1184
Letters
to
the Editor
THE METHYLFOLATE-TRAP HYPOTHESIS
SIR,-We read with interest your commentary1 on the methylfolate-trap hypothesis. You noted that there is an apparent disagreement between Chanarin2 and Herbert3 regarding the mechanism of impaired folate metabolism in the presence of vitamin-B12 deficiency. It was ’also pointed out that Noronha and Silverman4 laid the groundwork for the metabolic relationship between B12 and folic acid. In essence, vitamin Bl2 is needed as a coenzyme for N6-methyl tetrahydrofolate-homocysteine methyl transferase. The enzyme is responsible for the transferring of the methyl group from N6-methyl tetrahydrofolate, thereby converting homocysteine to methionine. It was thought by Herbert and others that methylfolate is actually trapped in the presence of vitamin-Bl2 deficiency, thereby causing cellular folate deficiency. One would reason that in such a situation the amount of methylfolate and folate derivatives within the B12-deficient cell should be, if not normal, certainly raised. However, as in the commentary, it was pointed out that tissue folate stores are in
decreased from normal in the presence of vitaminto the to the work of Tisman and Herbert.Tisman and Herbert were able to show that bone-marrow cells from patients wi Vitamin-B12 deficiency took up much less N6-methyl tetrahydrofolate than did normal bone-marrow cells. Addition of vitamin B12 to the incubation medium enhanced the cell uptake of methyl tetrahydrofolate only in Bl2-deficient
essence
Bl2 deficiency. Your editorial did not refer work by Das and Hoffbrand,5 nor did it refer
patients. The studies, in essence, supported the concept that vitamin B12 is a requirement for the transcellular movement of methyl-tetrahydrofolate into cells. Hence, the word trapped should be discarded, not only because it lacks biochemical dignity, but also because it is probably incorrect. It should also be noted that the work of Das and Hoffbrand supported such findings in lymphocytes. The methylfolate-trap hypothesis should be put to rest, since data from many laboratories cannot be forced to fit such a hypothesis. The hypothesis has been useful inasmuch as it has acted as a stimulus for research directed at either proving or disproving its proclamation. Lancet, April 12, 1975, p. 843. Chanarin, I. ibid. 1973, ii, 538. Herbert, V. ibid. 1974, ii, 834. Noronha, J. M., Silverman, M. in Vitamin B12 and Intrinsic Factor II (edited by H. C. Heinrich); p. 728. Stuttgart, 1962. 5. Das, K. C., Hoffbrand, A. V. Br. J. Hœmat. 1970, 19, 203. 6. Tisman, G., Herbert, V. Blood, 1973, 41, 465.
1. 2. 3. 4.
We feel that the work presented subsequently by Tisman and Herbert, showing the defect in cellular transport of methylfolate in vitamin-B12-deficient patients’ bonemarrow, is, in essence, compatible with the findings of low tissue-folate stores in the presence of pernicious anaemia " ,by others. If one insists on using the term trap ", one might say that vitamin B12 is the proprietor of a trap-door in the cell membrane; when vitamin B12 is not present, the door is closed and methylfolate cannot enter. When B12 is present, the door is held open. GLENN TISMAN Whittier-Montebello Cancer SHOW-JEN GRACE WU Research Institute, GEORGE E. SAFIRE Montebello, California 90640, EVELYN RODRIGUEZ. U.S.A.
BIOPSY IN CARCINOMA OF BREAST SiR,—In many centres, open biopsy with frozen-section examination is routine in the management of histological " operable " breast carcinoma. This approach has the disadvantage of risk of implantation of tumour cells from drapes, gloves, skin, or instruments, and the disadvantage of uncertainty by patient and staff of the treatment plan. Needle biopsy, which is quick and can be performed with local anaesthesia in an outpatient clinic obviates these disadvantages. It also has considerable psychological advantages in providing a definite histological report, so that the patient knows of her mastectomy before going to theatre. However, many surgeons have been discouraged from using the technique because of reports of cell seeding along the needle track1 or because of the risk of disseminating tumour cells peripherally by inserting a needle into the tumour 2-So increasing the risk not only of local recurrence but also of distant spread. In order to ensure that we were not endangering our patients by doing whichever biopsy method was most appropriate for the individual, we have looked at the details of biopsy techniques used in 200 patients who underwent mastectomy for " early " breast cancer in the Cardiff trial.3 Operated on between one and seven years ago, the patients are considered as four groups: (1) needle and open biopsy; (2) needle biopsy alone; (3) open biopsy
alone; (4)
biopsy. protocol did not define the method of establishing diagnosis, nor were biopsy techniques randomised. However, each of the groups is made up of comparable proportions of those features which were randomised, including clinical lymph-node status, position of tumour, menstrual status, and type of operation (table i). no
The trial
1. 2. 3.
Godwin, J. T. Ann. N.Y. Acad. Sci. 1956, 63, 1348. Ochsner, A., de Bakey, M. New Orl. med. surg. J. 1941, 93, 387. Forrest, A. P. M., Gleave, E. N., Roberts, M. M., Henk, J. M., Gravelle, I. H. Proc. R. Soc. Med. 1970, 63, 107.
TABLE I-DISTRIBUTION OF TRIAL VARIABLES
Letters
to
the Editor
THE METHYLFOLATE-TRAP HYPOTHESIS
SIR,-We read with interest your commentary1 on the methylfolate-trap hypothesis. You noted that there is an apparent disagreement between Chanarin2 and Herbert3 regarding the mechanism of impaired folate metabolism in the presence of vitamin-B12 deficiency. It was ’also pointed out that Noronha and Silverman4 laid the groundwork for the metabolic relationship between B12 and folic acid. In essence, vitamin Bl2 is needed as a coenzyme for N6-methyl tetrahydrofolate-homocysteine methyl transferase. The enzyme is responsible for the transferring of the methyl group from N6-methyl tetrahydrofolate, thereby converting homocysteine to methionine. It was thought by Herbert and others that methylfolate is actually trapped in the presence of vitamin-Bl2 deficiency, thereby causing cellular folate deficiency. One would reason that in such a situation the amount of methylfolate and folate derivatives within the B12-deficient cell should be, if not normal, certainly raised. However, as in the commentary, it was pointed out that tissue folate stores are in
decreased from normal in the presence of vitaminto the to the work of Tisman and Herbert.Tisman and Herbert were able to show that bone-marrow cells from patients wi Vitamin-B12 deficiency took up much less N6-methyl tetrahydrofolate than did normal bone-marrow cells. Addition of vitamin B12 to the incubation medium enhanced the cell uptake of methyl tetrahydrofolate only in Bl2-deficient
essence
Bl2 deficiency. Your editorial did not refer work by Das and Hoffbrand,5 nor did it refer
patients. The studies, in essence, supported the concept that vitamin B12 is a requirement for the transcellular movement of methyl-tetrahydrofolate into cells. Hence, the word trapped should be discarded, not only because it lacks biochemical dignity, but also because it is probably incorrect. It should also be noted that the work of Das and Hoffbrand supported such findings in lymphocytes. The methylfolate-trap hypothesis should be put to rest, since data from many laboratories cannot be forced to fit such a hypothesis. The hypothesis has been useful inasmuch as it has acted as a stimulus for research directed at either proving or disproving its proclamation. Lancet, April 12, 1975, p. 843. Chanarin, I. ibid. 1973, ii, 538. Herbert, V. ibid. 1974, ii, 834. Noronha, J. M., Silverman, M. in Vitamin B12 and Intrinsic Factor II (edited by H. C. Heinrich); p. 728. Stuttgart, 1962. 5. Das, K. C., Hoffbrand, A. V. Br. J. Hœmat. 1970, 19, 203. 6. Tisman, G., Herbert, V. Blood, 1973, 41, 465.
1. 2. 3. 4.
We feel that the work presented subsequently by Tisman and Herbert, showing the defect in cellular transport of methylfolate in vitamin-B12-deficient patients’ bonemarrow, is, in essence, compatible with the findings of low tissue-folate stores in the presence of pernicious anaemia " ,by others. If one insists on using the term trap ", one might say that vitamin B12 is the proprietor of a trap-door in the cell membrane; when vitamin B12 is not present, the door is closed and methylfolate cannot enter. When B12 is present, the door is held open. GLENN TISMAN Whittier-Montebello Cancer SHOW-JEN GRACE WU Research Institute, GEORGE E. SAFIRE Montebello, California 90640, EVELYN RODRIGUEZ. U.S.A.
BIOPSY IN CARCINOMA OF BREAST SiR,—In many centres, open biopsy with frozen-section examination is routine in the management of histological " operable " breast carcinoma. This approach has the disadvantage of risk of implantation of tumour cells from drapes, gloves, skin, or instruments, and the disadvantage of uncertainty by patient and staff of the treatment plan. Needle biopsy, which is quick and can be performed with local anaesthesia in an outpatient clinic obviates these disadvantages. It also has considerable psychological advantages in providing a definite histological report, so that the patient knows of her mastectomy before going to theatre. However, many surgeons have been discouraged from using the technique because of reports of cell seeding along the needle track1 or because of the risk of disseminating tumour cells peripherally by inserting a needle into the tumour 2-So increasing the risk not only of local recurrence but also of distant spread. In order to ensure that we were not endangering our patients by doing whichever biopsy method was most appropriate for the individual, we have looked at the details of biopsy techniques used in 200 patients who underwent mastectomy for " early " breast cancer in the Cardiff trial.3 Operated on between one and seven years ago, the patients are considered as four groups: (1) needle and open biopsy; (2) needle biopsy alone; (3) open biopsy
alone; (4)
biopsy. protocol did not define the method of establishing diagnosis, nor were biopsy techniques randomised. However, each of the groups is made up of comparable proportions of those features which were randomised, including clinical lymph-node status, position of tumour, menstrual status, and type of operation (table i). no
The trial
1. 2. 3.
Godwin, J. T. Ann. N.Y. Acad. Sci. 1956, 63, 1348. Ochsner, A., de Bakey, M. New Orl. med. surg. J. 1941, 93, 387. Forrest, A. P. M., Gleave, E. N., Roberts, M. M., Henk, J. M., Gravelle, I. H. Proc. R. Soc. Med. 1970, 63, 107.
TABLE I-DISTRIBUTION OF TRIAL VARIABLES
