amino-acids of tumour proteins

1
795 of T with slight deviation of the R-T segment in lead 3, for instance, cannot be considered significant unless the record can be compared with previous or subse- quent ones; a changing configuration then helps immensely in assessing the state of the heart. Again, the records obtained in pericarditis may sometimes be confused with those of myocardial infarction, and it is only when several consecutive records have been taken that the true significance of the findings can be decided. Precordial or chest leads, the latest inno- vation in electrocardiography, are undoubtedly valu- able from the point of view of investigation, but, partly as a result of the confusion in nomenclature only recently clarified by the joint report of the Cardiac Club and the American Heart Association,3 their clinical significance cannot yet be assessed. The danger seems to be that the introduction of multiple precordial leads will make the technique so unwieldy as to remove it from the domain of the practising cardiologist. Let us hope that workers on the subject will establish the significance of what has come to be known as lead 4 before proceeding any further with the question of multiple leads. Electrocardiographic interpretations divorced from clinical findings are useless and may be actively mis- leading. "Intelligently used," writes Barnes in the concluding sentences of his monograph, "the electro- cardiogram will elucidate as well as raise questions of normal and pathologic cardiac physiologic pro- cesses. Progress in its understanding will depend on sound clinical reasoning, on thorough knowledge of the anatomy and physiology of the heart, and last but not least, on a competent conception of the pathology of heart disease." These words might well be inscribed on every electrocardiograph before it left the manufacturer’s hands. AMINO-ACIDS OF TUMOUR PROTEINS THE work of Kogi and Erxleben gave promise of a distinct advance in our knowledge of the bio- chemistry of cancer, for their evidence suggested that an essential difference between the cells of normal and of malignant tissue was to be found in the constitu- tions of their proteins. Whereas the proteins of normal tissue were built up from the amino-acids of the usual l(+) series, those of cancer tissue appar- ently contained large amounts of amino-acids of the opposite optical configuration the d(-) series. It was therefore concluded that the malignant cell had lost the power of selecting only the " normal " amino- acids in building up its proteins, and that it was no longer bound by the restrictions governing organised cell growth. The fundamental importance of the question has stimulated further investigations by other workers, but until recently with very conflicting results. In a preliminary communication, Chibnall and others ’ reported that they had been able to isolate from three different samples of malignant tissue only the normal unracemised 1(+) glutamic acid. But the objection was raised by Isogl and Erxleben that the methods used by Chibnall were unsuitable for demonstrating the presence of the d(-) glutamic acid which they had found present, since there were considerable differences in the solubilities of the calcium salts and hydrochlorides of the two species. Later papers by Chibnall and 3. See Lancet, 1938, 1, 221. 4. Kögl, F., and Erxleben, H. Hoppe-Seyl, Z. 1939, 258, 57; see Lancet, 1939, 1, 1049. 5. Chibnall, A. C., Rees, M. W., Williams, E. F. and Boyland, E. Nature, 1939, 144, 71. 6. Kögl, and Erxleben, Hoppe-Seyl. Z. 1939, 261, 154 ; Nature, 1939, 144, 111; Kögl, Erxleben and Akkerman, Hoppe- Seyl. Z. 1939, 261, 141. others 7 show that there is no essential difference in the solubilities of the calcium salts, and further- more, that the methods of analysis used by Kögl and Erxleben make it possible to obtain the racemised product preferentially, even in the presence of a large excess of the "normal" l(+) glutamic acid. They point out that it is not legitimate to assume that because a small specimen isolated shows a high degree of racemisation it is representative of the whole. The discrepancies in the results of other workers 8 may therefore be attributed to variations in the methods of analysis and to the differences in the yields of material isolated. A representative specimen of the amino-acid is only to be obtained when the yield approaches the quantitative value. In a study of the glutamic acid present in seven different malignant tumours, Chibnall and his co-workers now find that although the d(-) form of glutamic acid is present it forms a small proportion of the whole, and furthermore that amounts of the same order of magnitude are to be found in normal tissues. They also observe that the plant protein gliadin gives much larger amounts of the d(-) glutamic acid, a. result which is confirmed by Town.9 Small amounts of partially racemised aspartic acid can also be isolated from both normal and malignant tissue proteins. It is therefore evident that the presence of amino-acids of the d(-) series is in no way characteristic of the proteins of malignant tissue. This conclusion receives support from the results of Lipmann and his colleagues 10 who approached the subject from a more biochemical point of view. By utilising the specific d amino-acid oxidase system of Krebs they have estimated the total d amino-acid content of a representative variety of benign, malig- nant and normal tissues and of a number of proteins including Bence-Jones protein, gliadin and insulin. The values found, which are stated to be maximum values, show that the d amino-acids are present in a uniformly small amount in all the materials analysed, the values being of the same order as those found by Chibnall for the glutamic acid. One may therefore con- clude that the proteins of malignant tissue are not specifically characterised by the presence of amino- acids of the "un-natural" d (-) series, and conse- quently that the main contention of Kögl and Erxleben is no longer tenable. LOCALISATION OF FOREIGN BODIES McGrigor 11 has described a fluoroscopic method by which a foreign body can be localised to within a quarter to half an inch in a few seconds, and Clark 12 has shown that by taking certain radiograms its situa- tion can be determined even more accurately in a few minutes. Nogier 13 has now evolved an ingenious technique based on parallax by which when a foreign body is embedded in a limb the radiologist can tell the operating surgeon whether he is moving his exploring forceps in the right direction and whether their point is above or below the foreign body. The position of the foreign body in one plane is first determined by screening. To ascertain its depth a 7. Chibnall, Rees, Williams and Boyland Nature, Feb. 4, 1940, p. 311 ; Biochem. J. 1940, 34, 285. 8. Arnow, L. E., and Opsahl, J. C. Science, 1939, 90, 257; Dittmar, C. Z. Krebsforsch. 1939, 49, 397, 444 ; Graff, S. J. Biol. Chem. 1939, 130, 13; Chargaff, E. Ibid, 1939, 130, 29 ; White, J. and White, F. R. Ibid, p. 435 ; Konikova, A. Nature, Feb. 4, 1940, p. 312. 9. Town, B. W. Nature, Feb. 24, 1940, p. 312. 10. Lipmann, F., Behrens, O. K., Kabit, E. A. and Burk, D. Science, Jan. 5, 1940, p. 21. 11. McGrigor, D.B. Brit. J. Radiol. 1939, 12, 619. 12. Clark, K. C. Radiography, 1939, 5, p. 195. 13. Nogier, T. Paris méd. March 16, 1940, p. 119.

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Page 1: AMINO-ACIDS OF TUMOUR PROTEINS

795

of T with slight deviation of the R-T segment in lead3, for instance, cannot be considered significant unlessthe record can be compared with previous or subse-quent ones; a changing configuration then helpsimmensely in assessing the state of the heart. Again,the records obtained in pericarditis may sometimesbe confused with those of myocardial infarction, and itis only when several consecutive records have beentaken that the true significance of the findings canbe decided. Precordial or chest leads, the latest inno-vation in electrocardiography, are undoubtedly valu-able from the point of view of investigation, but,partly as a result of the confusion in nomenclatureonly recently clarified by the joint report of theCardiac Club and the American Heart Association,3their clinical significance cannot yet be assessed. Thedanger seems to be that the introduction of multipleprecordial leads will make the technique so unwieldyas to remove it from the domain of the practisingcardiologist. Let us hope that workers on the subjectwill establish the significance of what has come tobe known as lead 4 before proceeding any furtherwith the question of multiple leads.Electrocardiographic interpretations divorced from

clinical findings are useless and may be actively mis-leading. "Intelligently used," writes Barnes in theconcluding sentences of his monograph, "the electro-cardiogram will elucidate as well as raise questionsof normal and pathologic cardiac physiologic pro-cesses. Progress in its understanding will depend onsound clinical reasoning, on thorough knowledge ofthe anatomy and physiology of the heart, and lastbut not least, on a competent conception of the

pathology of heart disease." These words might wellbe inscribed on every electrocardiograph before it leftthe manufacturer’s hands.

AMINO-ACIDS OF TUMOUR PROTEINS

THE work of Kogi and Erxleben gave promise ofa distinct advance in our knowledge of the bio-

chemistry of cancer, for their evidence suggested thatan essential difference between the cells of normal andof malignant tissue was to be found in the constitu-tions of their proteins. Whereas the proteins ofnormal tissue were built up from the amino-acids ofthe usual l(+) series, those of cancer tissue appar-ently contained large amounts of amino-acids of theopposite optical configuration the d(-) series. Itwas therefore concluded that the malignant cell hadlost the power of selecting only the " normal " amino-acids in building up its proteins, and that it was nolonger bound by the restrictions governing organisedcell growth. The fundamental importance of thequestion has stimulated further investigations byother workers, but until recently with very conflictingresults. In a preliminary communication, Chibnalland others ’ reported that they had been able toisolate from three different samples of malignanttissue only the normal unracemised 1(+) glutamicacid. But the objection was raised by Isogl andErxleben that the methods used by Chibnall wereunsuitable for demonstrating the presence of thed(-) glutamic acid which they had found present,since there were considerable differences in thesolubilities of the calcium salts and hydrochlorides ofthe two species. Later papers by Chibnall and

3. See Lancet, 1938, 1, 221.4. Kögl, F., and Erxleben, H. Hoppe-Seyl, Z. 1939, 258, 57;

see Lancet, 1939, 1, 1049.5. Chibnall, A. C., Rees, M. W., Williams, E. F. and Boyland, E.

Nature, 1939, 144, 71.6. Kögl, and Erxleben, Hoppe-Seyl. Z. 1939, 261, 154 ; Nature,

1939, 144, 111; Kögl, Erxleben and Akkerman, Hoppe-Seyl. Z. 1939, 261, 141.

others 7 show that there is no essential differencein the solubilities of the calcium salts, and further-more, that the methods of analysis used by Kögl andErxleben make it possible to obtain the racemisedproduct preferentially, even in the presence of a largeexcess of the "normal" l(+) glutamic acid. Theypoint out that it is not legitimate to assume thatbecause a small specimen isolated shows a high degreeof racemisation it is representative of the whole.The discrepancies in the results of other workers 8

may therefore be attributed to variations in themethods of analysis and to the differences in the yieldsof material isolated. A representative specimen of theamino-acid is only to be obtained when the yieldapproaches the quantitative value.

In a study of the glutamic acid present in sevendifferent malignant tumours, Chibnall and hisco-workers now find that although the d(-) form ofglutamic acid is present it forms a small proportionof the whole, and furthermore that amounts of thesame order of magnitude are to be found in normaltissues. They also observe that the plant proteingliadin gives much larger amounts of the d(-)glutamic acid, a. result which is confirmed by Town.9Small amounts of partially racemised aspartic acidcan also be isolated from both normal and malignanttissue proteins. It is therefore evident that thepresence of amino-acids of the d(-) series is in noway characteristic of the proteins of malignant tissue.This conclusion receives support from the results ofLipmann and his colleagues 10 who approached thesubject from a more biochemical point of view. Byutilising the specific d amino-acid oxidase system ofKrebs they have estimated the total d amino-acidcontent of a representative variety of benign, malig-nant and normal tissues and of a number of proteinsincluding Bence-Jones protein, gliadin and insulin.The values found, which are stated to be maximumvalues, show that the d amino-acids are present in auniformly small amount in all the materials analysed,the values being of the same order as those found byChibnall for the glutamic acid. One may therefore con-clude that the proteins of malignant tissue are notspecifically characterised by the presence of amino-acids of the "un-natural" d (-) series, and conse-quently that the main contention of Kögl andErxleben is no longer tenable.

LOCALISATION OF FOREIGN BODIES

McGrigor 11 has described a fluoroscopic method bywhich a foreign body can be localised to within aquarter to half an inch in a few seconds, and Clark 12has shown that by taking certain radiograms its situa-tion can be determined even more accurately in a fewminutes. Nogier 13 has now evolved an ingenioustechnique based on parallax by which when a foreignbody is embedded in a limb the radiologist can tellthe operating surgeon whether he is moving his

exploring forceps in the right direction and whethertheir point is above or below the foreign body. The

position of the foreign body in one plane is firstdetermined by screening. To ascertain its depth a

7. Chibnall, Rees, Williams and Boyland Nature, Feb. 4, 1940,p. 311 ; Biochem. J. 1940, 34, 285.

8. Arnow, L. E., and Opsahl, J. C. Science, 1939, 90, 257;Dittmar, C. Z. Krebsforsch. 1939, 49, 397, 444 ; Graff, S.J. Biol. Chem. 1939, 130, 13; Chargaff, E. Ibid, 1939, 130,29 ; White, J. and White, F. R. Ibid, p. 435 ; Konikova, A.Nature, Feb. 4, 1940, p. 312.

9. Town, B. W. Nature, Feb. 24, 1940, p. 312.10. Lipmann, F., Behrens, O. K., Kabit, E. A. and Burk, D.

Science, Jan. 5, 1940, p. 21.11. McGrigor, D.B. Brit. J. Radiol. 1939, 12, 619.12. Clark, K. C. Radiography, 1939, 5, p. 195.13. Nogier, T. Paris méd. March 16, 1940, p. 119.