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THE PINEAL AND NEOPLASIA
341
CANCER, ASTHMA, AND CYCLIC A.M.P. SiR,-In a retrospective study Alderson1 demonstrated that deaths from all cancers (excluding lung cancer) were significantly reduced in patients with asthma compared with the general population. He suggested that these patients may have been exposed to less carcinogen or that asthma may protect against malignancy by allergic or immunological mechanisms.1 Obviously the role of the immune system and control of cancer should be considered in attempting to explain Alderson’s observationsbut we suggest another hypothesis. We think that the lower frequency of cancer in the asthma group may be the result of a fascinating pharmacological effect involving cyclic A.M.P. These asthmatic patients had almost certainly been taking bronchodilators for a long time. Many of these drugs (e.g., theophylline) increase intracellular cyclic A.M.P. Theophylline blocks the phos-
phodiesterase which normally degrades cyclic
A.M.P.
It is thus conceivable that the intracellular level of cyclic A.M.P. in taking theophylline for a long time will be increased. This mechanism is not too unlikely, although resistance of adrenergic receptors has been suggested as the molecular basis of asthma. However, most of these studies have been done in severe cases of asthma which usually show variable nucleotide responses.8 Although the molecular mechanisms of cyclic A.M.P. are unknown, these nucleotides have been implicated in the regulation of cell-growth through multiple-pleiotropic biochemical pathways.4 In-vitro experiments have indicated that malignant tumour cells become normal in presence of cyclic A.M.P.õ,6 Malignant cells have low levels of intracellular cyclic A.M.P. Animal experiments have shown that cyclic A.M.P. given in vivo can retard or prevent the growth of some tumours. We propose that chronic asthmatic patients are less susceptible to cancer because they often take drugs which increase their intracellular cyclic A.M.P. level. If prospective and retrospective trials demonstrate such a link, bronchodilators could be used against cancer. Hôpital St. Pierre, Rue Haute 322, 1000 Brussels,
JOSEPH WYBRAN ANDRÉ GOVAERTS.
Belgium.
Their combined observations together of hepatitis in 274 recipients of anti-HBgcontaining blood (10-6%), whereas the incidence of hepatitis in 495 controls (recipients of anti-HBs-free blood) was 48 (9-7%). Admittedly, it is impossible for fundamental reasons to establish a zero-hypothesis by statistical analysis, independently of the number of observations. Nevertheless, all information available at present does not support the suspicion that anti-HBs-containing blood may be more dangerous than blood free of HBsAg and anti-HB., in spite of some possible theoretical considerations. Therefore, the risks connected with the rejection of nearly 10% of all blood donations might-especially in regions with periodic shortages of transfusion blood-hugely outweigh the desired but by no means established benefits.
taining blood.
gave 29
cases
German Red Cross Blood Transfusion Service, P.O.B. 1767, D-44 Muenster, Germany.
HARALD FIEDLER.
THE PINEAL AND NEOPLASIA
SIR,-May I draw your attention to several papers concerning the pineal gland and neoplasia, which were mentioned neither in your editorial (Nov. 23, p. 1235) nor in Dr Buswell’s letter (Jan. 4, p. 34). Lacassagne 1.2 has studied the
stimulating
effect of
pinealectomy
on
the
development and growth of chemically induced tumours. The influence of whole extracts of bovine pineal gland on human malignant tumours has been described in the Austrian literature. 3-7 Enlargement of the pineal has been observed in many patients with leukaemia or lymphoma,8 but atrophy too has been observed in patients who died of malignant neoplasia.9 Wildi has observed a fall in the number of mast cells in the pineal gland seen post mortem in carcinoma. 10 We have found 11 that Wistar rats injected intramuscularly with 500,000 Yoshida-sarcoma cells 2 months after neonatal pinealectomy survived on average 29-2 days, compared with similarly injected but unoperated controls (mean survival 55-5 days). Survival was reduced even further by neonatal thymectomy (mean survival 21-5 days) and simultaneous pinealectomy and thymectomy (17-3
days). frequency of metastases was surprisingly high in the pinealectomised animals, 15 out of 19 animals (78-9%) developing metastases in the pancreas. Similar results The
RISK OF TRANSFUSING BLOOD CONTAINING
ANTI-HBs
SiR,—Dr Seifert and Professor Ganzoni (Dec. 21, p. 1513) " believe that screening blood-donors for antiHBs will reduce the risk of transmitting hepatitis to some extent." Unfortunately, they seem to have overlooked that not only Dr Aach but also several other investigators 7-14 failed to establish increased infectivity of anti-HBs-conAlderson, M. Lancet, 1974, ii, 1475. Wybran, J., Fudenberg, H. H. J. clin. Invest. 1973, 52, 1026. Parker, C. W., Smith, J. W. ibid. p. 48. Kram, R., Mamont, P., Tomkins, G. M. Proc. natn. Acad. Sci. U.S.A. 1973, 70, 1432. 5. Johnson, G. S., Friedman, R. M., Pastan, I. ibid. 1971, 68, 425. 6. Hsie, A. W., Puck, T. T. ibid. p. 358. 7. Zuckerman, G., Hacker, E. J., Parker, B., Aach, R. D. Gastroenterology, 1973, 64, 827. 8. Alter, H. J., Holland, P. V., Purcell, R. H., Lander, J. J., Feinstone, S. M., Morrow, A. G., Schmidt, P. J. Ann. intern. Med. 1972, 77,
1. 2. 3. 4.
691. 9.
Reinicke, V., Poulsen, H., Banke, O., Dybkjaer, E. Acta path. microbiol. scand. sect. B, 1973, 81, 753. 10. Hollinger, F. B., Werch, J., Melnick, J. L. New Engl. J. Med. 1974, 290, 1104. 11. Goldfield, M. Personal communication, 1973. 12. Gocke, D. J., Panick, J. M. in Hepatitis and Blood Transfusion; p. 319. New York and London, 1972. 13. Caggiano, V. Discussion to ref. 6; p. 323. 14. Schlaak, M., Lehmann, H., Schober, A. Lecture 80. German Society for Internal Medicine, Wiesbaden, April, 1974.
were
also obtained when
tumour
cells
were
inoculated
subcutaneously in the neck or in various other locations. In another experiment 12the influence of pinealectomy on viral oncogenesis was studied. Polyoma-virus suspension was injected subcutaneously in newborn Wistar rats immediately after thymectomy, pinealectomy, or pinealectomy plus thymectomy. 64-5% of thymectomised rats and 33-3% of rats with both thymectomy and pinealectomy died of kidney tumours within 3-5 months of virus inoculation. Pinealectomised and control rats survived tumourfree for 10-12 months before being killed. It seems that pinealectomy has no influence on polyoma-virus oncogenesis. Institute for Cancer Research,
University of Vienna, Austria.
V. LAPIN.
1. Lacassagne, A. C. r. Acad. Sci. Paris, 1969, 269, 1043. 2. Lacassagne, A. Bull. Cancer, 1954, 54, 171. 3. Bergmann, W., Engel, P. Wien. klin. Wschr. 1950, 62, 79. 4. Bayer, R. Inf-dienst ost. Krebsgesellschaft, Steiermark, Mitt. 3, 1965, 3. 5. Sander, G., Schmid, S. Wien. klin. Wschr. 1952, 64, 505. 6. Hofstatter, R. Krebsarzt, 1968, 23, 97. 7. Hofstätter, R. Wien. klin. Wschr. 1950, 62, 1. 8. Rodin, A. E., Overall, J. Cancer, N. Y. 1967, 20, 1203. 9. Tapp, E., Blumfield, M. Br. J. Cancer, 1970, 24, 67. 10. Wildi, E., Frauchiger, E. in Progress in Brain Research, 1965,
11. 12.
vol. 10, p. 218. Lapin, V. Exp. Path. 1974, 9, 108. Lapin, V., Wrba, H. Unpublished.
CANCER, ASTHMA, AND CYCLIC A.M.P. SiR,-In a retrospective study Alderson1 demonstrated that deaths from all cancers (excluding lung cancer) were significantly reduced in patients with asthma compared with the general population. He suggested that these patients may have been exposed to less carcinogen or that asthma may protect against malignancy by allergic or immunological mechanisms.1 Obviously the role of the immune system and control of cancer should be considered in attempting to explain Alderson’s observationsbut we suggest another hypothesis. We think that the lower frequency of cancer in the asthma group may be the result of a fascinating pharmacological effect involving cyclic A.M.P. These asthmatic patients had almost certainly been taking bronchodilators for a long time. Many of these drugs (e.g., theophylline) increase intracellular cyclic A.M.P. Theophylline blocks the phos-
phodiesterase which normally degrades cyclic
A.M.P.
It is thus conceivable that the intracellular level of cyclic A.M.P. in taking theophylline for a long time will be increased. This mechanism is not too unlikely, although resistance of adrenergic receptors has been suggested as the molecular basis of asthma. However, most of these studies have been done in severe cases of asthma which usually show variable nucleotide responses.8 Although the molecular mechanisms of cyclic A.M.P. are unknown, these nucleotides have been implicated in the regulation of cell-growth through multiple-pleiotropic biochemical pathways.4 In-vitro experiments have indicated that malignant tumour cells become normal in presence of cyclic A.M.P.õ,6 Malignant cells have low levels of intracellular cyclic A.M.P. Animal experiments have shown that cyclic A.M.P. given in vivo can retard or prevent the growth of some tumours. We propose that chronic asthmatic patients are less susceptible to cancer because they often take drugs which increase their intracellular cyclic A.M.P. level. If prospective and retrospective trials demonstrate such a link, bronchodilators could be used against cancer. Hôpital St. Pierre, Rue Haute 322, 1000 Brussels,
JOSEPH WYBRAN ANDRÉ GOVAERTS.
Belgium.
Their combined observations together of hepatitis in 274 recipients of anti-HBgcontaining blood (10-6%), whereas the incidence of hepatitis in 495 controls (recipients of anti-HBs-free blood) was 48 (9-7%). Admittedly, it is impossible for fundamental reasons to establish a zero-hypothesis by statistical analysis, independently of the number of observations. Nevertheless, all information available at present does not support the suspicion that anti-HBs-containing blood may be more dangerous than blood free of HBsAg and anti-HB., in spite of some possible theoretical considerations. Therefore, the risks connected with the rejection of nearly 10% of all blood donations might-especially in regions with periodic shortages of transfusion blood-hugely outweigh the desired but by no means established benefits.
taining blood.
gave 29
cases
German Red Cross Blood Transfusion Service, P.O.B. 1767, D-44 Muenster, Germany.
HARALD FIEDLER.
THE PINEAL AND NEOPLASIA
SIR,-May I draw your attention to several papers concerning the pineal gland and neoplasia, which were mentioned neither in your editorial (Nov. 23, p. 1235) nor in Dr Buswell’s letter (Jan. 4, p. 34). Lacassagne 1.2 has studied the
stimulating
effect of
pinealectomy
on
the
development and growth of chemically induced tumours. The influence of whole extracts of bovine pineal gland on human malignant tumours has been described in the Austrian literature. 3-7 Enlargement of the pineal has been observed in many patients with leukaemia or lymphoma,8 but atrophy too has been observed in patients who died of malignant neoplasia.9 Wildi has observed a fall in the number of mast cells in the pineal gland seen post mortem in carcinoma. 10 We have found 11 that Wistar rats injected intramuscularly with 500,000 Yoshida-sarcoma cells 2 months after neonatal pinealectomy survived on average 29-2 days, compared with similarly injected but unoperated controls (mean survival 55-5 days). Survival was reduced even further by neonatal thymectomy (mean survival 21-5 days) and simultaneous pinealectomy and thymectomy (17-3
days). frequency of metastases was surprisingly high in the pinealectomised animals, 15 out of 19 animals (78-9%) developing metastases in the pancreas. Similar results The
RISK OF TRANSFUSING BLOOD CONTAINING
ANTI-HBs
SiR,—Dr Seifert and Professor Ganzoni (Dec. 21, p. 1513) " believe that screening blood-donors for antiHBs will reduce the risk of transmitting hepatitis to some extent." Unfortunately, they seem to have overlooked that not only Dr Aach but also several other investigators 7-14 failed to establish increased infectivity of anti-HBs-conAlderson, M. Lancet, 1974, ii, 1475. Wybran, J., Fudenberg, H. H. J. clin. Invest. 1973, 52, 1026. Parker, C. W., Smith, J. W. ibid. p. 48. Kram, R., Mamont, P., Tomkins, G. M. Proc. natn. Acad. Sci. U.S.A. 1973, 70, 1432. 5. Johnson, G. S., Friedman, R. M., Pastan, I. ibid. 1971, 68, 425. 6. Hsie, A. W., Puck, T. T. ibid. p. 358. 7. Zuckerman, G., Hacker, E. J., Parker, B., Aach, R. D. Gastroenterology, 1973, 64, 827. 8. Alter, H. J., Holland, P. V., Purcell, R. H., Lander, J. J., Feinstone, S. M., Morrow, A. G., Schmidt, P. J. Ann. intern. Med. 1972, 77,
1. 2. 3. 4.
691. 9.
Reinicke, V., Poulsen, H., Banke, O., Dybkjaer, E. Acta path. microbiol. scand. sect. B, 1973, 81, 753. 10. Hollinger, F. B., Werch, J., Melnick, J. L. New Engl. J. Med. 1974, 290, 1104. 11. Goldfield, M. Personal communication, 1973. 12. Gocke, D. J., Panick, J. M. in Hepatitis and Blood Transfusion; p. 319. New York and London, 1972. 13. Caggiano, V. Discussion to ref. 6; p. 323. 14. Schlaak, M., Lehmann, H., Schober, A. Lecture 80. German Society for Internal Medicine, Wiesbaden, April, 1974.
were
also obtained when
tumour
cells
were
inoculated
subcutaneously in the neck or in various other locations. In another experiment 12the influence of pinealectomy on viral oncogenesis was studied. Polyoma-virus suspension was injected subcutaneously in newborn Wistar rats immediately after thymectomy, pinealectomy, or pinealectomy plus thymectomy. 64-5% of thymectomised rats and 33-3% of rats with both thymectomy and pinealectomy died of kidney tumours within 3-5 months of virus inoculation. Pinealectomised and control rats survived tumourfree for 10-12 months before being killed. It seems that pinealectomy has no influence on polyoma-virus oncogenesis. Institute for Cancer Research,
University of Vienna, Austria.
V. LAPIN.
1. Lacassagne, A. C. r. Acad. Sci. Paris, 1969, 269, 1043. 2. Lacassagne, A. Bull. Cancer, 1954, 54, 171. 3. Bergmann, W., Engel, P. Wien. klin. Wschr. 1950, 62, 79. 4. Bayer, R. Inf-dienst ost. Krebsgesellschaft, Steiermark, Mitt. 3, 1965, 3. 5. Sander, G., Schmid, S. Wien. klin. Wschr. 1952, 64, 505. 6. Hofstatter, R. Krebsarzt, 1968, 23, 97. 7. Hofstätter, R. Wien. klin. Wschr. 1950, 62, 1. 8. Rodin, A. E., Overall, J. Cancer, N. Y. 1967, 20, 1203. 9. Tapp, E., Blumfield, M. Br. J. Cancer, 1970, 24, 67. 10. Wildi, E., Frauchiger, E. in Progress in Brain Research, 1965,
11. 12.
vol. 10, p. 218. Lapin, V. Exp. Path. 1974, 9, 108. Lapin, V., Wrba, H. Unpublished.