occurrence of a multidrug-resistant phenotype in human lung xenografts

2
in part from intcmal calcium stores. Desensitization toasecondaddition of active bombcsin congencrs occurs subsequent to initial addition of Tyfl-bombcsin. Structure-activity analysis showed the carboxyl-termi- nal octapcptide was the active portion of the peptide. Analogs in which the carboxyl terminus was oxidized or deamidated were inactive. Ranatensin, litorin, alytcsin, and GRP, but not physalaemin, were as active as Ty?-bombesin. A monoclonal antibody to the carboxyl terminus of bombesin selectively blocked the increased [Ca’+](O elic- ited by TyP-bombesin. These studies suggest that bombesin congcncrs can act on some small cell lung cancer cell lines by a pathway utilizing increased [Ca2*](i). Comparison of chrysene metabolism in epithelial human bronchial and Syrian hamster lung cells. Jacob J, Grimmer G, Raab G, Emura M, Riebe M, Mohr U. Biochem- isches tnstitut fur Umweltcarcinogene. 2070 Ahrensburg-Grosshans- dorf Cancer Lett 1987;38:171-80. Chrysene is metabolized to I-, 2-, 3-, and 4-hydroxychrysene and trans-l ,2- as well as trans-3.4.dihydroxydihydrochrysene in human and Syrian hamster epithelial lung cells as indicated by GC/MS analysis, whereas K-region oxidation is at most a very minor pathway. Cells of a permanent clonal line of fetal hamster lung metabolized 97% of the chrysene whereas fetal human bronchial cpithelial cells converted 24% of the substrate within 8 days incubation. In human cells oxidation at the 3,4-position predominates, whereas oxidation at the 1.2~position is the major pathway in hamster cells. Indication for a bay-region of chrysene in hamster cells has been obtained. Influence ofdocosahexaenoic acid in vitro on intracellular adriamy- tin concentration in lymphocytes and human adriamycin-sensitive and -resistant small-cell lung cancer cell lines, and on cytotoxicity in the tumor cell lines. Zijlstra JG, De Vries EGE, Muskiet FAJ, Martini IA,Timmer-Bosscha H, Mulder NH. Division of Medical Oncology, Departmen oftnternal Medicine, Universiry Hospital, 9713 EZ Groningen. Int J Cancer 1987;40:850-6. An increase in the therapeutic effects of cancer chemotherapeu- tic agents and circumvention of drug resistance in cancer cells might result from an increase in the intracellular drug level. Alteration of the lipid domain of the cell membrane can result in a higher intracellular drug level. This alteration was achieved in human lymphocytes and in human adriamycin (ADR)-sensitive and -resistant small-cell lung car- cinoma cells in vitro by incubation with docosahcxaenoic acid (22:6). Incorporation of the fatty acid in cellular phospholipids was measured by gas chromatographic analysis. A significant increase of 22:6 could be reached without lossof viability in all 3 cell types. Incorporation was demonstrated notably in the phosphatidyl choline, phosphatidyl etha- nolamine and phosphatidylserine, and was most pronounced in the phosphatidyl choline of the ADR-resistant line. After a I-hr incubation with ADR, a 10-300/o incrcasc in intracellularadriamycin concentration was found in all 3 cell types previously incubated for 4 days with 22:6. After 1 hr incubation with ADR there was no increase in cytotoxicity in the sensitive cell lint when measured by soft agar clonogcnic assay and a partial reversal (52 to 14) of resistance factor (ratio of drug doses to product 50% growth inhibition) in the resistant cell line. Increasing the time of ADR exposure from I to4 hr further reduced the resistance factor to 8.6. Glucose utilization in vivo by human pulmonary neoplasms. Nolop KB, Rhodes CG, Brudin LH et al.MRC Cyclofron Unit, Royal Poslgraduale ,Medical School, Hammersmi~h Hospital. London WI 2 OHS. Cancer 1987:60:2682-9. Neoplastic tissue in general shows a high rate of glucose consumption under both anaerobic and aerobic conditions. Using positron emission s21 tomography (PET) we measured the rate of uptake of the glucose analogue “fluoro-2-deoxy-D-glucose (‘*FDG) in I2 patients with car- cinema of the lung. The tumor types were six squamous cell, two large cell, two oat cell, one adenocarcinoma, and one undifferentiated carci- noma. In each patient a transaxial plane was selected that contained the bulk of the tumor tissue. Regional density and blood volume were measured. Following the intravenous injection of “FDG, the rates of uptake in the tumor and normal lung tissue were assessed from sequential scansover 1 hour. Ineachpatient therateofuptakeof”FDG in the tumor tissue was significantly increased relative to normal lung tissue. For the group therateofuptakeby thetumor was21 1.4~69.4ml/lOOg/hr(mean * SD) compared to 31.9. 13.2 in the contralateral lung (P < 0.05). The tumor-to-normal tissue ratioof 6.6 (range, 2.7 to 14.6) was higher than previously reported ratios for brain and liver tumors. In contrast to bram tumors there was little correlation between tumor type and rate of ‘*FDG uptake. Measurements of glucose metabolism taken in viva in human pulmonary tumors may lead to advances m screening, staging, and therapy. Secretion of antileucoprotease from a human lung tumor cell line Appelhans B, Ender B, Sachse G, Nikiforov T, Appelhans H. Ebert W. Insliw fur Organ&he Chemie und Biochemie, Technische ttochschule, 6100 Darmsladl. Febs Lett 1987;224: IA-11 Two human tumor cell lines were analyzed for the production of human antileucoprotease (ALP). One of them, a human squamous lung carcinoma cell line (HS-24) synthesized, as confirmed by Western blot analysis, high amounts of ALP in serum-free medium. The supematant inhibited elastase, chymotrypsin and lrypsin. Northern blot analysis with an 18-mer radiolabclled oligonucleotide, dcrivcd from an ALP specific cDNA clone, revealed a specific mRNA of about 700-800 nuclcotidcs in HS-24 tumor cells. In contrast, a secondary human lung tumor cell line (SB-3), derived from the adrenal cortex, did not synthesize ALP when assayed under identical conditions. The supema- tant inhibited only trypsin and chymotrypsin. Antitumor activity of pleural cavity macrophages and its regulation by pleural cavity lymphocytes in patients with lung cancer. NagashimaA,YasumotoK,NakahashiH.TakeoS, YanoT,NomotoK. Departmen of Surgery II, Faculty of Medicine, Kyushu Universiry, Higashi-ku, Fukuoka 812. Cancer Res. 1987;47:5497-500. Antitumor activities of pleural cavity macrophages (PCM) and pleural cavity lymphocytes (PCL) in lung cancer patients were exam- ined. Theeffect ofcoculture supematantsof PCL and autologous tumor cells on the cytostatic activity of macrophages was also examined. Cytostatic activity of PCM was not affected by an advance of metastasis to regional lymph nodes or increase of tumor size and difference of histological type. However, the cytostatic activity of PCM was mark- edly augmented when pleural invasion was limited to within the visceral pleuraalthough it was low when pleural invasion wasabsentorextended beyond the visceral pleura. On the other hand, PCL did not exert any cytolytic activity against various tumor target cells. However, coculture supcmatants of PCL and autologous tumor cells exhibited the activity of macrophage-activating factor against guinea-pig peritoneal macro- phagcs. Furthermore, the higher the cytostatic activity of PCM, the higher the macrophagc-actlvatmg factor activity of the coculture super- natant of PCL and autologous tumor cells was. These results suggested thatantitumoractivityofPCM wascontrolledby specifically sensitized PCL through lymphokines. Occurrence of a multidrug-resistant phenotype in human lung xenografts. Mattcm J. Bak M,Volm M. Department of Experimental Parhology. German Cancer Research Cenrer, D-6900 tteidelberg. Br J Cancer 1987:56:407-l 1. The intrinsic sensitivity of a panel of 8 human epidcrmoid lung cancer

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in part from intcmal calcium stores. Desensitization toasecondaddition of active bombcsin congencrs occurs subsequent to initial addition of Tyfl-bombcsin. Structure-activity analysis showed the carboxyl-termi- nal octapcptide was the active portion of the peptide. Analogs in which the carboxyl terminus was oxidized or deamidated were inactive. Ranatensin, litorin, alytcsin, and GRP, but not physalaemin, were as active as Ty?-bombesin. A monoclonal antibody to the carboxyl terminus of bombesin selectively blocked the increased [Ca’+](O elic- ited by TyP-bombesin. These studies suggest that bombesin congcncrs can act on some small cell lung cancer cell lines by a pathway utilizing increased [Ca2*](i).

Comparison of chrysene metabolism in epithelial human bronchial and Syrian hamster lung cells. Jacob J, Grimmer G, Raab G, Emura M, Riebe M, Mohr U. Biochem- isches tnstitut fur Umweltcarcinogene. 2070 Ahrensburg-Grosshans- dorf Cancer Lett 1987;38:171-80.

Chrysene is metabolized to I-, 2-, 3-, and 4-hydroxychrysene and trans-l ,2- as well as trans-3.4.dihydroxydihydrochrysene in human and Syrian hamster epithelial lung cells as indicated by GC/MS analysis, whereas K-region oxidation is at most a very minor pathway. Cells of a permanent clonal line of fetal hamster lung metabolized 97% of the chrysene whereas fetal human bronchial cpithelial cells converted 24% of the substrate within 8 days incubation. In human cells oxidation at the 3,4-position predominates, whereas oxidation at the 1.2~position is the major pathway in hamster cells. Indication for a bay-region of chrysene in hamster cells has been obtained.

Influence ofdocosahexaenoic acid in vitro on intracellular adriamy- tin concentration in lymphocytes and human adriamycin-sensitive and -resistant small-cell lung cancer cell lines, and on cytotoxicity in the tumor cell lines. Zijlstra JG, De Vries EGE, Muskiet FAJ, Martini IA,Timmer-Bosscha H, Mulder NH. Division of Medical Oncology, Departmen oftnternal Medicine, Universiry Hospital, 9713 EZ Groningen. Int J Cancer 1987;40:850-6.

An increase in the therapeutic effects of cancer chemotherapeu- tic agents and circumvention of drug resistance in cancer cells might result from an increase in the intracellular drug level. Alteration of the lipid domain of the cell membrane can result in a higher intracellular drug level. This alteration was achieved in human lymphocytes and in human adriamycin (ADR)-sensitive and -resistant small-cell lung car-

cinoma cells in vitro by incubation with docosahcxaenoic acid (22:6). Incorporation of the fatty acid in cellular phospholipids was measured by gas chromatographic analysis. A significant increase of 22:6 could be reached without lossof viability in all 3 cell types. Incorporation was demonstrated notably in the phosphatidyl choline, phosphatidyl etha- nolamine and phosphatidylserine, and was most pronounced in the phosphatidyl choline of the ADR-resistant line. After a I-hr incubation with ADR, a 10-300/o incrcasc in intracellularadriamycin concentration was found in all 3 cell types previously incubated for 4 days with 22:6. After 1 hr incubation with ADR there was no increase in cytotoxicity in the sensitive cell lint when measured by soft agar clonogcnic assay and a partial reversal (52 to 14) of resistance factor (ratio of drug doses to product 50% growth inhibition) in the resistant cell line. Increasing the time of ADR exposure from I to4 hr further reduced the resistance factor to 8.6.

Glucose utilization in vivo by human pulmonary neoplasms. Nolop KB, Rhodes CG, Brudin LH et al.MRC Cyclofron Unit, Royal Poslgraduale ,Medical School, Hammersmi~h Hospital. London WI 2 OHS. Cancer 1987:60:2682-9.

Neoplastic tissue in general shows a high rate of glucose consumption under both anaerobic and aerobic conditions. Using positron emission

s21

tomography (PET) we measured the rate of uptake of the glucose analogue “fluoro-2-deoxy-D-glucose (‘*FDG) in I2 patients with car- cinema of the lung. The tumor types were six squamous cell, two large cell, two oat cell, one adenocarcinoma, and one undifferentiated carci- noma. In each patient a transaxial plane was selected that contained the bulk of the tumor tissue. Regional density and blood volume were measured. Following the intravenous injection of “FDG, the rates of uptake in the tumor and normal lung tissue were assessed from sequential scansover 1 hour. Ineachpatient therateofuptakeof”FDG in the tumor tissue was significantly increased relative to normal lung tissue. For the group therateofuptakeby thetumor was21 1.4~69.4ml/lOOg/hr(mean * SD) compared to 31.9. 13.2 in the contralateral lung (P < 0.05). The tumor-to-normal tissue ratioof 6.6 (range, 2.7 to 14.6) was higher than previously reported ratios for brain and liver tumors. In contrast to bram tumors there was little correlation between tumor type and rate of ‘*FDG uptake. Measurements of glucose metabolism taken in viva in human pulmonary tumors may lead to advances m screening, staging, and therapy.

Secretion of antileucoprotease from a human lung tumor cell line Appelhans B, Ender B, Sachse G, Nikiforov T, Appelhans H. Ebert W. Insliw fur Organ&he Chemie und Biochemie, Technische ttochschule, 6100 Darmsladl. Febs Lett 1987;224: IA-11

V .

Two human tumor cell lines were analyzed for the production of human antileucoprotease (ALP). One of them, a human squamous lung carcinoma cell line (HS-24) synthesized, as confirmed by Western blot analysis, high amounts of ALP in serum-free medium. The supematant inhibited elastase, chymotrypsin and lrypsin. Northern blot analysis with an 18-mer radiolabclled oligonucleotide, dcrivcd from an ALP specific cDNA clone, revealed a specific mRNA of about 700-800 nuclcotidcs in HS-24 tumor cells. In contrast, a secondary human lung tumor cell line (SB-3), derived from the adrenal cortex, did not synthesize ALP when assayed under identical conditions. The supema- tant inhibited only trypsin and chymotrypsin.

Antitumor activity of pleural cavity macrophages and its regulation by pleural cavity lymphocytes in patients with lung cancer. NagashimaA,YasumotoK,NakahashiH.TakeoS, YanoT,NomotoK. Departmen of Surgery II, Faculty of Medicine, Kyushu Universiry, Higashi-ku, Fukuoka 812. Cancer Res. 1987;47:5497-500.

Antitumor activities of pleural cavity macrophages (PCM) and pleural cavity lymphocytes (PCL) in lung cancer patients were exam- ined. Theeffect ofcoculture supematantsof PCL and autologous tumor cells on the cytostatic activity of macrophages was also examined. Cytostatic activity of PCM was not affected by an advance of metastasis to regional lymph nodes or increase of tumor size and difference of histological type. However, the cytostatic activity of PCM was mark- edly augmented when pleural invasion was limited to within the visceral pleuraalthough it was low when pleural invasion wasabsentorextended beyond the visceral pleura. On the other hand, PCL did not exert any cytolytic activity against various tumor target cells. However, coculture supcmatants of PCL and autologous tumor cells exhibited the activity of macrophage-activating factor against guinea-pig peritoneal macro- phagcs. Furthermore, the higher the cytostatic activity of PCM, the higher the macrophagc-actlvatmg factor activity of the coculture super- natant of PCL and autologous tumor cells was. These results suggested thatantitumoractivityofPCM wascontrolledby specifically sensitized PCL through lymphokines.

Occurrence of a multidrug-resistant phenotype in human lung xenografts. Mattcm J. Bak M,Volm M. Department of Experimental Parhology. German Cancer Research Cenrer, D-6900 tteidelberg. Br J Cancer 1987:56:407-l 1.

The intrinsic sensitivity of a panel of 8 human epidcrmoid lung cancer

s22

xenografts to vincristine and actinomycin D has been examined and the cross-resistance patterns of the most vincristine-resistant and vin- cristine-sensitive tumour line were tested to a variety of other drugs, includingradiation.Theresultsdemonstratethatxenograftlinesderived from human lung tumours not previously treated with chemotherapy exhibit a similar general pattern of cross-resistance to the drugs vin- cristine, actinomycin D and adriamycin as is observed in human cell linesandinanimalmodelsselectedforresistance to thesedrugs. Itisalso shown that intrinsic resistance to vincristine can be partially overcome by verapamil. This may indicate a potential role of this substance in circumventing clinically observed drug resistance.

Pathology

Peripheral carcinoid tumours of the lung: A clinicopathological study. Abdi EA. Goel R, Bishop S, Bain GO. Department of Medicine, University of Alberta, Edmonton, Alra. J Surg Oncol 1988;39: 190-6.

Peripheral carcinoid tumours (PCT) of the lung are a distinct entity. These tumours arise from subsegmental or distal bronchioles, are usually well circumscribed and encapsulated, and contain varying amounts of spindle cells. Their histogenesis is from the Kultchitsky or neurosecretory type of cells. Of 52 patients with carcinoid tumours of the lung, 11 (21.1%) had PCT. The mean age was 60.2 years, 9 out of 11 patients were females, and about two-thirds of tumours were in the left lung (8 out of 13). No patient developed carcinoid syndrome, but three patients had nonspecific respiratory symptoms. Bronchoscopy was not helpful in diagnosing any of these cases. Four patients required a wedge resection of the lung; the other six underwent Iobectomy. One patient had tumours detected incidentally at autopsy. Mean tumour size was 2.39 cm (range 1 .O-5.0 cm); four tumours were 3.0 cm or larger in diameter. Three cases (27.3%) had regional lymph node metastases, but no systemic metastasis was discovered. Apart from the patient who was discovered to have carcinoid tumours at autopsy, all others are alive and disease-free from 1 to 6 years after surgery.

Reduction in risk of lung cancer among ex-smokers with particular reference to histologic type. Higgins IT, Wynder EL. American Health Foundarion, New York, NY 20017. Cancer 1988;62:2397-401.

Reduction of the risk of lung cancer as a result of giving up smoking is examined according to the number of years of cessation from smoking and the number of cigarettes that were smoked per day before quitting smoking. Patients with histologically diagnosed lung cancer from 26 hospitals in six cities in the US were compared with controls matched for age, sex, race, time of diagnosis, and hospital. Smoking habits were recorded by trained interviewers using a questionnaire. In men, a fairly consistent reduction in risk with years of cessation for each category of cigarettes per day before giving up smoking was found. In women, however, a much less consistent pattern was observed. Analysis of the data by histologic type of lung cancer showed that among women, as among men, risk was well and declined more consistently in those with Kreyberg I cancers that in those with Kreyberg II tumors. The inconsis- tency was seen mainly in patients with Kreyberg II cancers, which were more common among women.

Incidence of lung cancer by histological type from a population- based registry. Anton-Culver H, Culver BD, Kurosaki T, Osann KE, Lee JB. Depart-

mentofCommunityandEnvironmenta1 Medicine, UniversityofCalifor- nia, Irvine. CA 92717. Cancer Res 1988;48:6580-3.

Using data from a population-based registry, the Cancer Surveillance Program of Grange County, we examined patterns in lung cancer incidence by histological type for 1984 in Grange County, CA. Age- adjusted incidence rates per 100,000 population are 66.4 for men and 34.1 for women. Compared to 1983 rates for whites from all SEER areas combined, Orange County incidence rates are lower for men but equal for women. Squamous cell carcinoma incidence shows a strong male predominance [male/female 3.4; 95% confidence interval = (2.6,4.4)1, whereas the male/female incidence ratios for adenocarcinoma [male/ female I .4; 95% confidence interval = (1.1, 1.8)] and small cell carcinoma [male/female = 1.8; 95% confidence interval = 1.3,2.4)] are closertounity.Smoking habits wereabstractedfrommedicalrecordsfor 79% of cases. Only 8% of lung cancer cases (5% of men and 12% of women) with known smoking habits are nonsmokers. Adenocarcinoma is the most common cell type among women smokers and nonsmokers, while squamous cell carcinoma predominates in both male smokers and nonsmokers. Cases who smoked were younger at diagnosis than nonsmokers (PcO.001) for each cell type. Despite a greater proportion of nonsmokers, cases with adenocarcinoma were younger at diagnosis compared to small cell carcinoma (P<o.Ol) and squamous cell carci- noma (P<O.O5). The observed patterns of incidence rates by histological type are not entirely explained by current knowledge of the relationship between smoking and cell type.

Cytologic presentation of malignant mesothelioma in pleural effu- sions. Pedio G, Landolt-Weber U. Institute of Pathology. Department of Cytology. UniversityofZurich, CH-8091 Zurich. Exp Cell Bioll988;56: 21 l-6.

1.601 Pleural effusions were found to be malignant between 1976 and 1987. Among these were 26 (1.6% of the malignant effusions) mesothe- lioma. Only 2 cases showed pronounced cytologic features that made a definite diagnosis possible on cytologic criteria alone. In 20 cases diagnosis of mesothelioma was strongly suggested by the patients’ history and cytology of the effusion was compatible with mesothelioma. In the other4 cases special examinations (histo- and immunohistochem- istry, electron microscopy) led to the final diagnosis. The cytologic features of mesothelioma and other examination techniques, needed to resolve the differential diagnosis of mesothelioma versus other neo- plasm in pleural effusions, are discussed.

Expression of human milk fat globule antigens HMFGl and HMFG2 on ovarian tumours and lung tumours. Hay FG, Leonard RCF. University Department of Clinical Oncology, Western General Hospital. Edinburgh EH4 2XU. Dis Markers 1988;6:29-39.

The patterns of reactivity of the monoclonal antibodies HMFGl and HMFG2 were studied in epithelial ovarian turnours, small cell lung cancer, and non-small cell lung cancer. Twenty primary, paraffin embedded, ovarian tumours were analysed in addition to freshly ob- tained ascitic fluids (21). a node aspirate (l), solid metastatic tumours (3). and 6 established cell lines. SCLC tumours comprised paraffin embedded bronchial biopsies (3 1) and metastatic deposits (7) and fresh tissue from bronchial biopsies (3), pleural aspirates (4). bone marrows (5). node aspirates (6), solid metastatic tumour (3). and 4 cultured cell lines. Antigen expression was heterogeneous for all tumour types studied. However, significant differences in antigen expression were noted with the HMFG2 antibody between primary and metastatic lesions from both ovarian and small cell lung cancer groups.