An Investigation of the Value of Lead Compounds in the Treatment of Malignant Tumours
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AN INVESTIGATION OF THE VALUE OF LEAD COMPOUNDS IN THE TREATMENT OF MALIGNANT TUMOURS MEMBERS OF THE LIVERPOOL MEDICAL RESEARCH ORGANIZATION DIRECTOR, M. DATNOW, M.D., F.R.C.S.E. Organic Chemistry by B. Beileneolin, P1i.D. ; Q. F. Hownrd, P1i.D.; Dircctor, Professor I. M. Hcilbron. Pharmncology by T. N. A. Jeffconte, M.D., F.R.C.S.E.; Director, Professor W. J. Dilling (From the University of Liverpool) Some encouraging results that had been obtained in the treatment of cancer by injecting the lead salts of various organic acids were de- scribed by Blair-Bell (1). His researches have been followed up, and this paper deals with the results of the main therapeutic investigations that have so far been undertaken. It has been recorded (2) that fa- vourable reaults were obtained with lead salts of several aliphatic amino-acids, either in aqueous solution or in a suspended or super- saturated state, this last condition being attained readily by the ad- dition of gum acacia (2 per cent) or gelatin (2 per cent), to the aqueous solution of the lead salt (3). While endeavouring to lower the toxicity of these preparations, our attention was drawn to the value of sodium thiosulphate for reducing the poisonous effects of heavy metals; this is enhanced by the property of this salt to form with lead salts complex ions which increase consider- ably the solubility of the lead salt. It was found, also, that substitution of the amino-group was frequently beneficial, the most efficacious sub- stitute being the aryl-sulphonyl radicle. A number of such compounds have, therefore, been prepared and examined with the object of deter- mining to what extent curative power is dependent upon structure. Unfortunately, the results have so far afforded little helpful evidence, since all such compounds, with the exception of p-toluene sulphonyl- glycine, are about equal in their therapeutic value. After successful pharmacological tests, the lead compounds were tested out for their carcinotropic action on rabbits on which the Brown- Pearce rabbit tumour had been grafted. In our hands this tumour has behaved with extraordinary uniformity. In no case out of some thou- sand inoculations was the tumour found to retrogress after it had been satisfactorily established. The percentage of takes has been over 88 per cent. The usual span of life for a rabbit after grafting is between three and six weeks, although a few have survived up to three months. At the commencement of our investigations, Rections were always taken prior to treatment so as to substantiate the presence of active cancer, and at the same time a laparotomy was performed upon the rab- bits in order to observe the extent of the growth. Later our experience taught us that this was unnecessary, and a selection was made of the rabbits with the most advanced growths for treatment while the re- 531 532 LIVERPOOL MEDICAL RESEARCH ORQANIZATION mainder of each group was kept for control purposes. In no case was retrogression observed in an untreated control animal in which the tu- mour had been established. The rate of spread and period of survival of the treated animals were compared with those in animals not in- jected. Details will be given under the appropriate compounds. The lead preparations were all injected intravenously. Inhibition of the growth and survival of the rabbits for periods longer than the controls were taken as evidence of beneficial effect and good carcino- tropic action. This was further confirmed by histological examinations. Our attention was drawn to a preparation (R.232) by Dr. Collier (4) of the Koch Institute, Berlin, which is the lead potassium complex of 2 :6 dithiol pyridine-4-carboxylic acid (see H.152). We have investi- gated several analogous compounds in which lead is attached to a mercapto-group, but the results obtained are as yet insufficient to war- rant any deductions as to their value. In the preparation of these lead complexes, the usual aim is a lead content of 0.5 per cent, which is similar to that of the original (5) col- loidal lead (S.7), and which facilitates comparisons of the results ob- tained from different compounds. The method of administration to cancer patients has been intra- venous, commencing with initial doses of 3 to 5 C.C. of the 0.9 per cent Rolutions, subsequent dosage being entirely dependent on the response of the patient to treatment, which is estimated chiefly by the numbers of stippled red cells in the blood and by the renal excretion. The in- tervals between injections vary from one to eight weeks. They are fre- quent at first and are then gradually lengthened; patients are asked to report every six or eight weeks for six months, then every nine to twelve weeks for a year, aiid every twelve weeks after this. No untoward re- actions have been noticed. EXPERIMENTAL Lead acetylglycinate (H.71), prepared by double decomposition of sodium acetylglycinate aiid lead acetate in an aqueous solution (1 per cent gelatin), forms a colloidal suspension, which is stable for several days. Lead thiosulphute (H.80), with the addition of one, two, or three molecular proportions of sodium thiosulphate, yields a satisfactory solution containing complex lead sodium thiosulphate. Leud benzene suZphoiL?lZgZ~cin.at~(H.126) : Benzene sulphonylgly- cine, C,H,SO,. NH. CHrCOOH, was prepared in 85 per cent yield ac- cording to the method which has been described by Ihrfelt (6). Freshly distilled benzene sulphochloridc (8.8 ,m.) was mixed with aqueous po- tassium amino-acetate (from 3.8 gm. glyciiie in 100 C.C. water) and the whole warmed to between 50-60", dilute potassium hydroxide being added, with stirring, at such a rate that the solution remained faintly alkaliiie throughout. On completion of the reaction (one and a half hours), the filtered solution was acidified with hydrochloric acid, when almost pure benzene sulplioiiylglyciiic separated out. The solid, after LEAD COMPOUNDS IN TREATMENT OF MALIGNANT TUMOURS 533 recrystallisation from dilute alcohol, formed hard, colourless rhombs, m.p. 169". An aqueous solution of the lead salt, prepared by double decomposi- tion of sodium benzene sulphonylglycinate and the equivalent amount of lead acetate, at a concentration equal to 0.5 per cent lead, was unsatis- factory from the pharmacological point of view. In view of the results obtained by the addition of sodium thiosulphate to lead thiosulphate (see H.80), it was decided to treat the compound under discussion in a similar manner. Experience proved the following procedure to be the most efficacious manner of dispensing this arylsulphonylglycinate and the analogous ones described in this paper. For convenience all solutions 'of sodium arylsulphonylglycinates referred to in the following pages contain that weight of sodium salt in 100 C.C. solution which is equivalent to 5 gm. Pra. 1. EFFECTOF H. 186 (LEADBENZENE SULPHONYLULYCINATE) ON BWD PRESSURE, SIXOWINGSLIGHT FALL AND RAPID RECOVERYA~EB INJECTION INTRAVENOUSLYOF 5 C.C. lead. The sodium thiosulphate solution employed contains 248 gm. per litre of the pentahydrate. The preparation of H.126 which is typical of all such compounds is, therefore, carried out as follows : Solution A. 16 C.C. 5 per cent gum acacia solution. 4 e.c. lead acetate solution (containing 10 per cent lend). 20 C.C.distilled water. Solution B. 16 c.c. gum acacia solution. 8 c.e. stock sodium salt solution. 8 c.c. stock sodium thiosulphate solution. 8 C.C. distilled water. Equal volumes of solutions A and B are mixed thoroughly (usually in 3 C.C. portions) just before injection. The mixed solutions, on stand- ing for some days, gradually deposit lead sulphide, which renders them unsuitable for clinical use. Lead ions are undoubtedly present in these 534 LIVERPOOL MEDICAL RESEARCH ORGANIZATION preparations ; this is proved by the immediate formation of precipitates on addition of sodium phosphate or chromate to the mixture, but these precipitates show a decided difference in colour from the corresponding precipitates obtained with a simple lead salt. Potassium iodide does not precipitate lead iodide from these preparations. The compound was satisfactory from the pharmacological point of vicw (Fig. l),as it caused no material variation in the pulse or respira- tion, and the blood pressure changes were comparatively small, the fall tiveraging 15 mm. Hg and the recovery taking place rapidly in about 20 lo 30 seconds. These facts warranted the application of thiR prepara- tion for therapeutic purposes, but it was first tested on rabbits in which the Brown-Pearcc tumour had been satisfactorily established and in many cases had reached a very advanced stage. A batch of 23 rab- bits was used. Of these, 4 were completely cured, as no active growth was found post morfcm, although sect ions taken before treatment werc undoubtedly positive. The carciiiotropic .properties of this preparation are good as far as the Brown-Pearce turnour is concerned. The dos- ages and the histological findings will be recorded elsewhere, but it is of interest to note here that one of the rabbits lived for one year and eight months after inoculation with the growth, the usual survival period being three to six weeks. When treatment was commenced 011 this mimal, it had nodules in its peritoneal cavity, found at exploratory laparotomy, and there were secondary deposits in the left eye. An initial dose (10 c.c.) of H.126 was given intravenously and was fol- lowed eight days later by a further 5 C.C. The animal remained well for one year and seven months, when the eye turnour appeared to become active again. A fnrther dose of 10 C.C. was then given intravenously but the rabbit eventually died.