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Antitumor effect of cis-diamminedichloplatinum (II) and augmentation of activity against lung cancer of the rats
29
cytology and chest x-ray. For comparison purposes, expected prevalences ~ ~put,hn abnormalities were determined among those groups without known occupational hazards, standardized for age and smoking habits. The potroom workers returned a higher proportion of adequate samples of sputum (72% vs 57% expected) and demonstrated a higher prevalence of metaplasia (2.2% vs 1.7% expected) and dysplasia (8.4% vs 2.0% expected, p less than .05). Workers currently employed in the potrooms were more likely than those previously employed in the potrooms to have metaplasia (3.0% vs 1.4%), dysplasia (10.8% vs 5.6%) and moderate to severe dysplasia (6.6% vs 1.4%). The prevalence of dysplasia was higher among those employed before (as compared to those since) 1962: for dysplasia, 14.8% vs 3.9%; for moderate to severe dysplasia, 9.1% vs 1.3%. We conclude that aluminum potroom workers, especially those currently employed who have worked more than 20 years experience an excess of sputum cytological abnormalities.
Second P[imary Lung Cance~s. Wagenaar3, Sj.Sc., Berkel , J., Vanderschueren , R . G . A . J . M . i . Department of Pathology. 3. Departm,ent of Pulmonary Disr~, Antonius Hospit~i Koekoekslaan I, 3445 F:M Nieu~ege~n, The Netherlands. 2. [~'2~tment of Ep~demiology, Comprehensive Cancer Centre, Radboudkwartier 259, 3511 CK Utrecht, The Netherlands. Few data are available with regard to second primairy cancers of the lung. We analyzed the frequency of second primary lung cancers diagnosed in a large referral hospital during the period 1979-1984. The criteria for a second primary of the lung were different histologies, another intrapulmonary location and/or 3 year time interval between the diagnosis of the first and the second tumor. All cases in which second primaries were diagnosed were reviewed, including the pathologic picture. A total of 1609 primary lung cancers were diagnosed during the study period. In 106 cases a second primary was found during the follow-up period. A descriptive analysis will be presented of histology, subsite and tumorstage. The relative frequencies among patients with a single tumor will be compared with those with second primaries.
3,
BASICBIOLOGY
Inhibitory Effects of Organic Selenium on Metastasis of Lewis Lung Carcinoma in C57BL Mice. Tian, H.S., Liu, Y.H. Department of Pathology, Hubei Medical College, Wuhan, China.
The inhibitory effects of organic seleniumselenium yeast on metastasis of Lewis lung carcinoma were investigated in C57BL mice. The experiment was performed as follows: C57BL mice were divided into two groups, one group was supplemented with 2 ppm of selenium (in form of selenium yeast) in their diet and nother group was fed up with basal diet for control. All mice were inoculated with single cell suspension of Lewis lung carcinoma in their left hind muscles. After 21 days, all animals were killed. The result showed that the number of metastatic tumors in lung is obviously less in the group with selenium yeast than in the control (P<0.01). Such result suggests that selenium yeast can effectively inhibit the metastasis of Lewis lung carcinoma. The differences in ultr structures and cytochemistry observed were interesting. The mechanism of the inhibition were discussed.
Inhibitory Effects of Selenium Yeast and Sodium Selenite on Methylcholanthrene - Induced Lung Carcinoma in Rats. Tian, H.S., Xiong, Y.Y., Gao, W.Q., Liu, M.Q., Zuo, R.D. Department of Pathology, Hubei Medical College, Wuhan, China. The inhibitory effects of selenium yeast and sodium selenite on methylcholanthreneinduced lung carcinogenesis were examined in inbred Wistar rats. The animals were divided into three groups: Group I and II were supplemented with 2 ppm of selenium (organic form, in yeast) in their diet and with 1.5 ppm sodium selenite in their drinking water respectively, and group III were fed basal diet for control. The results showed that the rate of carcinogenesis in group I, II and III were 76.92% (P<0.01), 82.14% (P<0.05) and 100%, respectively. The hyperplasia and metaplasia of bronchial epithelium were striking in group III, however, the lymphocyte immune response were remarkable in group I and II. These results suggested that the selenium yeast and sodium selenite is effective in preventing the MCA-induced lung carcinogenesis in rats, and the former is more effective than the latter.
Antitum0r Effect of Cis-Dian~inedichloplatinum (II) and Augmentation of Activity Against Lung Cancer of the Rats. Shimada, K., Yasuda, S., Yagisawa, H., Horie, S. Dokkyo University School of Medicine, Tochigi, Japan. Antitumor effect of cisplatin(CDDP) against transplanted Sato lung cancer and augmentation of the obtained antitumor activity by means of zinc and bismus salt were studied. In ten Donryu rats, CDDP was administered intr~peritoneally for 4 times with intervals 3 days from day 1 at doses of 2 mg/kg. Following data were evaluated in these rats and non-treated control group: I) Survival of animal, 2) Tumor size, 3) Cytostatic activity of spleen cells. Results obtained were as follows; a) Mean ~urv~val of control group was 21.1 days, whereas
30
80% of CDDP group was tumor-free at 120 djys after tumor ~no¢lation. b) ~he cytostatic activity of CDDP treated animals was 90% and 51% with control at effector to target rations of 50:1. c) The augmentation of activity of CDDP with zinc or bismus salt was elevated. In conclusion, the antitumor effect augmented when tumorbearing rats were injected zinc or bismus one day before CDDP acministration. The mechanism of this efficacy of those metals will be discussed. Bioassay of Cisplatin by Clonogenic Assay. Sasaki, Y., Saijo, N., Futami, H., Fujita, J., Shimizu, E., Ishihara, J., Kanzawa, F., Hoshi, A. National Cancer Center, Tokyo, Japan. In spite of its broad antitumor spectrum and high response rate, there remain many problems to determine the precise pharmacokinetics of cisplatin (CDDP). In this study, a new bioassay method of CDDP using human tumor clonogenic assay (HTCA) is presented and the pharmacokinetics of active form CDDP measured by HTCA is also reported. Twelve patients with histologically confirmed primary lung cancer were entered in this study. CDDP was administered by four different treatment arms; Arm A: 80 mg/m? IV infusion of Day i, Arm B: 20 mg/m- IV infusion from day 1 to day 4, Arm C: 120 mg/m IV infusion of day i, Arm D: i00 mg/body intra pleural injection. The basic procedure used in this study was that of Hamburger and Salmon with a little modification. As a target cell line, PC-9, a lung adenocarcinoma cell line kindly provided by Prof. Hayata, was used. Plasma from healthy volunteers containing various concentration of CDDP were prepaired for obtaining standard curve. With Arm A and Arm B, active CDDP over 1.0 ug/ml disappeared from plasma within 30 minutes after administration, but in Arm C, active form CDDP was detected even after 2 hours and the peak concentration was 7.5 ug/ml. With Arm D, active form CDDP was delected in some cases. Glycerol-Induced Promoting Action on Murine Pulmonary Tumorigenesis by a Single Administration of 4-Nitroquinoline 1-Oxide (4NQO) in ddY Mice. Inayama, Y., Kitamura, H., Ito, T., Kanisawa, M. Department of Pathology, Yokohama City University School of Medicine, Yokohama, Japan. The nonciliated bronchiolar cell (Clara cell) is considered to have significant metabolic activity, and also expected to be one of the possible progenitor cells of lung tumor. We found that the oral ad-
ministration of glycerol (GL) induced significant morphological changes of the Clara cell organelles, which may suggest some alteration in the metabolism of the Claz-a cell..This study was carried out to examine a possible modification of pulmonary tumorigenesis by GL. Animals: 6week-old ddY male mice, i0 ea. per group, were used. GL: 5% solution was given as drinking water ad libitum (I~). Carcinogen: A single dose of 4NQO, 0.3 mg, was given s.c. ( , ) . Table indica.~.~.ip ~ ° b 0=0 tes: a: Per cent "~tIIH,H,,,,7. 0 o 070 of tumor-bearing mi~i~ 10 i 0.J~0.1 ce. b: Total tumor . 80 35 3,5_~1.4 ",HH,,,,HH; 88 n 2.K'0.5 number, c : Mean tu: ~ p 1 1 1 ~ 9. 70 19 1 . 9 - 0 . 6 ,/iI~ ~ 44 lO I . | ~ 0 . 6 mor number per mou".w1~ ............... 8 0.9";0.', se.
Both an incidence of tumor-bearing mice and a number of induced tumor per mouse were enhanced in all the groups received combined admini, stration of 4NQO and GL, compared with the nontreated or noncombined groups. Present results showed glycerol is a promotor substance to 4NQO pulmonary carcinogenesis. Questions how glycerol modifies metabolism in Clara cells remain to be solved. Almost the same results are being obtained from the further large scale experiment. Comparative Studies on the Metabolism of the Lung Carcinogen N-Nitrosodiethylamine in Hamster Lung and Htnnan Lung Cancer Cell Lines. Schuller, H.M., McMahon, J.B., Falzon, M, Laboratory of Experimental Therapeutics and Metabolism, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20205, U.S.A. N-nitrosodiethylamine (DEN) is a powerful lung carcinogen in the hamster in which it induces a high incidence of Clara cell-derived adenocarcinomas. Studies on covalent binding of radioactive DEN in hamsters indicate that the pulmonary Clara cell is the principal site of metabolic activation of the compound. In the present series of investigations, pretreatment of hamsters with cytochrome P-450 inhibitor significantly reduced covalent binding of DEN in the lung and completely inhibited the development of DENinduced lung tumors. As a comparative approach to these animals experiments, well differentiated human lung cancer cell lines of defined cell lineage, as established by electron microscopy, were used to study DEN-metabolism in vitro. In keeping with the hamster data, the cancer cell line with features of Clara cell was significantly more potent in metabolizing DEN than all other cell lines and was inhibitable by a known inhibitor of cytochrome P-450 enzymes. Our data demonstrate a striking correlation of metabolic activation of DEN and its inhibition between the hamster Clara cells and the corresponding human lung cancer cell line and are of potential importance for lung cancer prevention in man.
cytology and chest x-ray. For comparison purposes, expected prevalences ~ ~put,hn abnormalities were determined among those groups without known occupational hazards, standardized for age and smoking habits. The potroom workers returned a higher proportion of adequate samples of sputum (72% vs 57% expected) and demonstrated a higher prevalence of metaplasia (2.2% vs 1.7% expected) and dysplasia (8.4% vs 2.0% expected, p less than .05). Workers currently employed in the potrooms were more likely than those previously employed in the potrooms to have metaplasia (3.0% vs 1.4%), dysplasia (10.8% vs 5.6%) and moderate to severe dysplasia (6.6% vs 1.4%). The prevalence of dysplasia was higher among those employed before (as compared to those since) 1962: for dysplasia, 14.8% vs 3.9%; for moderate to severe dysplasia, 9.1% vs 1.3%. We conclude that aluminum potroom workers, especially those currently employed who have worked more than 20 years experience an excess of sputum cytological abnormalities.
Second P[imary Lung Cance~s. Wagenaar3, Sj.Sc., Berkel , J., Vanderschueren , R . G . A . J . M . i . Department of Pathology. 3. Departm,ent of Pulmonary Disr~, Antonius Hospit~i Koekoekslaan I, 3445 F:M Nieu~ege~n, The Netherlands. 2. [~'2~tment of Ep~demiology, Comprehensive Cancer Centre, Radboudkwartier 259, 3511 CK Utrecht, The Netherlands. Few data are available with regard to second primairy cancers of the lung. We analyzed the frequency of second primary lung cancers diagnosed in a large referral hospital during the period 1979-1984. The criteria for a second primary of the lung were different histologies, another intrapulmonary location and/or 3 year time interval between the diagnosis of the first and the second tumor. All cases in which second primaries were diagnosed were reviewed, including the pathologic picture. A total of 1609 primary lung cancers were diagnosed during the study period. In 106 cases a second primary was found during the follow-up period. A descriptive analysis will be presented of histology, subsite and tumorstage. The relative frequencies among patients with a single tumor will be compared with those with second primaries.
3,
BASICBIOLOGY
Inhibitory Effects of Organic Selenium on Metastasis of Lewis Lung Carcinoma in C57BL Mice. Tian, H.S., Liu, Y.H. Department of Pathology, Hubei Medical College, Wuhan, China.
The inhibitory effects of organic seleniumselenium yeast on metastasis of Lewis lung carcinoma were investigated in C57BL mice. The experiment was performed as follows: C57BL mice were divided into two groups, one group was supplemented with 2 ppm of selenium (in form of selenium yeast) in their diet and nother group was fed up with basal diet for control. All mice were inoculated with single cell suspension of Lewis lung carcinoma in their left hind muscles. After 21 days, all animals were killed. The result showed that the number of metastatic tumors in lung is obviously less in the group with selenium yeast than in the control (P<0.01). Such result suggests that selenium yeast can effectively inhibit the metastasis of Lewis lung carcinoma. The differences in ultr structures and cytochemistry observed were interesting. The mechanism of the inhibition were discussed.
Inhibitory Effects of Selenium Yeast and Sodium Selenite on Methylcholanthrene - Induced Lung Carcinoma in Rats. Tian, H.S., Xiong, Y.Y., Gao, W.Q., Liu, M.Q., Zuo, R.D. Department of Pathology, Hubei Medical College, Wuhan, China. The inhibitory effects of selenium yeast and sodium selenite on methylcholanthreneinduced lung carcinogenesis were examined in inbred Wistar rats. The animals were divided into three groups: Group I and II were supplemented with 2 ppm of selenium (organic form, in yeast) in their diet and with 1.5 ppm sodium selenite in their drinking water respectively, and group III were fed basal diet for control. The results showed that the rate of carcinogenesis in group I, II and III were 76.92% (P<0.01), 82.14% (P<0.05) and 100%, respectively. The hyperplasia and metaplasia of bronchial epithelium were striking in group III, however, the lymphocyte immune response were remarkable in group I and II. These results suggested that the selenium yeast and sodium selenite is effective in preventing the MCA-induced lung carcinogenesis in rats, and the former is more effective than the latter.
Antitum0r Effect of Cis-Dian~inedichloplatinum (II) and Augmentation of Activity Against Lung Cancer of the Rats. Shimada, K., Yasuda, S., Yagisawa, H., Horie, S. Dokkyo University School of Medicine, Tochigi, Japan. Antitumor effect of cisplatin(CDDP) against transplanted Sato lung cancer and augmentation of the obtained antitumor activity by means of zinc and bismus salt were studied. In ten Donryu rats, CDDP was administered intr~peritoneally for 4 times with intervals 3 days from day 1 at doses of 2 mg/kg. Following data were evaluated in these rats and non-treated control group: I) Survival of animal, 2) Tumor size, 3) Cytostatic activity of spleen cells. Results obtained were as follows; a) Mean ~urv~val of control group was 21.1 days, whereas
30
80% of CDDP group was tumor-free at 120 djys after tumor ~no¢lation. b) ~he cytostatic activity of CDDP treated animals was 90% and 51% with control at effector to target rations of 50:1. c) The augmentation of activity of CDDP with zinc or bismus salt was elevated. In conclusion, the antitumor effect augmented when tumorbearing rats were injected zinc or bismus one day before CDDP acministration. The mechanism of this efficacy of those metals will be discussed. Bioassay of Cisplatin by Clonogenic Assay. Sasaki, Y., Saijo, N., Futami, H., Fujita, J., Shimizu, E., Ishihara, J., Kanzawa, F., Hoshi, A. National Cancer Center, Tokyo, Japan. In spite of its broad antitumor spectrum and high response rate, there remain many problems to determine the precise pharmacokinetics of cisplatin (CDDP). In this study, a new bioassay method of CDDP using human tumor clonogenic assay (HTCA) is presented and the pharmacokinetics of active form CDDP measured by HTCA is also reported. Twelve patients with histologically confirmed primary lung cancer were entered in this study. CDDP was administered by four different treatment arms; Arm A: 80 mg/m? IV infusion of Day i, Arm B: 20 mg/m- IV infusion from day 1 to day 4, Arm C: 120 mg/m IV infusion of day i, Arm D: i00 mg/body intra pleural injection. The basic procedure used in this study was that of Hamburger and Salmon with a little modification. As a target cell line, PC-9, a lung adenocarcinoma cell line kindly provided by Prof. Hayata, was used. Plasma from healthy volunteers containing various concentration of CDDP were prepaired for obtaining standard curve. With Arm A and Arm B, active CDDP over 1.0 ug/ml disappeared from plasma within 30 minutes after administration, but in Arm C, active form CDDP was detected even after 2 hours and the peak concentration was 7.5 ug/ml. With Arm D, active form CDDP was delected in some cases. Glycerol-Induced Promoting Action on Murine Pulmonary Tumorigenesis by a Single Administration of 4-Nitroquinoline 1-Oxide (4NQO) in ddY Mice. Inayama, Y., Kitamura, H., Ito, T., Kanisawa, M. Department of Pathology, Yokohama City University School of Medicine, Yokohama, Japan. The nonciliated bronchiolar cell (Clara cell) is considered to have significant metabolic activity, and also expected to be one of the possible progenitor cells of lung tumor. We found that the oral ad-
ministration of glycerol (GL) induced significant morphological changes of the Clara cell organelles, which may suggest some alteration in the metabolism of the Claz-a cell..This study was carried out to examine a possible modification of pulmonary tumorigenesis by GL. Animals: 6week-old ddY male mice, i0 ea. per group, were used. GL: 5% solution was given as drinking water ad libitum (I~). Carcinogen: A single dose of 4NQO, 0.3 mg, was given s.c. ( , ) . Table indica.~.~.ip ~ ° b 0=0 tes: a: Per cent "~tIIH,H,,,,7. 0 o 070 of tumor-bearing mi~i~ 10 i 0.J~0.1 ce. b: Total tumor . 80 35 3,5_~1.4 ",HH,,,,HH; 88 n 2.K'0.5 number, c : Mean tu: ~ p 1 1 1 ~ 9. 70 19 1 . 9 - 0 . 6 ,/iI~ ~ 44 lO I . | ~ 0 . 6 mor number per mou".w1~ ............... 8 0.9";0.', se.
Both an incidence of tumor-bearing mice and a number of induced tumor per mouse were enhanced in all the groups received combined admini, stration of 4NQO and GL, compared with the nontreated or noncombined groups. Present results showed glycerol is a promotor substance to 4NQO pulmonary carcinogenesis. Questions how glycerol modifies metabolism in Clara cells remain to be solved. Almost the same results are being obtained from the further large scale experiment. Comparative Studies on the Metabolism of the Lung Carcinogen N-Nitrosodiethylamine in Hamster Lung and Htnnan Lung Cancer Cell Lines. Schuller, H.M., McMahon, J.B., Falzon, M, Laboratory of Experimental Therapeutics and Metabolism, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20205, U.S.A. N-nitrosodiethylamine (DEN) is a powerful lung carcinogen in the hamster in which it induces a high incidence of Clara cell-derived adenocarcinomas. Studies on covalent binding of radioactive DEN in hamsters indicate that the pulmonary Clara cell is the principal site of metabolic activation of the compound. In the present series of investigations, pretreatment of hamsters with cytochrome P-450 inhibitor significantly reduced covalent binding of DEN in the lung and completely inhibited the development of DENinduced lung tumors. As a comparative approach to these animals experiments, well differentiated human lung cancer cell lines of defined cell lineage, as established by electron microscopy, were used to study DEN-metabolism in vitro. In keeping with the hamster data, the cancer cell line with features of Clara cell was significantly more potent in metabolizing DEN than all other cell lines and was inhibitable by a known inhibitor of cytochrome P-450 enzymes. Our data demonstrate a striking correlation of metabolic activation of DEN and its inhibition between the hamster Clara cells and the corresponding human lung cancer cell line and are of potential importance for lung cancer prevention in man.