- Email: [email protected]
Phenytoin may increase the efficacy of temozolomide by methylating DNA-repair enzyme, O6-methylguanine-DNA methyltransferase in patients with glioblastoma
Correspondence
819
Does Estradiol induced inhibition of 11b-hydroxysteroid dehydrogenase 1 explain effects of the postmenopausal hormone replacement therapy? I have read with great interest the article ‘‘Estradiol induced inhibition of 11b-hydroxysteroid dehydrogenase 1: an explanation for the postmenopausal hormone replacement therapy effects’’ by Cohen [1]. This hypothesis defines the inhibition of the conversion of cortisone to the active glucocorticoid cortisol by estradiol as a mechanism explaining adverse effect of postmenopausal hormone replacement therapy, e.g., the onset of asthma. Concerning the known anti-inflammatory action of cortisol this is an intriguing theory, but what is the experimental evidence it is based on? The publication by Ligeiro de Oliveira [2] cited by P.G. Cohen to substantiate the inhibition of the 11b-hydroxysteroid dehydrogenase 1 (11b-HSD1) by estradiol does not report experiments investigating 11bHSD1 activity or any other form or steroid metabolism. The effects of estradiol on the 11b-HSD1 are diverse and may be species and tissue specific: In rat liver 11b-HSD1 activity is lower after estradiol treatment [3], in rat kidney estradiol suppresses 11b-HSD1 mRNA and protein expression [4]. Promoter analysis of the baboon 11bHSD1 gene shows an induction by estradiol of a reporter gene incorporating the 50 -flanking region of the 11b-HSD1 gene [5]. Regulation of human 11b-HSD1 expression and activity by estradiol is not known but investigations are on the way that will aid to a qualified reconsideration of the hypothesis formulated by P.G. Cohan.
References [1] Cohen PG. Estradiol induced inhibition of 11beta-hydroxysteroid dehydrogenase 1: an explanation for the postmenopausal hormone replacement therapy effects. Med Hypotheses 2005;64:989–91. [2] Ligeiro de Oliveira AP, Oliveira-Filho RM, da Silva ZL, Borelli P, Tavares de LW. Regulation of allergic lung inflammation in rats: interaction between estradiol and corticosterone. Neuroimmunomodulation 2004;11:20–7. [3] Low SC, Assaad SN, Rajan V, Chapman KE, Edwards CR, Seckl JR. Regulation of 11 beta-hydroxysteroid dehydrogenase by sex steroids in vivo: further evidence for the existence of a second dehydrogenase in rat kidney. J Endocrinol 1993;139:27–35. [4] Gomez-Sanchez EP, Ganjam V, Chen YJ, Liu Y, Zhou MY, Toroslu C, et al. Regulation of 11-beta-hydroxysteroid dehydrogenase enzymes in the rat kidney by estradiol. Am J Physiol Endocrinol Metab 2003;285:E272–9. [5] Pepe GJ, Davies WA, Dong KW, Luo H, Albrecht ED. Cloning of the 11b-hydroxysteroid dehydrogenase (11b-HSD)- 2 gene in the baboon: effects of estradiol on promoter activity of 11b-HSD-1 and -2 in placental JEG-3 cells. Biochim Biophys Acta Gene Struct Expression 1999;1444:101–10.
Volker Ba ¨hr Department of Endocrinology Diabetes and Nutrition ´ Universita ¨tsmedizin Berlin Charite Campus Benjamin Franklin ¨t Gemeinsame Einrichtung der Freien Universita ¨t zu Berlin Berlin und der Humboldt-Universita Hindenburgdamm 30, D 12200 Berlin, Germany Tel.: +49 30 8445 2636; fax: +49 30 8445 4204 E-mail address: [email protected]
doi:10.1016/j.mehy.2005.04.018
Phenytoin may increase the efficacy of temozolomide by methylating DNA-repair enzyme, O6-methylguanine-DNA methyltransferase in patients with glioblastoma To The Editor, Glioblastoma is the most common primary brain tumor in adults. Standard therapy is surgical resection
followed by adjuvant radiotherapy and chemotherapy. Many phase 3 trials have demonstrated a better outcome with the addition of chemotherapy (usually with a nitrosourea drug) to radiotherapy, but a
820 significant prolongation of survival has never been observed [1]. Temozolomide, an oral alkylating agent, has demonstrated antitumor activity as a single agent in the treatment of recurrent glioma. It depletes the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). This effect may be important because low levels of MGMT in tumor tissue are associated with longer survival among patients with glioblastoma who are receiving nitrosourea-based adjuvant chemotherapy [2]. Recently, promising phase 3 study by Stupp et al. [3] in adults with newly diagnosed glioblastoma showed that the addition of temozolomide to radiotherapy resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Moreover, Hegi et al. [4] reported that patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit. Substantial number of patients with brain tumors has a propensity to develop seizures. Although there is a debate ongoing whether an antiepileptic drug (AED) should be prescribed prophylactically at the time that a brain tumor is detected, currently substantial number of patients still use AED prophylactically such as phenobarbital, phenytoin, or valproic acid. In animal study, it was shown that phenytoin treatment tended to increase methylation capacity in the brain [5]. Although there is no study in the literature showing the methylation effect of phenytoin specifically on MGMT in glioblastoma cells, phenytoin may show synergism with temozolomide by methylating MGMT further that may increase the efficacy of temozolomide. In vitro studies and analysis of patients that use both temozolomide and phenytoin may give a clue to reveal this proposal.
References [1] DeAngelis LM. Chemotherapy for brain tumors – a new beginning. N Engl J Med 2005;352:1036–8.
Correspondence [2] Hegi ME, Diserens AC, Godard S, et al. Clinical trial substantiates the predictive value of O6-methylguanineDNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 2004;10:1871–4. [3] Stupp R, Mason WP, van den Brent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma. N Engl J Med 2005;352: 987–996. [4] Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997–1003. [5] Carl GF, Smith ML, Furman GM, et al. Phenytoin treatment and folate supplementation affect folate concentrations and methylation capacity in rats. J Nutr 1991;121:1214–21.
Ozden Altundag 8181 Fannin Street No. 728 Houston, TX 77054 USA Kadri Altundag Department of Medical Oncology Hacettepe University Faculty of Medicine Ankara, Turkey 8181 Fannin Street No. 728 Houston, TX 77054 USA Tel.: +1 713 563 0765; fax: +1 713 794 4385 Email address: [email protected] Cem Boruban Department of Medical Oncology Selcuk University, Faculty of Medicine Konya Turkey Muzaffer B. Altundag Department of Radiation Oncology Ankara Oncology Hospital Ankara, Turkey Selahattin Turen Department of Pulmonary and Critical Care Medicine, Memorial Hermann Hospital University of Texas at Houston Medical School Houston, USA
doi:10.1016/j.mehy.2005.04.007
Insoluble fibrin may reduce turbulence and bind blood components into clots To the Editor Recently published studies may partially explain the regulation of coagulation. Defects in Factor XIII
cause bleeding [1], presumably via the faulty formation of three-dimensional ‘‘insoluble’’ fibrin [2], which normally increases blood viscosity [3] and connects blood components [4]. Pulsatile
819
Does Estradiol induced inhibition of 11b-hydroxysteroid dehydrogenase 1 explain effects of the postmenopausal hormone replacement therapy? I have read with great interest the article ‘‘Estradiol induced inhibition of 11b-hydroxysteroid dehydrogenase 1: an explanation for the postmenopausal hormone replacement therapy effects’’ by Cohen [1]. This hypothesis defines the inhibition of the conversion of cortisone to the active glucocorticoid cortisol by estradiol as a mechanism explaining adverse effect of postmenopausal hormone replacement therapy, e.g., the onset of asthma. Concerning the known anti-inflammatory action of cortisol this is an intriguing theory, but what is the experimental evidence it is based on? The publication by Ligeiro de Oliveira [2] cited by P.G. Cohen to substantiate the inhibition of the 11b-hydroxysteroid dehydrogenase 1 (11b-HSD1) by estradiol does not report experiments investigating 11bHSD1 activity or any other form or steroid metabolism. The effects of estradiol on the 11b-HSD1 are diverse and may be species and tissue specific: In rat liver 11b-HSD1 activity is lower after estradiol treatment [3], in rat kidney estradiol suppresses 11b-HSD1 mRNA and protein expression [4]. Promoter analysis of the baboon 11bHSD1 gene shows an induction by estradiol of a reporter gene incorporating the 50 -flanking region of the 11b-HSD1 gene [5]. Regulation of human 11b-HSD1 expression and activity by estradiol is not known but investigations are on the way that will aid to a qualified reconsideration of the hypothesis formulated by P.G. Cohan.
References [1] Cohen PG. Estradiol induced inhibition of 11beta-hydroxysteroid dehydrogenase 1: an explanation for the postmenopausal hormone replacement therapy effects. Med Hypotheses 2005;64:989–91. [2] Ligeiro de Oliveira AP, Oliveira-Filho RM, da Silva ZL, Borelli P, Tavares de LW. Regulation of allergic lung inflammation in rats: interaction between estradiol and corticosterone. Neuroimmunomodulation 2004;11:20–7. [3] Low SC, Assaad SN, Rajan V, Chapman KE, Edwards CR, Seckl JR. Regulation of 11 beta-hydroxysteroid dehydrogenase by sex steroids in vivo: further evidence for the existence of a second dehydrogenase in rat kidney. J Endocrinol 1993;139:27–35. [4] Gomez-Sanchez EP, Ganjam V, Chen YJ, Liu Y, Zhou MY, Toroslu C, et al. Regulation of 11-beta-hydroxysteroid dehydrogenase enzymes in the rat kidney by estradiol. Am J Physiol Endocrinol Metab 2003;285:E272–9. [5] Pepe GJ, Davies WA, Dong KW, Luo H, Albrecht ED. Cloning of the 11b-hydroxysteroid dehydrogenase (11b-HSD)- 2 gene in the baboon: effects of estradiol on promoter activity of 11b-HSD-1 and -2 in placental JEG-3 cells. Biochim Biophys Acta Gene Struct Expression 1999;1444:101–10.
Volker Ba ¨hr Department of Endocrinology Diabetes and Nutrition ´ Universita ¨tsmedizin Berlin Charite Campus Benjamin Franklin ¨t Gemeinsame Einrichtung der Freien Universita ¨t zu Berlin Berlin und der Humboldt-Universita Hindenburgdamm 30, D 12200 Berlin, Germany Tel.: +49 30 8445 2636; fax: +49 30 8445 4204 E-mail address: [email protected]
doi:10.1016/j.mehy.2005.04.018
Phenytoin may increase the efficacy of temozolomide by methylating DNA-repair enzyme, O6-methylguanine-DNA methyltransferase in patients with glioblastoma To The Editor, Glioblastoma is the most common primary brain tumor in adults. Standard therapy is surgical resection
followed by adjuvant radiotherapy and chemotherapy. Many phase 3 trials have demonstrated a better outcome with the addition of chemotherapy (usually with a nitrosourea drug) to radiotherapy, but a
820 significant prolongation of survival has never been observed [1]. Temozolomide, an oral alkylating agent, has demonstrated antitumor activity as a single agent in the treatment of recurrent glioma. It depletes the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). This effect may be important because low levels of MGMT in tumor tissue are associated with longer survival among patients with glioblastoma who are receiving nitrosourea-based adjuvant chemotherapy [2]. Recently, promising phase 3 study by Stupp et al. [3] in adults with newly diagnosed glioblastoma showed that the addition of temozolomide to radiotherapy resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Moreover, Hegi et al. [4] reported that patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit. Substantial number of patients with brain tumors has a propensity to develop seizures. Although there is a debate ongoing whether an antiepileptic drug (AED) should be prescribed prophylactically at the time that a brain tumor is detected, currently substantial number of patients still use AED prophylactically such as phenobarbital, phenytoin, or valproic acid. In animal study, it was shown that phenytoin treatment tended to increase methylation capacity in the brain [5]. Although there is no study in the literature showing the methylation effect of phenytoin specifically on MGMT in glioblastoma cells, phenytoin may show synergism with temozolomide by methylating MGMT further that may increase the efficacy of temozolomide. In vitro studies and analysis of patients that use both temozolomide and phenytoin may give a clue to reveal this proposal.
References [1] DeAngelis LM. Chemotherapy for brain tumors – a new beginning. N Engl J Med 2005;352:1036–8.
Correspondence [2] Hegi ME, Diserens AC, Godard S, et al. Clinical trial substantiates the predictive value of O6-methylguanineDNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 2004;10:1871–4. [3] Stupp R, Mason WP, van den Brent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma. N Engl J Med 2005;352: 987–996. [4] Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997–1003. [5] Carl GF, Smith ML, Furman GM, et al. Phenytoin treatment and folate supplementation affect folate concentrations and methylation capacity in rats. J Nutr 1991;121:1214–21.
Ozden Altundag 8181 Fannin Street No. 728 Houston, TX 77054 USA Kadri Altundag Department of Medical Oncology Hacettepe University Faculty of Medicine Ankara, Turkey 8181 Fannin Street No. 728 Houston, TX 77054 USA Tel.: +1 713 563 0765; fax: +1 713 794 4385 Email address: [email protected] Cem Boruban Department of Medical Oncology Selcuk University, Faculty of Medicine Konya Turkey Muzaffer B. Altundag Department of Radiation Oncology Ankara Oncology Hospital Ankara, Turkey Selahattin Turen Department of Pulmonary and Critical Care Medicine, Memorial Hermann Hospital University of Texas at Houston Medical School Houston, USA
doi:10.1016/j.mehy.2005.04.007
Insoluble fibrin may reduce turbulence and bind blood components into clots To the Editor Recently published studies may partially explain the regulation of coagulation. Defects in Factor XIII
cause bleeding [1], presumably via the faulty formation of three-dimensional ‘‘insoluble’’ fibrin [2], which normally increases blood viscosity [3] and connects blood components [4]. Pulsatile