Heterogeneity of lung cancer cells with respect to the amplification and rearrangement of myc family...
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s13 Antitumor activity of a new platinum compound (glycolate o,o’) diammioeplatinum (II) (254-S), against non-small cell lung carci- noma grown in a human tumor clonogenic assay system. Kanzawa F, Matsushima Y, Nakano H et al. Pharmacology Division, National Cancer Center Research Instirute, Chuo-ku, Tokyo 104. Anti- cancer Res 1988;8:323-8. (Glycolate-0.0’) diammineplatinum (II) (254-S) is one of the plati- num derivatives showing high activity against rodent solid tumors and lack of renal toxicity. We have used a human tumor clonogenic assay (HTCA) as a disease-oriented drug screening model for new antitumor drugs, in order to test the antitumor activity of 254-S against non-small cell lung carcinoma (NSCLC) and to compare its activity with that of cisplatin (CDDP) and of carboplatin (CBDCA). The overall in vitro response rate (definedas less than 50% survival of tumor colony forming units) for 254-S was observed in lo/29 and 20/30 evaluable specimens isolated freshly from NSCLC patients with continuous exposureat 1 and IO*g/ml,respectively, indicatingapositivedose-responserelationship. Dose dependent cytotoxicity was also confirmed in 4 human tumor cell linesderivedfrom NSCLCpatients,Theantitumoractivityof254-S was 3.6fold that of CBDCA, but two fifths that of CDDP. A comparison of these in vitro results with the toxic properties of 254-S such as low nephrotoxicity suggests that 254-S is a promising new drug against NSCLC. Heterogeneity of lung cancer cells with respect to the amplification and rearrangement of myc family oncogenes. Yokota J, Wada M, Yoshida T et al. National Cancer Cenrer Research Institute, Chuo-ku. Tokyo 104. Oncogene 1988;2:607-11. Seventy lung tumors from 53 patients were analysed for alterations ofmyc family oncogenes, c-myc, N-myc and L-myc, to evaluate when activation of these genes occurs during tumor development. The 53 cases were 17 small cell carcinoma (SCCs), 18 adenocarcinomas, 12 squamous cell carcinomas (SqCs), 4 large celJ carcinomas and 2 adenosquamous carcinoma. Either N-myc or L-myc was amplified in 4 of the 17 (one N-myc and 3 L-myc) SCCs (24%). while c-myc was amplified in 3 of the 12 SqCs (25%). In one SCC, amplification of N- myc was found in the primary tumor, a pulmonary hilar lymph node metastasisandapleural metastasis, butnot inalivermetastasisorapara- aortic lymph node metastasis. In one SqC, c-myc was amplified in a pleural metastasis and a lymph node metastasis, but not in the primary tumor. In 2 cases of SCCs,amplification or rearrangement of c-myc was detected only in the cell lines, but not in the original tumors taken from the same individuals. These results indicate that tumor cells were heterogeneous for amplification and rearrangement of myc family oncogenes, and suggest that activation of these oncogenes in SCCs and SqCs occurs not at the time of maligmant transformation but during tumor progression. Lung cancer biology. Camey DN, De Leij L. Department of Medical Oncology, Mater Misericordiae Hospital, Dublin 7. Semin Oncol 1988;15:199-214. Advances in the understanding of the biology of lung cancer have progressed rapidly over the past decade while treatment results have remained essentially unchanged. It is clear that the knowledge of the heterogeneity of lung cancer cell types in respect of growth properties, biomarker expression, oncogene expression, and antigen expression needs to be applied in the clinic; and their role in predicting response to cytotoxic therapy and survival needs prospective evaluation. In addition the application of cell lines in screening for tumor-specific cytotoxic agents should provide for a more rational approach for drug selection in future clinicaJ trials. Finally the development of magnetic resonance spectroscopy may also play a role both in further understanding the biology of lung cancer, and in the clinical assessment of tumor sensitiv- ity in vivo. More recent data using DNA probes specific for the cytogenetic deletion on chromosome 3, previously identified in only SCLC, suggests that this deletion 3p 14-23 is common to most, if not all, cell types of lung cancer. This adds further to the hypothesis that a common stem cell exists from which all histologic types of lung cancer arise. Comparison of chemosensitivity of transplantable non-small cell bronchial turnouts of rats in syngeneic hosts and in nude rodents. Kal HB, Van Bekkum DW. Radiobiological Institute TNO. 2288 GJ Rijswijk. Eur J Cancer Clin Oncol 1988;24:999-1003. Four transplantable poorly to well differentiated bronchial carcino- mas, originally induced in the lungs of WAG/Rij and BN rats, were used to study their responsiveness to cytostatic drugs when growing in syngeneic hosts or in nude mice or rats. Growth delay was the endpoint determined. The responsiveness to drugs was specific for each tumour line and between tumours it was heterogeneous. In general, the same tumour specific pattern of response was observed regardless whether tumours grew in syngenic hosts or in nude mice or nude rats. These results indicate that the stroma of the host does not contribute signifi- cantly to the response of the tumour, but that the intrinsic sensitivity of the malignant cells is the prevailing factor. Extended growth of a human squamous lung cancer cell line in a simple, chemically defined medium. Houen G. Laboratory of Cancer Biology, Panum Instiwe, DK-2200 Copenhagen. Med Sci Res 1988;16:497-8. A human squamous lung cancer cell line was found to be capable of extended growth in a simple, chemically defined medium based on RPMl 1640 with addition of hydrocortisone, insulin, transferrin and ethanolamine. This cell line excretes tibronectin into the medium explaining the independence of added attachment factors. The A 431 and the 3T3 cell line did not grow in this medium. Selective growth inhibition of human lung cancer cell lines bearing a surface glycoprotein gpl60 by ‘2SI-labeled anti-gpl60 monocloaal antibody. Sugiyama Y, Chen F-A, Takita H, Bankert RB. Department ofMolecu- lar Immunology, Rowe11 Park Memorial Inslilute. Buffalo, NY 14263. Cancer Res 1988;48:2768-73. Monoclonal antibody 5E8 which is specific for a M(r) 160,000 glycoprotein (gp160) on the surface of human lung cancer was radiola- beled with12sl. Radiolabeled 5E8 antibody is shown here to suppress the growth of gp160 positive human lung tumor cell lines in a dose- dependentfashion,butthissameradiolabeledantibodydoesnotalterthe growth of gp160 negative lung tumor cell lines. Neither the unlabeled 5E8 nor a control radiolabeled monoclonal antibody hasany effect upon the growth of gp160 positive tumors. The specificity of radiolabeled antibody mediated tumor killing is further demonstrated by the ability ofunlabeled5E8 toinhibittumorkilling by ‘“I-5lXTheefficiencywith which the labeled tumor specific antibody suppressed tumor colony formation is enhanced by increasing the molar ratio of l=l to 5E8. This ratio could be increased to a level of two without affecting the capacity of the antibody to bind to the ccl1 surface antigen. An attempt to increase the efficiency of tumor killing by the addition of a second antibody subscqucnt to incubation with lUl-5E8 was unsuccessful. These results indicate that ‘“I is a viable isotope and gp 160 represents an appropriate target for radioimmunotherapy of human lung cancer.
Transcript of Heterogeneity of lung cancer cells with respect to the amplification and rearrangement of myc family...
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Antitumor activity of a new platinum compound (glycolate o,o’) diammioeplatinum (II) (254-S), against non-small cell lung carci- noma grown in a human tumor clonogenic assay system. Kanzawa F, Matsushima Y, Nakano H et al. Pharmacology Division, National Cancer Center Research Instirute, Chuo-ku, Tokyo 104. Anti- cancer Res 1988;8:323-8.
(Glycolate-0.0’) diammineplatinum (II) (254-S) is one of the plati- num derivatives showing high activity against rodent solid tumors and lack of renal toxicity. We have used a human tumor clonogenic assay (HTCA) as a disease-oriented drug screening model for new antitumor drugs, in order to test the antitumor activity of 254-S against non-small cell lung carcinoma (NSCLC) and to compare its activity with that of cisplatin (CDDP) and of carboplatin (CBDCA). The overall in vitro response rate (definedas less than 50% survival of tumor colony forming units) for 254-S was observed in lo/29 and 20/30 evaluable specimens isolated freshly from NSCLC patients with continuous exposureat 1 and IO*g/ml,respectively, indicatingapositivedose-responserelationship. Dose dependent cytotoxicity was also confirmed in 4 human tumor cell linesderivedfrom NSCLCpatients,Theantitumoractivityof254-S was 3.6fold that of CBDCA, but two fifths that of CDDP. A comparison of these in vitro results with the toxic properties of 254-S such as low nephrotoxicity suggests that 254-S is a promising new drug against NSCLC.
Heterogeneity of lung cancer cells with respect to the amplification and rearrangement of myc family oncogenes. Yokota J, Wada M, Yoshida T et al. National Cancer Cenrer Research Institute, Chuo-ku. Tokyo 104. Oncogene 1988;2:607-11.
Seventy lung tumors from 53 patients were analysed for alterations ofmyc family oncogenes, c-myc, N-myc and L-myc, to evaluate when activation of these genes occurs during tumor development. The 53 cases were 17 small cell carcinoma (SCCs), 18 adenocarcinomas, 12 squamous cell carcinomas (SqCs), 4 large celJ carcinomas and 2 adenosquamous carcinoma. Either N-myc or L-myc was amplified in 4 of the 17 (one N-myc and 3 L-myc) SCCs (24%). while c-myc was amplified in 3 of the 12 SqCs (25%). In one SCC, amplification of N- myc was found in the primary tumor, a pulmonary hilar lymph node metastasisandapleural metastasis, butnot inalivermetastasisorapara- aortic lymph node metastasis. In one SqC, c-myc was amplified in a pleural metastasis and a lymph node metastasis, but not in the primary tumor. In 2 cases of SCCs,amplification or rearrangement of c-myc was detected only in the cell lines, but not in the original tumors taken from the same individuals. These results indicate that tumor cells were heterogeneous for amplification and rearrangement of myc family oncogenes, and suggest that activation of these oncogenes in SCCs and SqCs occurs not at the time of maligmant transformation but during tumor progression.
Lung cancer biology. Camey DN, De Leij L. Department of Medical Oncology, Mater Misericordiae Hospital, Dublin 7. Semin Oncol 1988;15:199-214.
Advances in the understanding of the biology of lung cancer have progressed rapidly over the past decade while treatment results have remained essentially unchanged. It is clear that the knowledge of the heterogeneity of lung cancer cell types in respect of growth properties, biomarker expression, oncogene expression, and antigen expression needs to be applied in the clinic; and their role in predicting response to cytotoxic therapy and survival needs prospective evaluation. In addition the application of cell lines in screening for tumor-specific cytotoxic agents should provide for a more rational approach for drug selection in future clinicaJ trials. Finally the development of magnetic resonance
spectroscopy may also play a role both in further understanding the biology of lung cancer, and in the clinical assessment of tumor sensitiv- ity in vivo. More recent data using DNA probes specific for the cytogenetic deletion on chromosome 3, previously identified in only SCLC, suggests that this deletion 3p 14-23 is common to most, if not all, cell types of lung cancer. This adds further to the hypothesis that a common stem cell exists from which all histologic types of lung cancer arise.
Comparison of chemosensitivity of transplantable non-small cell bronchial turnouts of rats in syngeneic hosts and in nude rodents. Kal HB, Van Bekkum DW. Radiobiological Institute TNO. 2288 GJ Rijswijk. Eur J Cancer Clin Oncol 1988;24:999-1003.
Four transplantable poorly to well differentiated bronchial carcino- mas, originally induced in the lungs of WAG/Rij and BN rats, were used to study their responsiveness to cytostatic drugs when growing in syngeneic hosts or in nude mice or rats. Growth delay was the endpoint determined. The responsiveness to drugs was specific for each tumour line and between tumours it was heterogeneous. In general, the same tumour specific pattern of response was observed regardless whether tumours grew in syngenic hosts or in nude mice or nude rats. These results indicate that the stroma of the host does not contribute signifi- cantly to the response of the tumour, but that the intrinsic sensitivity of the malignant cells is the prevailing factor.
Extended growth of a human squamous lung cancer cell line in a simple, chemically defined medium. Houen G. Laboratory of Cancer Biology, Panum Instiwe, DK-2200 Copenhagen. Med Sci Res 1988;16:497-8.
A human squamous lung cancer cell line was found to be capable of extended growth in a simple, chemically defined medium based on RPMl 1640 with addition of hydrocortisone, insulin, transferrin and ethanolamine. This cell line excretes tibronectin into the medium explaining the independence of added attachment factors. The A 431 and the 3T3 cell line did not grow in this medium.
Selective growth inhibition of human lung cancer cell lines bearing a surface glycoprotein gpl60 by ‘2SI-labeled anti-gpl60 monocloaal antibody. Sugiyama Y, Chen F-A, Takita H, Bankert RB. Department ofMolecu- lar Immunology, Rowe11 Park Memorial Inslilute. Buffalo, NY 14263. Cancer Res 1988;48:2768-73.
Monoclonal antibody 5E8 which is specific for a M(r) 160,000 glycoprotein (gp160) on the surface of human lung cancer was radiola- beled with12sl. Radiolabeled 5E8 antibody is shown here to suppress the growth of gp160 positive human lung tumor cell lines in a dose- dependentfashion,butthissameradiolabeledantibodydoesnotalterthe growth of gp160 negative lung tumor cell lines. Neither the unlabeled 5E8 nor a control radiolabeled monoclonal antibody hasany effect upon the growth of gp160 positive tumors. The specificity of radiolabeled antibody mediated tumor killing is further demonstrated by the ability ofunlabeled5E8 toinhibittumorkilling by ‘“I-5lXTheefficiencywith which the labeled tumor specific antibody suppressed tumor colony formation is enhanced by increasing the molar ratio of l=l to 5E8. This ratio could be increased to a level of two without affecting the capacity of the antibody to bind to the ccl1 surface antigen. An attempt to increase the efficiency of tumor killing by the addition of a second antibody subscqucnt to incubation with lUl-5E8 was unsuccessful. These results indicate that ‘“I is a viable isotope and gp 160 represents an appropriate target for radioimmunotherapy of human lung cancer.
