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Promotive effect of diethylstilbestrol on urethan-induced mouse lung tumorigenesis
Chemosphere 41 (2000) 187±190
Promotive eect of diethylstilbestrol on urethan-induced mouse lung tumorigenesis Y.G. Jiang *, J.K. Chen, Z.L. Wu Institute for Chemical Carcinogenesis, Guangzhou Medical College, Guangzhou 510182, People's Republic of China
Abstract The eect of diethylstilbestrol (DES) on urethan-induced mouse lung tumorigenesis was assessed by a single intraperitoneal injecting of urethan (50 mg/kg) or/and multi intramuscular injecting of DES (5 or 50 mg/kg). All mice were sacri®ced 18 weeks after administration, and the lung tumors were examined histopathologically. DES did not produce an elevated lung tumor response when administered alone, but it produced a statistically signi®cant enhancement of incidence of tumors, average number of tumors, incidence of cancers and constituent ratio of malignant tumors when given in conjunction with urethan. The results indicated that DES may be a promoter in lung tumor formation. Ó 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction It has been very clear that sexual hormones play an important role in the genesis of cancers, such as carcinoma of endometrium and mammary cancer, etc., the relation of sexual hormones to the genesis of tumors in non-target organs such as liver, stomach and esophagus has also been reported (Cagle et al., 1990; Li and Jiang, 1991; Matsui et al., 1991). Epidemiological investigations have shown that the genesis of female lung adenocarcinoma might be associated with sexual hormones, but few studies on the relation between female hormones and lung tumor in experimental animals have been reported. Therefore, the present study was conducted to observe the eect of diethylstilbestrol (DES) on urethaninduced mouse lung tumors. 2. Materials and methods 2.1. Experimental animals and chemicals Female Kunming mice, with bodyweights of 17±20 g, were provided by the Animal Farm of Medical Experi*
Corresponding author.
ment attached to the Health Department of Guangzhou Province. DES and urethan were both products of Sigma Company. Urethan was dissolved in saline, and DES was dissolved in dimethylsulfoxide (DMSO) and diluted with saline. 2.2. Experimental methods and designation of groups The mice were divided randomly in seven groups, the control groups were of saline and DMSO + saline, respectively, and the treatment groups were the following: urethan group (U), low dose of DES (DES(LD)), high dose of DES (DES(HD)), low dose of DES + urethan (DES(LD) + U), high dose of DES + urethan (DES(HD) + U). Mice in groups of U, DES(LD) + U and DES(HD) + U were injected intraperitoneally, only once, with urethan at a dose of 500 mg/kg. One week later, mice in each treatment group were injected intramuscularly with DES solution, the dose for DES(LD) and DES(LD) + U groups was 5 mg/kg, and that for DES(HD) and DES(HD) + U groups was 50 mg/kg, the injection was once every week for each mouse for 18 weeks. After the week of the ®nal injection the mice were dissected, the lungs were ®xed with formaldehyde, and pieces of tumor and normal lung tissue were, respectively, taken out for routine paran slices, and the slices
0045-6535/00/$ - see front matter Ó 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 0 4 5 - 6 5 3 5 ( 9 9 ) 0 0 4 1 0 - 5
188
Y.G. Jiang et al. / Chemosphere 41 (2000) 187±190
were subject to hemotoxilin eosin staining, then observed by microscopy. 2.3. Methods of statistical analysis The comparisons of mouse body weights and average amount of tumors between dierent groups were made by t test, and the comparison of incidences of tumors between dierent groups was by the v2 test. 3. Results 3.1. Eects of urethan and DES on the body weights of mice The body weight gains of mice in the two solvent controls were not dierent from each other, and no tumor was found in the mice in the two groups, so they were merged as one group for statistical analysis. Up to the end of the experiment the body weight gains in each treatment group were not statistically dierent from that in control, indicating that the exposure of urethan and DES individually to mice had no obvious eect on body weights, the two drugs had no general toxicity, and the selection of doses was reasonable. 3.2. Pathological examination of the lung tumors By direct observation and by use of the anatomical microscope, lung tumors were identi®ed, and with diameters of 0.1±2 mm. The tumors were beneath the pulmonary pleura and prominent slightly on the surface of lungs. Pathological observation under the microscope showed the lung tumors were of two kinds: either benign or malignant tumor. The benign lung tumors were adenomas and papillomas (predominantly the former), and the malignant lung tumors were adenocarcinomas, papillary carcinomas and mixed carcinomas (predominantly the former). The mixed carcinomas displayed
qualities consistent with the former two types of carcinoma. The incidence of lung tumor and the average number of lung tumors in the LD or HD groups of DES exposed were not statistically dierent from that in the control (Table 1). When the two groups of combination of urethan and DES were compared with the group of urethan only, both the incidence of tumors and the average number of tumors were signi®cantly dierent between the above groups. This indicated that DES and urethan have potential synergistic action. Although the incidences of tumors in the group of DES(LD) + U and that of DES(HD) + U were not statistically dierent from each other, the average number of tumors in the later group was statistically higher than that in the former group. This indicated that the eect of DES on the genesis of the tumor seemed dose-dependent. More tumors were found in the right lungs than that in the left lungs, this might be relative to the larger area of right lung than left lung. The incidence of malignant lung tumors and the ratio of malignant tumors to total tumors in group of DES(LD) + U seemed higher than that in group of only urethan, but with no statistical dierence between them (Table 2); However, when the group of DES(HD) + U was compared with that of only urethan, the above indexes in the two groups were statistically dierent from each other. This suggested that DES at the HD was able to promote urethan-induced transformation from benign to malignant tumor, and the two agents evidenced synergism. The incidence of malignant tumors and the ratio of malignant to total tumors in the DES(HD) + U group were statistically higher than that in the DES(LD) + U group.
4. Discussion The role of sexual hormones in the genesis of lung cancer has recently been paid more attention
Table 1 Eect of urethan or/and DES on lung tumorigenesis
a
Group
No. of mice treated
No. of mice with tumors
Incidence of tumor (%)
No. of lung tumors Left
Right
Total
Mean no. of tumors per mouse x s
Control U DES(LD) DES(HD) DES(LD)+U DES(HD)+U
58 27 26 27 28 26
0 9 1 2 17 20
0.0 33.3* 3.8 7.4 60.7a; b 76.9a;c
0 5 0 0 14 29
0 12 1 2 36 70
0 17 1 2 50 99
0.00 0.69 1.04a 0.04 0.19 0.07 0.26 1.80 1.79a;c 3.81 2.83a;c;d
Compared with control, P < 0.01. Compared with U, P < 0.05. c Compared with U, P < 0.01. d Compared with DES(L) + U, P < 0.01. b
Y.G. Jiang et al. / Chemosphere 41 (2000) 187±190
189
Table 2 Malignancy rate of lung tumors induced by urethan or/and DES Group
Control U DES(LD) DES(HD) DES(LD)+U DES(HD)+U
No. of mice treated
No. of mice with MT
Incidence of MT (%)
No. of tumors
No. of MT AC
PC
MC
Total
Constituent ratio of MT (%)
58 27 26 27 28 26
0 5 0 0 9 17
0.0 18.5a 0.0 0.0 32.1a 65.3a; b; c
0 17 1 2 50 99
0 4 0 0 14 45
0 1 0 0 4 13
0 0 0 0 1 3
0 5 0 0 19 61
0.0 29.4a 0.0 0.0 38.0a 61.6a;d; e
MT ± malignant tumor, AC ± adenocarcinoma, PC ± papillocarcinoma, MC ± mixed cancer Compared with control, P < 0.01. b Compared with U, P < 0.01. c Compared with DES(LD)+U, P < 0.05. d Compared with U, P < 0.05. e Compared with DES(LD) + U, P < 0.01. a
(Cagle et al., 1990; Li et al., 1991; Zang et al., 1993). Many epidemiological investigations have shown that dierent carcinogenic factor induces lung cancers of dierent cell type, the constituent ratio of the cell types has sex-speci®city, which is characteristic of males with mainly squamous epithelial carcinoma and females with mainly adenocarcinoma (Qing et al., 1997). Squamous epithelial carcinoma was related to smoking and some professional hazards, while adenocarcinoma was most frequent in non-smoking and some professional hazards, while adenocarcinoma was most frequent in nonsmoking people, especially in non-smoking females with lung cancers, the proportion of adenocarcinoma was 76% (Fontham et al., 1994). Those who had received estrogen treatment experienced increased risk of developing lung adenocarcinoma (Taioli and Wynder, 1994). These ®ndings indicate that the dierences of cell types in lung cancers between the sexes and the higher incidence of adenocarcinoma in female may be related to their dierential sexual hormones. It has been reported that estrogen-binding proteins were detected in internal organs in rats such as lung, liver, and pancreas. Khosla, et al. (1979) found that when pregnant rabbits were administrated with 17-b-estradiol p.o., the content of surfactant on pulmonary alveoli in the fetal rabbits was increased by 4-folds, and the sensitivity of surfactant content to the stimulus of sexual hormones was potentiated (Khosla and Rooney, 1979). In recent years it has been reported that there are estrogen receptors in human lung cancer tissues (Cagle et al., 1990), especially female lung adenocarcinomas show a higher rate of estrogen receptor-positive cases (Zang et al., 1993). These ®ndings suggest that lung adenocarcinoma may be a kind of estrogen-dependent tumor. In the present study when the mice were administrated DES, the incidence of tumors and the average number of tumors in the LD or HD group were not statistically dierent from that in the solvent control,
indicating that DES itself does not induce lung tumor. However, in the two groups of DES in combination with urethan both the incidences of tumors and average number of tumors were higher than that in the group of urethan only, the dierence was statistically signi®cant. Although in the DES(LD) + U group the incidence of carcinoma and the proportion of malignant tumors were not statistically dierent from that in the group of urethan only, the increased incidence of carcinoma and the elevated proportions of malignant tumors in total tumors indicated that estrogen may be a carcinoma promoter, with a potential to increase the carcinogenicity of other carcinogens. Based on the present data, it could be concluded that estrogen is not a direct carcinogen to lung epithelium but rather is kind of carcinoma promoter. In a liver tumor-inducing model in rats in which estrogen was applied, diethylnitrosamine (DEN) was the initiator and estradiol was the promoter, when administrated with estradiol for 60 days, no tumors occurred in the rats, while liver tumors occurred in 80% of the rats administrated with DEN and estradiol simultaneously (Li et al., 1991). Studies with compound tablets of estrogen plus pregnendione (EP) in mice resulted in a similar conclusion, i.e., sexual hormones or c-rays did not induce any tumor individually, but when they were administrated in combination they induced tumors in the tested mice with a high incidence of tumors (Gao et al., 1993). In in vitro experiment malignant transformation in Syrian hamster embryo cells was successfully induced by c-rays at low dose in combination with EP, while neither c-rays nor EP induced malignant cell transformation individually. This further suggests that the in¯uence of estrogen on the genesis of tumors is promotion, taking part in carcinogenesis by synergism with other carcinogen(s). In summary, the results of the present study indicate that the higher incidence of lung adenocarcinoma in women may be related to the estrogen level. This viewpoint remains to be further studied.
190
Y.G. Jiang et al. / Chemosphere 41 (2000) 187±190
References Cagle, P.T., Mody, D.R., Schwartz, M.R., 1990. Estrogen and progesterone receptors in bronchogenic carcinoma. Cancer Research 50, 6632±6635. Fontham, E.T., Correa, P., Reynolds, P. et al., 1994. Environmental tobacco smoke and lung cancer in nonsmoking women: A multicenter stud. Journal of American Medical Association 271, 1752. Gao, F.M., Jiang, H.Y., Yu, L. et al., 1993. Studies on mechanisms and antagonistic methods for female hormones carcinogenesis. Chinese Sciences, B ed., 23, 283. Khosla, S.S., Rooney, S.A., 1979. Stimulation of fetal lung surfactant production by administration of 17-b-estradiol to the maternal rabbit. American Journal of Obstet Gynccology 133, 213. Li, J.Y., Jiang, Y.Y., 1991. Estrogen receptor in tumors of injestive system. Foreign Medical Sciences, Fascicle of Surgery 4, 193.
Li, J.J., Mueller, G.C., Sekely, L.I. et al., 1991. Current perspectives and future trends in hormonal carcinogenesis. Cancer Research 51, 3626. Matsui, M., Kojima, O., Uehara, Y. et al., 1991. Characterization of estrogen receptor in human gastric cancer. Cancer 68, 305. Qing, C., Chen, Y.Z., Du, Y.X., 1997. The trends in historical types of lung cancer during 1980±1988, Guangzhou, China. Lung Cancer 17, 219±230. Taioli, E., Wynder, E.L., 1994. Endocrine factors and adenocarcinoma of the lung in women. J. Natl. Cancer Inst. 86, 869. Zang, W.F., Sun, X.W., Lan, Y.B. et al., 1993. Studies of clinical pathology on 57 cases of female lung carcinoma by detection of receptors of estrogen and progestrogen. Chinese Journal of Oncology 15, 434.
Promotive eect of diethylstilbestrol on urethan-induced mouse lung tumorigenesis Y.G. Jiang *, J.K. Chen, Z.L. Wu Institute for Chemical Carcinogenesis, Guangzhou Medical College, Guangzhou 510182, People's Republic of China
Abstract The eect of diethylstilbestrol (DES) on urethan-induced mouse lung tumorigenesis was assessed by a single intraperitoneal injecting of urethan (50 mg/kg) or/and multi intramuscular injecting of DES (5 or 50 mg/kg). All mice were sacri®ced 18 weeks after administration, and the lung tumors were examined histopathologically. DES did not produce an elevated lung tumor response when administered alone, but it produced a statistically signi®cant enhancement of incidence of tumors, average number of tumors, incidence of cancers and constituent ratio of malignant tumors when given in conjunction with urethan. The results indicated that DES may be a promoter in lung tumor formation. Ó 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction It has been very clear that sexual hormones play an important role in the genesis of cancers, such as carcinoma of endometrium and mammary cancer, etc., the relation of sexual hormones to the genesis of tumors in non-target organs such as liver, stomach and esophagus has also been reported (Cagle et al., 1990; Li and Jiang, 1991; Matsui et al., 1991). Epidemiological investigations have shown that the genesis of female lung adenocarcinoma might be associated with sexual hormones, but few studies on the relation between female hormones and lung tumor in experimental animals have been reported. Therefore, the present study was conducted to observe the eect of diethylstilbestrol (DES) on urethaninduced mouse lung tumors. 2. Materials and methods 2.1. Experimental animals and chemicals Female Kunming mice, with bodyweights of 17±20 g, were provided by the Animal Farm of Medical Experi*
Corresponding author.
ment attached to the Health Department of Guangzhou Province. DES and urethan were both products of Sigma Company. Urethan was dissolved in saline, and DES was dissolved in dimethylsulfoxide (DMSO) and diluted with saline. 2.2. Experimental methods and designation of groups The mice were divided randomly in seven groups, the control groups were of saline and DMSO + saline, respectively, and the treatment groups were the following: urethan group (U), low dose of DES (DES(LD)), high dose of DES (DES(HD)), low dose of DES + urethan (DES(LD) + U), high dose of DES + urethan (DES(HD) + U). Mice in groups of U, DES(LD) + U and DES(HD) + U were injected intraperitoneally, only once, with urethan at a dose of 500 mg/kg. One week later, mice in each treatment group were injected intramuscularly with DES solution, the dose for DES(LD) and DES(LD) + U groups was 5 mg/kg, and that for DES(HD) and DES(HD) + U groups was 50 mg/kg, the injection was once every week for each mouse for 18 weeks. After the week of the ®nal injection the mice were dissected, the lungs were ®xed with formaldehyde, and pieces of tumor and normal lung tissue were, respectively, taken out for routine paran slices, and the slices
0045-6535/00/$ - see front matter Ó 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 0 4 5 - 6 5 3 5 ( 9 9 ) 0 0 4 1 0 - 5
188
Y.G. Jiang et al. / Chemosphere 41 (2000) 187±190
were subject to hemotoxilin eosin staining, then observed by microscopy. 2.3. Methods of statistical analysis The comparisons of mouse body weights and average amount of tumors between dierent groups were made by t test, and the comparison of incidences of tumors between dierent groups was by the v2 test. 3. Results 3.1. Eects of urethan and DES on the body weights of mice The body weight gains of mice in the two solvent controls were not dierent from each other, and no tumor was found in the mice in the two groups, so they were merged as one group for statistical analysis. Up to the end of the experiment the body weight gains in each treatment group were not statistically dierent from that in control, indicating that the exposure of urethan and DES individually to mice had no obvious eect on body weights, the two drugs had no general toxicity, and the selection of doses was reasonable. 3.2. Pathological examination of the lung tumors By direct observation and by use of the anatomical microscope, lung tumors were identi®ed, and with diameters of 0.1±2 mm. The tumors were beneath the pulmonary pleura and prominent slightly on the surface of lungs. Pathological observation under the microscope showed the lung tumors were of two kinds: either benign or malignant tumor. The benign lung tumors were adenomas and papillomas (predominantly the former), and the malignant lung tumors were adenocarcinomas, papillary carcinomas and mixed carcinomas (predominantly the former). The mixed carcinomas displayed
qualities consistent with the former two types of carcinoma. The incidence of lung tumor and the average number of lung tumors in the LD or HD groups of DES exposed were not statistically dierent from that in the control (Table 1). When the two groups of combination of urethan and DES were compared with the group of urethan only, both the incidence of tumors and the average number of tumors were signi®cantly dierent between the above groups. This indicated that DES and urethan have potential synergistic action. Although the incidences of tumors in the group of DES(LD) + U and that of DES(HD) + U were not statistically dierent from each other, the average number of tumors in the later group was statistically higher than that in the former group. This indicated that the eect of DES on the genesis of the tumor seemed dose-dependent. More tumors were found in the right lungs than that in the left lungs, this might be relative to the larger area of right lung than left lung. The incidence of malignant lung tumors and the ratio of malignant tumors to total tumors in group of DES(LD) + U seemed higher than that in group of only urethan, but with no statistical dierence between them (Table 2); However, when the group of DES(HD) + U was compared with that of only urethan, the above indexes in the two groups were statistically dierent from each other. This suggested that DES at the HD was able to promote urethan-induced transformation from benign to malignant tumor, and the two agents evidenced synergism. The incidence of malignant tumors and the ratio of malignant to total tumors in the DES(HD) + U group were statistically higher than that in the DES(LD) + U group.
4. Discussion The role of sexual hormones in the genesis of lung cancer has recently been paid more attention
Table 1 Eect of urethan or/and DES on lung tumorigenesis
a
Group
No. of mice treated
No. of mice with tumors
Incidence of tumor (%)
No. of lung tumors Left
Right
Total
Mean no. of tumors per mouse x s
Control U DES(LD) DES(HD) DES(LD)+U DES(HD)+U
58 27 26 27 28 26
0 9 1 2 17 20
0.0 33.3* 3.8 7.4 60.7a; b 76.9a;c
0 5 0 0 14 29
0 12 1 2 36 70
0 17 1 2 50 99
0.00 0.69 1.04a 0.04 0.19 0.07 0.26 1.80 1.79a;c 3.81 2.83a;c;d
Compared with control, P < 0.01. Compared with U, P < 0.05. c Compared with U, P < 0.01. d Compared with DES(L) + U, P < 0.01. b
Y.G. Jiang et al. / Chemosphere 41 (2000) 187±190
189
Table 2 Malignancy rate of lung tumors induced by urethan or/and DES Group
Control U DES(LD) DES(HD) DES(LD)+U DES(HD)+U
No. of mice treated
No. of mice with MT
Incidence of MT (%)
No. of tumors
No. of MT AC
PC
MC
Total
Constituent ratio of MT (%)
58 27 26 27 28 26
0 5 0 0 9 17
0.0 18.5a 0.0 0.0 32.1a 65.3a; b; c
0 17 1 2 50 99
0 4 0 0 14 45
0 1 0 0 4 13
0 0 0 0 1 3
0 5 0 0 19 61
0.0 29.4a 0.0 0.0 38.0a 61.6a;d; e
MT ± malignant tumor, AC ± adenocarcinoma, PC ± papillocarcinoma, MC ± mixed cancer Compared with control, P < 0.01. b Compared with U, P < 0.01. c Compared with DES(LD)+U, P < 0.05. d Compared with U, P < 0.05. e Compared with DES(LD) + U, P < 0.01. a
(Cagle et al., 1990; Li et al., 1991; Zang et al., 1993). Many epidemiological investigations have shown that dierent carcinogenic factor induces lung cancers of dierent cell type, the constituent ratio of the cell types has sex-speci®city, which is characteristic of males with mainly squamous epithelial carcinoma and females with mainly adenocarcinoma (Qing et al., 1997). Squamous epithelial carcinoma was related to smoking and some professional hazards, while adenocarcinoma was most frequent in non-smoking and some professional hazards, while adenocarcinoma was most frequent in nonsmoking people, especially in non-smoking females with lung cancers, the proportion of adenocarcinoma was 76% (Fontham et al., 1994). Those who had received estrogen treatment experienced increased risk of developing lung adenocarcinoma (Taioli and Wynder, 1994). These ®ndings indicate that the dierences of cell types in lung cancers between the sexes and the higher incidence of adenocarcinoma in female may be related to their dierential sexual hormones. It has been reported that estrogen-binding proteins were detected in internal organs in rats such as lung, liver, and pancreas. Khosla, et al. (1979) found that when pregnant rabbits were administrated with 17-b-estradiol p.o., the content of surfactant on pulmonary alveoli in the fetal rabbits was increased by 4-folds, and the sensitivity of surfactant content to the stimulus of sexual hormones was potentiated (Khosla and Rooney, 1979). In recent years it has been reported that there are estrogen receptors in human lung cancer tissues (Cagle et al., 1990), especially female lung adenocarcinomas show a higher rate of estrogen receptor-positive cases (Zang et al., 1993). These ®ndings suggest that lung adenocarcinoma may be a kind of estrogen-dependent tumor. In the present study when the mice were administrated DES, the incidence of tumors and the average number of tumors in the LD or HD group were not statistically dierent from that in the solvent control,
indicating that DES itself does not induce lung tumor. However, in the two groups of DES in combination with urethan both the incidences of tumors and average number of tumors were higher than that in the group of urethan only, the dierence was statistically signi®cant. Although in the DES(LD) + U group the incidence of carcinoma and the proportion of malignant tumors were not statistically dierent from that in the group of urethan only, the increased incidence of carcinoma and the elevated proportions of malignant tumors in total tumors indicated that estrogen may be a carcinoma promoter, with a potential to increase the carcinogenicity of other carcinogens. Based on the present data, it could be concluded that estrogen is not a direct carcinogen to lung epithelium but rather is kind of carcinoma promoter. In a liver tumor-inducing model in rats in which estrogen was applied, diethylnitrosamine (DEN) was the initiator and estradiol was the promoter, when administrated with estradiol for 60 days, no tumors occurred in the rats, while liver tumors occurred in 80% of the rats administrated with DEN and estradiol simultaneously (Li et al., 1991). Studies with compound tablets of estrogen plus pregnendione (EP) in mice resulted in a similar conclusion, i.e., sexual hormones or c-rays did not induce any tumor individually, but when they were administrated in combination they induced tumors in the tested mice with a high incidence of tumors (Gao et al., 1993). In in vitro experiment malignant transformation in Syrian hamster embryo cells was successfully induced by c-rays at low dose in combination with EP, while neither c-rays nor EP induced malignant cell transformation individually. This further suggests that the in¯uence of estrogen on the genesis of tumors is promotion, taking part in carcinogenesis by synergism with other carcinogen(s). In summary, the results of the present study indicate that the higher incidence of lung adenocarcinoma in women may be related to the estrogen level. This viewpoint remains to be further studied.
190
Y.G. Jiang et al. / Chemosphere 41 (2000) 187±190
References Cagle, P.T., Mody, D.R., Schwartz, M.R., 1990. Estrogen and progesterone receptors in bronchogenic carcinoma. Cancer Research 50, 6632±6635. Fontham, E.T., Correa, P., Reynolds, P. et al., 1994. Environmental tobacco smoke and lung cancer in nonsmoking women: A multicenter stud. Journal of American Medical Association 271, 1752. Gao, F.M., Jiang, H.Y., Yu, L. et al., 1993. Studies on mechanisms and antagonistic methods for female hormones carcinogenesis. Chinese Sciences, B ed., 23, 283. Khosla, S.S., Rooney, S.A., 1979. Stimulation of fetal lung surfactant production by administration of 17-b-estradiol to the maternal rabbit. American Journal of Obstet Gynccology 133, 213. Li, J.Y., Jiang, Y.Y., 1991. Estrogen receptor in tumors of injestive system. Foreign Medical Sciences, Fascicle of Surgery 4, 193.
Li, J.J., Mueller, G.C., Sekely, L.I. et al., 1991. Current perspectives and future trends in hormonal carcinogenesis. Cancer Research 51, 3626. Matsui, M., Kojima, O., Uehara, Y. et al., 1991. Characterization of estrogen receptor in human gastric cancer. Cancer 68, 305. Qing, C., Chen, Y.Z., Du, Y.X., 1997. The trends in historical types of lung cancer during 1980±1988, Guangzhou, China. Lung Cancer 17, 219±230. Taioli, E., Wynder, E.L., 1994. Endocrine factors and adenocarcinoma of the lung in women. J. Natl. Cancer Inst. 86, 869. Zang, W.F., Sun, X.W., Lan, Y.B. et al., 1993. Studies of clinical pathology on 57 cases of female lung carcinoma by detection of receptors of estrogen and progestrogen. Chinese Journal of Oncology 15, 434.