaesthetized rats.

The pancreatic polypeptide family includes three members, neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP), with sequence homology between members and species varying from approximately 50 to 80%. Some of these peptides were compared in the mammalian cardiovascular system for activity mediated by actions on pre- (Y2) and post-junctional (Y1) NPY receptors. NPY and PYY, with sequence homology of 67% have similar actions on Y1 and Y2 receptors. Rat pancreatic polypeptide (rPP) with sequence homology of approximately 50% is inactive at both. This study reports that the chimeric peptide, hPP1-11/NPY12-36 and the truncated peptide NPY2-36 show similar activity to NPY mediated through both receptor types in vivo, while salmon PYY (sPYY), with 81% homology to NPY, has improved potency at both receptor subtypes. NPY3-36 has equal activity with NPY on actions mediated through Y2 receptors, but significantly reduced activity mediated through Y1 receptors. Two NPY antagonists were also examined: PYX2 was inactive in vivo and 1229U91 showed potent, long-lasting activity on Y1 receptor-mediated effects.

Activity of centrally truncated analogues of neuropeptide Y at Y1 and Y2 receptor subtypes in vivo.

Neuropeptide Y (NPY), a sympathetic cotransmitter, has both prejunctional and postjunctional actions in the cardiovascular system. In anaesthetized rats, the bioassay system used here, NPY attenuates cardiac vagal action (a prejunctional or Y2 action) and increases blood pressure (a postjunctional or Y1 action). Several NPY analogues were tested against NPY. In these, centrally located amino acid sequences of various lengths were removed, and replaced with simpler 'spacers'. As the parent NPY molecule is considered to exist in a U-shape, these central truncations were intended to shorten the depth of the U, while maintaining the integrity of its two ends. The centrally truncated NPY analogues examined here retain activity at both receptor subtypes in vivo. These findings indicate that the U-shape of the parent molecule probably exists to assist stability, but that receptor binding occurs through sequences closer to the termini.

The role of radiation therapy in Graves' ophthalmopathy.

Graves' ophthalmopathy can occur in 25-30% of patients with hyperthyroidism. This condition can result in serious visual disturbance and disfigurement. The treatment options for symptomatic disease are oral corticosteroids or orbital irradiation. Ten patients with Graves' ophthalmopathy were treated with external beam radiotherapy at Saint Lukes Hospital from March 1991 to February 1994. Eight of these patients had excellent response with minimal morbidity. We believe that orbital radiotherapy is effective and well tolerated, and should replace corticosteroid therapy as the initial treatment modality in these patients.

A case control study of malignant melanoma.

A case-control study of 100 cases of malignant melanoma (MM) and 100 matched controls has been completed. The male:female ratio of patients with MM was 1:2.4, which is similar to that found in other European studies and the mean age was 49.1 years (range 19-82 years). Significant differences were seen between cases and controls for area of residence and social class, more cases than controls came from rural areas (P = 0.007) and cases were of higher social class than controls (P = 0.003) and had attained a higher level of education (P = 0.005). Phenotypic differences between cases and controls were also observed, namely cases were more likely to have light coloured (blue/grey/green) eyes (P = 0.003) and to have had fair/red hair at age 20 (P = 0.004). Cases were also more likely than controls to dislike exposure to hot sun (P = 0.008) to report sunburning easily (P = 0.001) and to have experienced episodes of sunburn with blistering more frequently than controls (P = 0.01). History of longterm exposure to ultraviolet radiation (UV) through working outdoors, leisure activities, living abroad in sunny climates, or sun holidays was similar between cases and controls. This study supports evidence from elsewhere that episodes of acute sunburn in susceptible individuals increase risk of MM and that longterm regular exposure to UV which is important in non-melanoma skin cancer does not play a major role in the development of MM.

Comparison of triamcinolone acetonide with indomethacin in the treatment of acute gouty arthritis.

Twenty-seven patients presenting within 5 days of the onset of crystalline proven acute gout were prospectively treated with either indomethacin 50 mg tid or triamcinolone acetonide 60 mg intramuscularly. Patients with contraindications to therapy with indomethacin received triamcinolone acetonide. They were followed for 30 days. Resolution of all symptoms occurred at an average of 8 days for the indomethacin patients and 7 days in the triamcinolone patients. No side effects or episodes of rebound gout attacks occurred with the triamcinolone acetonide therapy. It is as safe and effective as indomethacin in the treatment of acute gout, and is particularly useful in patients with contraindications to therapy with nonsteroidal antiinflammatory drugs.

Risk factors for non-melanoma skin cancer.

A case control study of risk factors for non-melanoma skin cancer (NMSC) was carried out on 396 patients and individually age and sex-matched controls. Cases were significantly more likely than controls to have had a rural domicile (P = 0.007), light eye colour (P = 0.004) a tendency to develop sunburn very easily (P less than 0.05) and a family history of NMSC (P less than 0.001). Other indices of exposure or sensitivity to ultraviolet (UV) radiation did not differ significantly between the two groups. It is suggested that while the role of UV radiation in the aetiology of NMSC is not in doubt, other factors not yet identified must also be important, at least among the Irish population.

The effect of ethanol on the radiation response of CHO-K1 cells.

The radiobiological response of CHO-K1 cells treated with ethanol is described. Both radioprotective and radiosensitising effects were found, depending on the duration of exposure before irradiation and the number of cells exposed. In spite of effects of ethanol on the shoulder of the primary survival curve, split-dose recovery was not affected. The radiobiological effect of alcohols is normally attributed either to radical scavenging or to oxidation. The findings presented here do not support either of these mechanisms.

Radiobiologic response of CHO-KI cells treated with vitamin A.

Treatment of CHO-KI cells with vitamin A altered their response to subsequent gamma irradiation. In general longterm preincubation with low doses of the vitamin caused a relative increase in the number of cells surviving a given radiation dose. The effect resulted in an increase in the D0 of the survival curve. Long or short term exposure to high concentrations of the vitamin caused a decrease in the number of surviving cells leading to a decrease in the extrapolation number of the survival curve. Recovery of cells from radiation damage, assessed using the split dose technique, was also impaired by vitamin A pretreatment. A mechanism involving repair of potentially lethal damage may explain the protective effect of vitamin A since this was highly dependent on the cell density of cultures at the time of irradiation. However, in view of the data showing that the vitamin A concentrations necessary to alter the radiation survival curve shoulder caused a significant release of sialic acid into the medium, a mechanism involving membrane stability may account for both the reduction in repair/recovery capacity of the treated cells and the radioprotective effect.

Glucose analogues alter the response of CHO-KI cells to gamma irradiation.

Pretreatment of CHO-KI cells with 2-deoxy-D-glucose or L-glucose, two glucose analogues, reduces their survival if subsequently exposed to 60Co irradiation. The reduction in survival is constant irrespective of the time the cells are in contact with the analogues before irradiation and occurred even when cells were irradiated 6 hours after plating, suggesting that cell cycle effects are probably not involved. Interestingly, split-dose recovery was not affected to the expected degree, despite a reduction in the extrapolation number of the primary curve. It is suggested that interference with energy production from glucose is responsible for the reduced capacity of cells to survive the irradiation.

Long-term culture of differentiated human thyroid tissue.

Human thyroid cells obtained during surgery have been maintained in monolayer culture for at least 2 months and without loss of morphological or functional differentiation. Samples as small as 0.5 g could be cultured but best results were obtained with samples of 5-10 g. The technique used was developed in this laboratory for sheep tissue and was applicable without significant modification to human tissue. It depends on the complete absence of media changes at any time during the culture period. Energy substrates are replenished by the addition of concentrated glucose solutions to the existing media at carefully monitored intervals. Differences in both morphology and function could be observed between cultures derived from patients with different diseases, suggesting that the technique could have predictive value.