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Apoptotic Tumor Cell Death Induced by Estramustine in Patients with Malignant Glioma1

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Apoptotic Tumor Cell Death Induced by Estramustine in Patients with Malignant Glioma1 Vol. 4, 87-91, January 1998 Clinical Cancer Research 87 Apoptotic Tumor Cell Death Induced by Estramustine in Patients with Malignant Glioma1 Christina Valibo, A. Tommy Bergenheim, effects in human glioma cells in vitro (1, 2) and in a rat glioma Per Bergstrom, Per-Olof Gunnarsson, and model (3). The effects seem to involve the microtubuli system, resulting in an arrest of glioma cells in G2-M phase of the cell Roger Henriksson2 cycle (1, 4, 5). In addition, other cytotoxic effects involving cell Departments of Oncology [C. V., P. B., R. H.] and Neurosurgery [A. T. B.], UmeA University, 5-901 85 Ume#{225},Sweden, and Pharmacia membrane-coupled events (6-8) and DNA (2, 8) are involved. Upjohn, Lund, Sweden [P-O. G.] The phenomena of apoptosis, programmed cell death, has gained increased interest in experimental tumor research, and recently, it was suggested that EaM causes programmed cell ABSTRACT death in an experimental glioma model (9). In the present study, Estramustine phosphate (EMP), a cytotoxic drug used we have been able to demonstrate that EaM induces apoptosis in in the treatment of prostatic carcinoma, is metabolized and malignant glioma in the clinical situation. exerts specific cytotoxic effects in malignant glioma in vitro and in vivo. In the present study, we have evaluated the cytotoxic effect of EMP in the clinical situation with regard MATERIALS AND METHODS to appearance of DNA damage and its correlation to the Patients. Eighteen patients with supratentorial astrocy- uptake of estramustine (EaM) in human malignant astrocy- toma grade III-IV operated on at the Department of Neurosur- toma tissue. Ten patients were given 280 mg of EMP p.o. gery were included in the study. The mean age was 54 years 12 h before surgery. Specimens from brain tumor tissue (range, 21-77 years), and the male:female ratio was 1 1 :7. Ten were collected during surgery and used for detection of patients were given 280 mg of EMP p.o. The time was chosen fragmented DNA, a hallmark of apoptosis, with in situ end from earlier pharmacokinetic studies (10), and the dose of EMP labeling (ISEL) and agarose gel techniques. The main me- is routinely used in the treatment of patients with advanced tabolite of EMP in glioma tissue, EaM, was analyzed with prostatic carcinoma. Exclusion criteria were cardiac failure, gas chromatography. It was demonstrated that EMP in- angina pectoris, and impaired liver or renal function. Eight duced clusters of ISEL-positive tumor cells and fragmenta- patients served as controls and did not receive EMP. All patients tion of DNA on agarose gels in patients treated with EMP. In routinely received 8 mg of betamethason i.v. 12 and 2 h before the same patients, a significant uptake of EaM in tumor surgery. The study was approved by the local ethical committee, tissue was demonstrated. In control patients, who were not and informed consent was obtained individually from each treated with EMP, and in two EMP-treated patients with no patient. uptake of EaM, no signs of fragmented DNA and only a few At surgery, specimens of tumor tissue were collected for scattered ISEL-positive cells were seen in the tumor tissue. routine histopathological analysis and for the analysis described Signs of apoptosis were also seen in two different experi- below. The interval between administration of EMP and sample mental models, i.e., in vitro cell cultures of rat glioma cells taking was approximately 12 h. Specimens for analysis were and an in vivo rat glioma model. It is suggested that EaM can removed with special attention to avoid denaturation. The sam- induce apoptosis by a direct effect on a subpopulation of ples were immediately fixated in formalin or frozen and stored glioma cells in human brain tumors in the clinical situation. at -70#{176}Cuntil analyzed. In Vitro Experiments. A nitrosourea-induced rat glioma INTRODUCTION cell line BT4C (kindly provided by Prof. Rolf Bjerkvig, Uni- EaM,3 a fusion molecule between l73-estradiol and nor- versity of Bergen, Bergen, Norway) was used for this study to nitrogen mustard, has been shown to exert specific cytotoxic evaluate direct effects on single cells. The tumor cells were cultured in DMEM (Fbowlab, Glasgow, United Kingdom) sup- plemented with 10% FCS and 60 mg/biter gentamicin at 37#{176}C with 5% CO2 for at least 3 days, until the cell growth was exponential. The medium was changed every second or third Received 5/8/97; revised 9/1 1/97; accepted 9/23/97. day. EMP (Estracyt; Kabi-Pharmacia, Berger, Sweden) was The costs of publication of this article were defrayed in part by the dissolved in sterile water and diluted in DMEM to give the payment of page charges. This article must therefore be hereby marked concentration 20 p.g/mI. The cells were exposed to EMP for 1, advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 2, 3, 4, 8, 24, and 96 h before DNA integrity analysis. In I Supported by grants from the Swedish Cancer Society, Lions Cancer addition, cells treated as described above were spun down and Research Foundation (UmeA, Sweden), and Lundberg’s Research Foun- analyzed using the ISEL technique. dation (Gothenburg, Sweden). Rat Glioma Model. A rat glioma model using inbred 2 To whom requests for reprints should be addressed. Phone: 46-90- BD-IX rats and the BT4C glioma cell line was set up. The cells 7850000; Fax: 46-90-7852031. 3 The abbreviations used are: EaM, estramustine; EMP, estramustine were grown as a monolayer for 1 week before implantation. phosphate; ISEL, in situ end labeling. Cells growing in log phase were harvested and trypsinized Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 1998 American Association for Cancer Research. 88 Apoptotic Tumor Cell Death Induced by EaM Table 2 ISEL and expression of p53, bcl-2, and c-myc in eight ,‘ control patients with astrocytoma grade III-IV ISEL p53 bcl-2 c-myc Patient no. (%) (%) (%) (%) I 0 10 0 0 2 0 0 0 0 3 1 8 0 0 4 0 5 0 0 5 0 60 0 0 6 3 2 0 0 7 0 0 0 0 8 0 0 0 0 Quantitative analysis of ISEL Fig. I Clusters of apoptotic cells in malignant glioma analyzed using the ISEL technique in patients treated with EMP (X80). 600 0 Table 1 Uptake of EaM. the main metabolite of EMP. in 10 patients ‘C 500 with astrocytoma grade III-IV and the percentage of tumor cells U, U) positive for ISEL and immunohistochemistry (p53. bcl-2. and c-myc) a 400 Tumor Serum U Patient EaM EaM T:S ISEL p53 bcl-2 c-myc no. (ng/g’) (ngIg) EaM” (%) (%) (%) (%) p300 I 0 0 * 0 0 0 0 -J Lu 200 2 13 0 * 40 5 0 0 Cl) 3 138 10 14 50 0 0 4 0 4 26 0 5 35 0 0 5 100 5 125 6 21 5 0 0 0 6 50 2 25 30 0 0 0 E 7 15 2 7.5 10 0 0 0 C 8 0 0 * 0 5 0 0 10 - C’,) C”) 9 86 4 22 22 0 0 0 0 10 70 5 14 24 0 0 0 hours Fig. 2 Quantitative analysis of ISEL-positive apoptotic cells in a rat Mean 52.3 2.9 17.5 glioma model in vivo at various time points after EaM treatment. “ 1:5, tumor:serum ratio; , not applicable. totic at this time (12, 13). The number of ISEL-positive cells before being spun down and diluted in MEM supplemented with was quantified in the light microscope. Five randomly chosen 5% BD-IX rat serum to give 20,000 cells/S p.1 ‘. The rats, 8-14 areas (5 X l0- cm2) in each section were counted. Sections weeks old, were anesthetized by i.p. administration of 1.8 mu were also processed for routine staining with H&E. kg of a 1 : 1 : 1 mixture of fluanisonum ( 10 mg/mb ‘ ), fentan- Analysis of DNA Integrity. Paraffin sections of human ylum [0.2 mg/m1 ‘ (Hypnorm)], and midazolam [5 mg/ml glioma specimens were deparaffinated and rehydrated according (Dormicum)]. The cells were transplanted under stereotactic to standard histological procedures. The tissue fragments were conditions in the caudate nucleus. EaM was dissolved in ethanol then suspended in digestion buffer and treated with DNase-free and castor oil to a concentration of 10 mg/mb. Twenty-four days RNase. The samples were loaded into agarose gel containing after implantation, tumor samples were taken out 0.5, 1 , 2, 4, 8, ethidium bromide. Electrophoresis was performed, and the gels 24, and 96 h after administration of EaM (20 mg/mb, i.p.). were viewed by transillumination with UV light and photo- Samples of tumor and normal brain were treated as described for graphed. X-HindIII standard was used as molecular size stand- each method. The study was approved by the local ethical ard. The analysis was performed according to the method de- committee. scribed previously (9, 14). ISEL. Samples of tumor tissue from each patient and rat Immunohistochemistry (p53, bcl-2, and c-myc). The glioma tissue were fixed in formalin and embedded in paraffin. deparaffinated sections were heated in a microwave in 0.01 M In situ detection of apoptotic cells using nucleotides of which citrate buffer (pH 6), and incubation with the primary antibodies one is labeled [AlP, dGTP, CICTP, and biotin dUTP (Boehringer [p53 (Ab6; clone do-b ; Oncogene Science, Uniondale, NY), Mannheim, Mannheim, Germany)] and DNA-polymerase 1 bcl-2 (clone 124; Cambridge Biotechnology, Cambridge, MA), (Sigma, St.
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