Effects on Malignant Cell Growth

LeVan, Gordon and Stefani, Onocology (1972),1268 reported that intraperitoneal PHT (3 mg/kg/day, for three days) prolonged the life span of mice that had been implanted with Ehrlich ascites tumor. On day twenty-two, 43% of the PHT-treated mice were alive compared with no survivors in the control group.

1268. LeVan, H., Gordon, P., and Stefani, S., Effect of diphenylhydantoin on survival and morphology of Ehrlich ascites tumor mice, Oncology, 26: 25-32, 1972.

Levo, Naunyn-Schmeideberg's Archiv fur Pharmakologie (1974),1279 in a controlled study, observed that PHT (0.5 mg/day, for seven days) reduced the incidence of lung adenomas induced by urethane in SWR mice. Fourteen mice were treated with PHT, fifteen were injected with the solvent used to suspend PHT, and fifteen were untreated. The animals were sacrificed after twelve weeks. The fifteen mice treated with solvent had a total of seventy adenomas. The fifteen untreated mice had a total of sixty-eight adenomas. The fourteen mice treated with PHT had a total of forty-one adenomas. See also Ref. 1955.

1279. Levo, Y., The protective effect of hydantoin treatment on carcinogenesis, Naunyn-Schmiedeberg’s Arch. Pharmacol., 285: 29-30, 1974.
1955. Levo, Y., Markowitz, 0. and Trainin, N., Hydantoin immunosuppression and carcinogenesis, Clin. Exp. Immun., 19: 521-7, March 1975.

Kornblith, Callahan and Caswell, Neurosurgery (1978),1934 reported that PHT inhibited the growth of seven of ten cultured human astrocytoma cell lines. PHT (20-100 µg/ml) produced significant dose-dependent growth reduction. At comparable doses, the growth of normal fibroblasts and astrocytes was unaffected.

1934. Kornblith, P. L., Callahan, L. V. and Caswell, P. A., Growth-inhibitory effects of diphenylhydantoin on human brain tumor cells in culture, Neurosurgery, 2(2): 122-7, 1978.

Kornblith, Hartnett, Anderson, Quindlen and Smith, Neurosurgery (1979),1933 described significant growth inhibition by PHT of two murine astrocytoma cell lines in tissue culture. When the same tumor cells were implanted subcutaneously or intracranially in rats, the PHT-treated group showed significantly slower rates of tumor growth than the untreated group. Both tumor volume and number of actively dividing tumor cells were less in the PHT-treated group.

1933. Komblith, P. L., Hartnett, L. C., Anderson, L. P., Quindien, E. A., and Smith, B. H., Growth-inhibitory effect of diphenylhydantoin on murine astrocytomas, Neurosurgery, 5(2): 259-63, 1979.

Anisimov, Ostriumova and Dilman, Bulletin of Experimental Biology and Medicine (1980),2294 reported that administration of PHT (7.5 mg/kg/day) for three weeks prior to the induction of rat mammary tumors by 7,12-dimethylbenzanthracene reduced the incidence of such tumors by approximately 25%.

2294. Anisimov, V. N., Ostroumova, M. N., Dilman, V. N., Inhibition of the carcinogenic effect of 7,12-dirnethylbenz (a) anthracene in fernale rats by buforynin, phenytoin, pineal polypeptide extract, and L-dopa, Bull. Exp. Biol. Med., 89(6): 81922, 1980.

Dilman and Anisimov, Gerontology (1980),1806 reported that treatment of female C3H/Sn mice with PUT (2 mg/day, five days per week), decreased spontaneous tumor incidence by 2.3 times and prolonged mean life span by 25%, compared to controls. A similar effect was observed with phenformin.

1806. Dilman, V. M. and Anisimov, V. N., Effect of treatment with phenformin, diphenylhydantoin or L-dopa on life span and tumour incidence in C3H/Sn mice, Gerontology, 26: 241-6, 1980.

Shiba and Weinkam, Cancer Chemotherapy and Pharmacology (1983),2949 studied the effects of PHT, in combination with the chemotherapy agent procarbazine, on the lifespan of mice implanted with L1210 ascites leukemia cells. Procarbazine by itself increased lifespan by 29-32%. The addition of PHT (60 mg/kg) increased lifespan by a further 24%. Phenobarbital was effective to a lesser degree and methylprednisolone had no effect. The authors suggest that PHT achieves its beneficial effects on lifespan by inducing cytochrorne P-450 enzymes and thus increasing the production of metabolites of procarbazine with antitumor activity.

2949. Shiba, D. A., Weinkam, B. J., The in vivo cytotoxic activity of procarbazine and procarbazine metabolites against L1210 ascites leukemia cells in CDF-1 mice and the effects of pretreatment with procarbazine phenobarbital, diphenylhydantoin and methylprednisolone, Cancer Chemother. Pharmacol., 11(2): 124-9, 1983.

Lemon, Stohs, Heinicke, Pfeiffer and Campbell, Proceedings of the American Association for Cancer Research (1984),2701 noting reports of a lower incidence of breast and genital cancer among epileptic women taking anticonvulsants for more than ten years, evaluated the prophylactic activity of PHT against 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors in female rats. All control rats (133) developed breast carcinoma within six to nine months of DMBA exposure. Oral PHT (0.1%, in water), started fifteen days prior to DMBA exposure and continued for the six-to nine-month observation period, protected eleven of fifty-nine rats indefinitely from mammary tumors (p<.01). The combination of PHT and monthly subcutaneous estriol treatment prevented mammary tumors in fifteen of sixteen animals. The authors found that PHT induced hepatic aryl hydrocarbon hydroxylases and other monooxygenases after one week and suggest that the protective action of PHT is due to its ability to increase DMBA metabolism. See also Ref. 2587.

2701. Lemon, H. M., Stohs, S. J., Heinicke, R., Pfeiffer, R., Campbell, J. L., Anti-mammary carcinogenic activity of phenytoin (5,5' diphenylhydantoin), Proc. Am. Assoc. Cancer Res., 25: 128, 1984.

2587. Heinicke, R. J., Stobs, S. J., Al-Turk, W., Lemon, H. M., Chronic phenytoin administration and the hepatic mixed function oxidase system in female rats, Gen. Pharmacol., 15(2): 85-9, 1984.

Singer and Slesinger, Epilepsia (1985),2956 studied the effects of PHT, phenobarbital, carbamazepine and valproic acid on the growth and neurochemistry of a neuroblastorna X glioma cell Clone (NG 108-15) in culture. All four agents suppressed cell growth, but PHT (12.5-50 µg/ml) and valproic acid had the greatest effect. PHT also decreased activity of choline acetyl-transferase and ß-galactosidase.

2956. Singer, H. S., Slesinger, P., Effect of anticonvulsants on a neuroblastoma X glioma hybrid cell line: cell growth and synaptic neurochemistry, Epilepsia, 26(5): 519, 1985.

See also Refs. 507, 967, 1205, 1323, 1324, 1475, 1769, 1807, 1935, 1993, 2045, 2093, 2293, 2379, 2381, 2387, 2454, 2455, 2540, 2750, 2754, 3095.

507. Shafer, W. G., Effect of Dilantin sodium on various cell lines in tissue culture, Proc. Soc. Exp. Biol. Med., 108: 694-696, 1961.
967. Dilman, V. M., Elivbaeva, G. V., Vishnevskii, A. S., Tsyrilina, E. V., and Bulovskaia, L. N., Justification of the use of diphenine (diphenylhydantoin) in oncologic practice, Vop. Onkol., 17: 70-72, 1971.
1205. Kasai, S. and Yoshizumi, T., Effect of diphenylhydantoin sodium on the proliferation of cultured cells in vitro, Bull. Tokyo Dent. Coll., 12: 223-234, 1971.
1323. MacKinney, A. A. and Booker, H. E., Diphenylhydantoin effects on human lymphocytes in vitro and in vivo, Arch. Inmm. Med., 129: 988-992, 1972.
1324. MacKinney, A. A. and Vyas, R., Diphenylhydantoininduced inhibition of nucleic acid synthesis in cultured human lymphocytes, Proc. Soc. Exp. BW. Med., 141: 89-92, 1972.
1475. Robineaux, R., Lorans, G., and Beaure D’Augeres, C., Action of diphenylhydantoin on the growth and respiration of cell in culture, Rev. Europ. Etudes Clin. Biol., 15: 1066-1071, 1970.
1769. Chalfie, M. and Perlman, R. L., Inhibition of catecholamine synthesis and tyrosine 3-monooxygenase activation in pheochromocytoma cells by diphenylhydantoin, Neurochem., 29: 757-9, 1977.
1807. Dilman, V. M., Bershtein, L. M., Tsyriina, E. V., Bobrov, Y. F., Kovaleva, I. G., Vasileva, I. A. and Kryloya, N. V., The correction of endocrinous metabolic disturbances in oncological patients. The effect of biguanides (phenformin and adebit), miskleron, and diphenine, Vopr. Onhol., 21(11): 33-9, 1975.
1935. Kornblith, P. L., Caswell, P. A., Bogoch, S., Callahan, L. V. and Dreyfus, J., Effects of diphenylhydantoin on cultured human glial cells, In Vitro, 324, April, 1976.
1993. Muller, N. R., Tsyrlina, E. V., Ostroumova, M. N. and Shemerovskaya, T. G., The effect of diphenine on the growth and metastasis of experimental malignant tumors, Vopr. Onkol., 21(7): 86-90, 1975.
2045. Richelson, E. and Tuttle, J. B., Diphenylhydantoin inhibits ionic excitation of mouse neuroblastoma cells, Brain Res., 99:209-12,1975.
2093. Study, R. E., Phenytoin inhibition of cyclic guanosine 3 2:5 2-monophosphate (cGMP) accumulation in neuroblastoma cells by calcium channel blockade, J. Pharmacol. Exp. Titer., 215(3): 575-81, 1980.
2293. Anisimov, V. N., The effect of buformin and diphenine on the lifetime, estral function, and frequency of spontaneous tumors in rats, Vopr. Onkol., 26(6): 42-8, 1980.
2379. Catterall, W. A., Inhibition of voltage-senisitive sodium channels in neuroblastoma cells by antiarrhythmic drugs. Mol. Pharmacol., 20: 356-62, 1981.
2381. Chalfie, M., Hoadley, D., Pastan, S., Perlman, R. L., Calcium uptake into rat pheochromocytoma cells, J. Neurochem., 27: 1405-9, 1976.
2387. Chapman, J. R., Roberts, D. W., Schol, H. M., Bagwell, C. B., Hudson, J. L., Flow cytometric analysis of the effects of phenytoin and its major metabolite on mitogen stimulated mouse spleen cells, Int. J. Immunopharmacol., 5(5): 471-8, 1983.
2454. Dilman, V. D., Therapy for aging and diseases of compensation in light of the elevating mechanism of their development, Diseases of Aging, Wright, J., Ed., PSG, Inc., Boston, 283-302, 1981.
2455. Dilman, V. M., Cancer susceptibility. Diseases of Aging, Wright, J., Ed., PSG, Inc., Boston, 205-33, 1981.
2540. Gingrich, S. A., Smith, P. J., Shapiro, L. E., Surks, M. I., 5,5 2-diphenylhydantoin (phenytoin) attenuates the action of 3,5,3 2-triiodo-l-thyronine in cultured GC cells, Endocrinology, 116(6): 2306-13, 1985.
2750. MacKinney, A. A., Vyas, R., Lee, S. S., The effect of parahydroxylation of diphenylhydantoin on metaphase accumulation, Proc. Soc. Exp. Biol. Med., 149: 371-5, 1975.
2754. MacKinney, A. A., Vyas, R. S., Walker, D., Hydantoin drugs inhibit polymerization of pure microtubular protein, Pharmacol. Exp. Ther., 204(l): 189-94, 1978.
3095. Yi, S. J., Seitz, P. K., Cooper, C. W., Inhibition of in vitro secretion of rat calcitonin by phenytoin, Fed. Proc, 46(3): 393, 1987.