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lumbar spine. The correlation was most striking in thefirst metatarsophalangeal joint. The findings suggestthat osteoarthrosis predisposes to pain in these joints.In the knees pain was common in the absence of radio-logical evidence of any type of arthritis, but loss of workwas related to the presence and severity of osteoarthrosis.Injury or a damp home did not seem to be responsiblefor the production of symptoms; and mental instability,particularly neurosis, produced no increase in the

complaint-rate. Obesity, on the other hand, was verydefinitely connected with symptoms. This inquiryestablishes clearly the statistical association of radio-

logical osteoarthrosis and symptoms, but it gives littleclue to the mechanism of production in these patients.Some evidence suggests that ligamentous sprains in

joints rendered unstable by the disease may be toblame.21 The injury producing the sprains may betrivial and forgotten by the patient. LLOYD-ROBERTS 22

suggested that traction on the contracted capsule of theosteoarthrosic hip was the main cause of pain in thatjoint. The pain which patients with osteoarthrosis

experience may be due, however, to the increased

vasciilarity of bone rather than to bony outgrowths orcapsular changes,23-25 and similar appearances have beennoted in gorillas.26 The good results of operations suchas intertrochanteric osteotomy for osteoarthrosis of the

hip may come not only from mechanical effects but alsofrom changes in blood-supply. PHILLIPS et a1.27 haveshown by phlebography of the femoral head and neckthat the relief of pain after intertrochanteric osteotomyis associated with a return to normal in the pattern ofvenous drainage.

Radiosensitisers

FAILURE to achieve a cure in cancer is seldom due torecurrence of the primary tumour: the cause is the

presence of disseminated disease at the time of firsttreatment. None the less, radiotherapy is oftenunsuccessful because the primary lesion has not beencompletely eradicated, and such patients might be

helped by radiosensitisers. To have any practical valuesensitisation must be selective; since the maximum dosethat can be given to the tumour is dictated by thetolerance of the surrounding tissue, nothing is gained ifall cells are sensitised to the same extent. Sensitiserswhich are taken up preferentially by cancer cells wouldsolve this problem; but so far success has not beencomplete.28 In radiobiology new methods of differentialsensitisation by chemical substances have been developed,but none is yet applicable in clinical practice.The well-known oxygen effect may be exploited with

chemical substances as well as by the use of high-pressure oxygen. Cells are more sensitive to X raysand other sparsely ionising radiations in an oxygenated

21. Kellgren, J. H. Clin. Sci. 1940, 4, 303.22. Lloyd-Roberts, G. C. J. Bone Jt Surg. 1953, 35B, 627.23. Trueta, J., Harrison, M. H. M. ibid. p. 442.24. Harrison, M. H. M., Schajowicz, F., Trueta, J. ibid. p. 598.25. Trueta, J. Lancet, 1956, i, 58.26. Stecher, R. M. Lab. Invest. 1958, 7, 445.27. Phillips, R. S., Bulmer, J., Hoyle, G., Davies, W. Upublished.28. Mitchell, J. S. Studies in Radiotherapeutics. Oxford, 1960.

environment than in an anoxic one. Raising the oxygenpressure during radiotherapy will sensitise viable cellsin an anoxic part of a tumour without altering theamount of damage done to critical healthy tissue, sincethese cannot be sensitised further by raising the oxygentension above the normal values. The unfavourabledifferential in radiosensitivity between the anoxictumour cells and the normally oxygenated cells can bereduced either by agents which protect oxygenatedcells but not anoxic cells or by radiosensitisers whichsensitise anoxic cells but not oxygenated cells. The

sulphydryl chemical protective agents-e.g., cysteineand cysteamine-have long been known 29 to exhibit thedesired selectivity; and in rats skin damage by localirradiation with X rays is reduced by cysteamine, whilethe radiation response of an anoxic sarcoma isunaffected.3° While in principle greater destruction oftumours can be obtained for the same amount of normaltissue damage, the toxicity of the protective agentsmakes their clinical use virtually impossible. Sulphydrylbinding agents-notably N-ethylmaleimide (N.E.M.) andiodoacetate-have the inverse effect in sensitisingcertain bacteria 31 to a greater extent under anoxia thanin air. The maximum concentration of these substancestolerated by mammalian cells is very much less thanthat needed to sensitise bacteria, which are relativelyresistant to sulphydryl poisons, and the degree ofsensitisation that has been achieved in mammalian

systems is therefore small.32 33 There is hope, however,that the toxicity problem may be overcome; andanother class of compounds 34-organic nitroxides-hasbeen shown 35 to have the same radiobiological propertiesas N.E.M. but to be less toxic to mammalian cells inculture.36The most effective method of rendering cells (mam-

malian as well as bacterial) more sensitive to radiationis to grow them in media containing substances whichare structurally related but not identical with the normalpurines and pyrimidines that make up nucleic acids.

Biologically active analogues are incorporated into theD.N.A. of the cell 37 in place of a normal base. The mostwidely studied of these is bromodesoxyuridine (B.U.D.R.)which is utilised by the cell and replaces thymidine inD.N.A. All cells containing B.U.D.R. in their D.N.A. aremore sensitive to radiation, whether oxygen is presentor not; and this method of sensitisation seemed to havelittle to offer in increasing differentials in radiation

response. Nevertheless in a series of mouse lymphomacells, which varied rather widely in their initial radio-sensitivity, B.U.D.R. had a much greater effect on theradioresistant than on the radiosensitive cell lines 38; thenet effect was that after growth in B.U.D.R. the differencesin the sensitivity of the various mutants had largely29. Bacq, Z. M. Chemical Protection against Ionizing Radiations. Spring-

field, Ill., 1965.30. Alexander, P. in Oxygen in the Animal Organism (edited by F. Dickens

and E. Neil); p. 548. Oxford, 1964.31. Bridges, B. A. Nature, Lond. 1960, 188, 415.32. Quintiliani, M., Boccacci, M. Rc. Ist. sup. Sanita, 1959, 23, 5.33. Alexander, P. Br. J. Radiol. 1961, 34, 401.34. Hoffmann, A. K., Henderson, A. T. J. Am. chem. Soc. 1961, 83, 4671.35. Emmerson, P. T., Howard-Flanders, P. Radiat. Res. 1965, 26, 54.36. Klimec, M. Nature, Lond. 1966, 209, 1256.37. Djordjevic, B., Szybalski, W. J. exp. Med. 1960, 112, 509.38. Lett, J. T., Parkins, G., Alexander, P., Ormerod, M. G. Nature, Lond.

1964, 203, 593.

1359

disappeared. This raises the possibility that in tumoursof mixed-cell population the cells most refractory toradiation may be sensitised to the greatest extent.

Clinical investigation of this possibility is beset with

difficulties, and the most important aspect of currentwork is that the mechanism of the differentialsensitisation is being elucidated.One of the principal factors responsible for the

differences in sensitivity of different mammalian cells tomitotic death-i.e., to the type of radiation death whichprevents dividing cells from proliferating indefinitely-appears to be their capacity for restoring radiation-induced intracellular lesions, and many procedureswhich modify radiosensitivity are believed to act at thelevel of enzymic repair and not at that of the primaryradiation lesion.39 That metabolic processes can repairradiation damage has long been known,40 but the detailsof the mechanism are only now becoming understood.The main impetus to this work came from investigationsinto killing by ultraviolet light.41 Ultraviolet light-though not ionising radiations such as X rays-causestwo thymidine units in the cell D.N.A. to be linked, andsuch dimers can be lethal. Bacteria resistant to ultra-violet light are characterised by the capacity to excisethese abnormal regions in the D.N.A. and to replacethem hv normal comnonents. while radiosensitive

mutants cannot do so. One important and probablylethal change produced in cells exposed to ionisingradiation is rupture of the D.N.A. molecule by scissionof the main-chain. In the extremely resistant micro-organism, Micrococcus radiodurans, immediately afterdoses of X rays which were insufficient to kill, theD.N.A. was degraded; but this damage was made goodand the size of the D.N.A. molecules returned to normalas a result of metabolic processes after irradiation.42

Apparently the joining up of the radiation-inducedbreaks requires that part of the D.N.A. is removed; andan important part of the repair process is an action byhydrolytic enzymes which release nucleotides from theirradiated D.N.A. The mechanism by which the actionof the nucleases is initiated and stopped is unknown,but apparently the presence of B.U.D.R. interferes withthe precise control of the excision process.43 For cell

killing by ultraviolet light the action of B.U.D.R. is notconfined to the repair process but also provides a pointof weakness which results in main-chain scission as a

primary event.44 In the case of X rays, B.U.D.R. seemsto act mainly on repair in the radioresistant mammaliancells, whereas the smaller degree of sensitisation in thesensitive strains is due to B.U.D.R. influencing radiationaction at the primary level. 38 These studies are impor-tant in that they show that the radiation response ofcells can be influenced at the repair level, and thereforethat selective modification is possible because cells vary39. Alexander, P., Lett, J. T., Dean, C. J. Progr. biochem. Pharmac. 1965,

1, 22.40. Stapleton, G. E., Billen, D., Hollaender, A. J. Bact. 1952, 63,

805.41. Setlow, R. B., Carrier, W. L. Proc. U.S. natn. Acad. Sci. 1964, 51,

226.42. Dean, C. J., Feldschreiber, B., Lett, J. T. Nature, Lond. 1966, 209,

49.43. Aoki, S., Boyce, R. P., Howard-Flanders, P. ibid. p. 686.44. Boyce, R. P. ibid. p. 688.

in their capacity for repair. Now that the mechanismsof repair are becoming better understood, new methodsof sensitisation may be found which can be used in

therapy.The experiments that have been described have dealt

with radiation lesions which, if not repaired, would belethal. There is another class of cellular damage whichis important in the usual methods of radiotherapy andwhich is sublethal: its existence is revealed when theradiation is given not in one exposure but in a numberof fractions. After the first dose a proportion of thedividing cells in the exposed volume will have beenkilled. Those that survive are not quite normal, in thatthey are more sensitive than the original cell populationto subsequent ionising radiation. This increased sensi-

tivity-or sublethal damage-is not permanent, and intime the cells recover and regain their original radio-sensitivity. The magnitude of this phenomenon andthe time-course of recovery vary for different mammaliancells.45 Thus a certain dose of radiation which kills

50% of a population of dividing cells may kill 90% ofthe cells that have survived the first fraction if therehas been no repair or sublethal damage. When thisrepair is complete, then this second irradiation willonce again kill only 50% of the dividing cells. There

may be clinical situations where interference with

repair of sublethal damage is of value in a suitablytimed course of radiotherapy, and considerable attentionis now being devoted to a search for agents which

might do this.

Annotations

OUTPATIENT SERVICES

INTEREST in the organisation and functioning of theNational Health Service was neglected for some yearsafter its introduction; and it was only three years ago,when the Oxford Regional Hospital Board’s survey 46 waspublished, that studies of how hospitals dealt with out-patients came into real prominence .47 48 An analysis ofofficial outpatient statistics 49 by a team at Guy’s Hospitalnow shows that, while the national use of outpatientdepartments has increased, the use of these facilities inLondon teaching hospitals has changed little. In all thehospital groups attendances at the general medical,general surgical, and pxdiatric clinics have fallen, whileattendances at the more highly specialised departmentshave risen. In a more detailed study 50 of the populationserved by the outpatient department of Guy’s Hospitalhalf the padents were found to live within 5 miles of thehospital, while most of the others either worked nearbyor had a general practitioner who had trained at Guy’s.61 % of the G.P.s’ letters accompanying patients mentionedno diagnosis, and the proportion of uninformative letters45. Elkind, M. M., Sutton, H. ibid. 1959, 184, 1293.46. Oxford Regional Hospital Board, Operational Research Unit. Hospital

Out-patient Services. Oxford, 1963.47. See Lancet, 1963, ii, 1151.48. See ibid. 1964, ii, 1377.49. Blaney, R., Acheson, R. M., Butterfield, W. J. H., Chamberlain, J.

Med. Care, 1966, 4, 89.50. Chamberlain, J., Acheson, R. M., Butterfield, W. J. H., Blaney, R.

ibid. p. 81.