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Preclinical study on immunoradiotherapy with 35S labeled monoclonal antibody SZ39
Tuesday, 8 July 1997
Basic Sciences- Neuro-oncology
S129
Comparisonof meta-tetrahydroxyphenylchlorin, IP-3-244I 5-aminulevulinic acid and
immunohistochem ical studies showed reactivity of a mouse anti-Axl monoclonal antibody withmembrane-proteinsof astrocytes of allanalyzed tissues as well haematoporphyrin-derivate in the C6 rat glioma as those of meningioma cells. model This suggests that the receptor tyrosine kinase Axl is not important lor the transformation and progression of astrocytic brain tumors and that axl might not A. Obwegeser , R.Jakober, S. Stocker" H. Stepp', H. Kostron.Univ. Kliniktiu code for the supposed tumor suppressor gene onromosome ch 19q in brain Neurochirurgie , Innsbruk,Austria.1 Laserforschungslabor,Munich, Germany tumors . Introduction:Malignant glioma is a disease with poor prognosis, furthermore The meaning of AxI as an neuronal adhesion molecule has to be elucidated. glial tumors are often rather bad to visualize within normal brain. As the use of porphyrins for the detection and treatment of tumors is undergoing mtensive investigation, new sensitizers and applicationsmay be a therapeutic and P-3-247I Preclinical study onimmunoradiotherapy with 35S diagnostic tool in the managementof these fatal tumors . labeledmonoclonalantibodySZ39 We investigatedthe uptake of 5-ALA and M· THPC in a rat glioma model and Oing Lan, Oiang Huang, Ziwei Du. DepartmentofNeurosurgery,Second compared it to data of HPD which are known from the literature . suznou MedicalCollege, Suzhou, Jiangsu, PR China AffiliatedHospilal of Methods:We inoculated C6 glioma cells into the right frontal lobe of adult rats. C14·/abeled M-THPC and 5-ALA were injected prior to killing of the ani- Antiglioma monoclonal antibody (MAb) 5Z39 was labeled with 35S. The effect of mals. C6-glioma tissue, normal tissue (ipsi and contralateral) liver and skin wasthe immunoradiotherapeutic agent , 35S·MAb SZ39, was evaluated preclinically . removed after 7 different time points (12 h to 48 h for M-THPC and 2 min to 8 Methods:The cytotoxicityof 355-MAb SZ39 against glioma was tested with h for 5·ALA , 3 to 5 animals per group). The samples were weighted. dissolved the MIT method, comparing with that of 35SnlgG, 35S + MAb SZ39 and 35S. pharmacokineticsof 35S-MAb SZ39 wereassessed and subjected to liquid scintillationcounting . Additionally 21 rats were injected Target treatment effect and with 120 mg/kg unlabeled 5-ALA. in these rats fluorescence measurement and in 42 glioma·bearingnude mice. The statisticalsignificanceof differenceswas determined with P= 0.05. H.E. staining of brain sections was performed . Uptake of HPD was investigated Results: 35S-MAb SZ39 had a strong cytotoxic effect on glioma and apby a member of our group in 1983. (J-Neurosurg . 1986 May; 64 (5): 768-74). Results:C-14 labeled 5-ALA and M-THPC showed a significant higher up- peared 4.2·fold and 4.0-fold more toxic than 35S_ nlgG and 35S + MAb 5Z39, lake in tumor tissue with a maximum after 15 min in 5-ALA and a maximum after respectively. In theglioma·bearlngnude mice, 35S-MAb SZ39 could be spe36 h in M·THPC injected rats. After injection of radiolabeled HPD a brain-tumor cially localized in glioma . The ratio to 35S· nlgG and 35S as 4.1 and 4.87. Its ratio of 1:3 could be observed , after 5·ALA administration , the ratio was aboutpharmacokineticsfitted a 3-eompartmental model. The dose- time equation was Ct == 1559276e - 3,49t + 9n313e- 0 51 + 21682e - 0 .017l . Tumor growth delay of one 1:4. The best ratio showed M-THPC (1:15). The fluorescenceimages correspondedvery well to tumor tissue in the week was observed with 103.6 MBq 355·MAb SZ39. The tumor inhibitoryrate H.E. stained sections, the maximalintensityof fluorescence after correction for was 50% at 26 days afteradministrationof 35S-MAb SZ39. Conclusion:35S-MAb5Z39 has a good prospect as an immunoradiotheraautofluorescencewas reached within 2 h. Conclusion:M -THPC and 5-ALA is a good tumor localizer in the rat glioma peutic agent and is worth further studying. model, thusphotodynamictherapy and diagnosis with 5-ALA and M-THPC is a promising approach for the treatmentof glial tumors .
I
I P-3-245I
IP-3-24S! studied Glial componentof differenttypes of braintumors byGFAP immunoreactivity
Chromosal aberration and DNA-aneuploidy of brain tumorswith use offluorescencein situhybridization and flowcytometry
V. Plperski. S. Jovanovic. M. Papov ic, K. Drabek , M. Rakic1, M. Janicijevic1 .
CenterforBiomedicalResearchICN Galenika, YugoslaVia. Institute for Neurosurgery,ClinicalCenterofSerbia. Belgrade, Yugoslavia
K. Kawamoto, H. Kasal, Y. NumaT. , Tsuchida. X. Liu,Y. Tsukazaki. Dept. of
Introduction:GFAP is the majorconstituentof intermediatefilaments in normal , reactive and neoplastic astrocytes . It serves asmarkerof a glialdifferentialion . An analysiswas made ofchromosomalaberrations in brain tumors using the Materials and Methods: In this study GFAPimmunoreactivitywas invesfluorescencein situ hybridization(FISH) technique. DNA histograms were sitigated in different types of brain tumors , includastrocytomas(7), ing glioblastomas (5). meningiomas (5) and metastatic tumors (5). TIssue samples obtained multaneouslyobtained by flowcytometry(FCM) to make a comparative study of histological malignancy of 30 gliomas and 26 meningiomas. In the study offrom neurosurgery were fixed in buffered 4% formaldehyde, sectioned on a cryostat and stainedimmunohistochemically lor GFAP using a polyc!onal rabbit FISH, DNA probes forchromosomes7, 9, 10 and 17 were used to cause a peroxidasemethod. reaction, withchromosome22 added for meningiomas. In gliomas as a whole, anti·GFAP antibody and avidin-biotin Results:Our results showed different expression of GFAP immunoreactivity chromosomes7 and 17 showed high values and chromosomes 9 and 10 low In gradus II, III and IV, values . Grade IV gliomas showed higher values for chromosome 17 and lower in different types of brain tumors . astrocytomasWHO characteristicmorphology. GFAP for chromosome10. In mininqlomas,many cases showed a low value for chro- GFAP was present in virtually all cells with in cell mosome 22. In gliomas, the DNA index showed a correlation with the grade, was also present in many cells and cell processesglioblastomas.Some popuiatlons in metastatic brain tumors also expressed GFAP immunoreactivity, and a positive correlationparticularlywith chromosome 17 in FISH. Recurrent whereas in meningiomas there was no positive GFAP staining. and atypicalmeningiomashad a high DNA index. Conclusion:The results provide furtherevidence for the significanceof GFAP as a marker of glial differentiation in different types of brain tumors .
Neurosurgery,Kansai MedicalUniversity.Osaka, Japan
IP-3-246I preferentially AXL, a transformingreceptortyrosinekinase, is not expressed inastrocyticbraintumors 3, F.V. Landeghem 3, D.R.R. Krex 1, E. Guthmann2 , G. Stoltenburg-Dietinger H.•J. Gruss4, M. Schmidt2 , A. Neubauer2 . 1 NeurosurgicalDep., Carl Gustav
Caws UniversityofDresden, Germany, 2 Dep. ofHaematologyandOncology, VirchowKlinikum, Humboldt-University of Berlin,Germany, 3 Instituteof Neuropathology,Free Universityof Berlin, Germany, 4 Dep. ofHaematology andOncology,Universityof ULM, Germany
Intratumoral delivery of an anti-BFGF IP-3-2491 counteractsgliomaprogression antibody in vivo M. Saini 1, M. Bellinzona1 , A. Stan 2, M. Samii 1. 1 Dept. ofNeurosurgery, NordstadtHospital,Hannover. Germany, 21nslitute ofNeuropathology,Medical School,Hannover, Germany
Introduction:Malignant gliomas are the most common of human brain tuReceptor tyrosine kinases p layacentral role in transducing extracellularsignals mors ; they are characterized by hypervascu/arityand rapid cellular proliferation. across the cell membrane into intracellularsignalling pathways. This in tum The main treatment modalities are surgical excision and radiotherapy . Several chemotherapeuticschemas have been employed with only very limited success leads to cell prolifera tion, differentiationor other responses. Axl (also called Ufo/Ark) is the founding member of a growing subgroup and relevant side effects. Basic fibroblast growth factor (bFGF) polypeptide is a 01 these transmembraneousreceptor proteins characterized by a unique ex- with mitogenic activity on glial cells and one of the most potent angiogeneticfacco-expressingbFGF and tracellularstructure resembling that of neuronal adhesion molecules . Axl is a tors.GIi
Basic Sciences- Neuro-oncology
S129
Comparisonof meta-tetrahydroxyphenylchlorin, IP-3-244I 5-aminulevulinic acid and
immunohistochem ical studies showed reactivity of a mouse anti-Axl monoclonal antibody withmembrane-proteinsof astrocytes of allanalyzed tissues as well haematoporphyrin-derivate in the C6 rat glioma as those of meningioma cells. model This suggests that the receptor tyrosine kinase Axl is not important lor the transformation and progression of astrocytic brain tumors and that axl might not A. Obwegeser , R.Jakober, S. Stocker" H. Stepp', H. Kostron.Univ. Kliniktiu code for the supposed tumor suppressor gene onromosome ch 19q in brain Neurochirurgie , Innsbruk,Austria.1 Laserforschungslabor,Munich, Germany tumors . Introduction:Malignant glioma is a disease with poor prognosis, furthermore The meaning of AxI as an neuronal adhesion molecule has to be elucidated. glial tumors are often rather bad to visualize within normal brain. As the use of porphyrins for the detection and treatment of tumors is undergoing mtensive investigation, new sensitizers and applicationsmay be a therapeutic and P-3-247I Preclinical study onimmunoradiotherapy with 35S diagnostic tool in the managementof these fatal tumors . labeledmonoclonalantibodySZ39 We investigatedthe uptake of 5-ALA and M· THPC in a rat glioma model and Oing Lan, Oiang Huang, Ziwei Du. DepartmentofNeurosurgery,Second compared it to data of HPD which are known from the literature . suznou MedicalCollege, Suzhou, Jiangsu, PR China AffiliatedHospilal of Methods:We inoculated C6 glioma cells into the right frontal lobe of adult rats. C14·/abeled M-THPC and 5-ALA were injected prior to killing of the ani- Antiglioma monoclonal antibody (MAb) 5Z39 was labeled with 35S. The effect of mals. C6-glioma tissue, normal tissue (ipsi and contralateral) liver and skin wasthe immunoradiotherapeutic agent , 35S·MAb SZ39, was evaluated preclinically . removed after 7 different time points (12 h to 48 h for M-THPC and 2 min to 8 Methods:The cytotoxicityof 355-MAb SZ39 against glioma was tested with h for 5·ALA , 3 to 5 animals per group). The samples were weighted. dissolved the MIT method, comparing with that of 35SnlgG, 35S + MAb SZ39 and 35S. pharmacokineticsof 35S-MAb SZ39 wereassessed and subjected to liquid scintillationcounting . Additionally 21 rats were injected Target treatment effect and with 120 mg/kg unlabeled 5-ALA. in these rats fluorescence measurement and in 42 glioma·bearingnude mice. The statisticalsignificanceof differenceswas determined with P= 0.05. H.E. staining of brain sections was performed . Uptake of HPD was investigated Results: 35S-MAb SZ39 had a strong cytotoxic effect on glioma and apby a member of our group in 1983. (J-Neurosurg . 1986 May; 64 (5): 768-74). Results:C-14 labeled 5-ALA and M-THPC showed a significant higher up- peared 4.2·fold and 4.0-fold more toxic than 35S_ nlgG and 35S + MAb 5Z39, lake in tumor tissue with a maximum after 15 min in 5-ALA and a maximum after respectively. In theglioma·bearlngnude mice, 35S-MAb SZ39 could be spe36 h in M·THPC injected rats. After injection of radiolabeled HPD a brain-tumor cially localized in glioma . The ratio to 35S· nlgG and 35S as 4.1 and 4.87. Its ratio of 1:3 could be observed , after 5·ALA administration , the ratio was aboutpharmacokineticsfitted a 3-eompartmental model. The dose- time equation was Ct == 1559276e - 3,49t + 9n313e- 0 51 + 21682e - 0 .017l . Tumor growth delay of one 1:4. The best ratio showed M-THPC (1:15). The fluorescenceimages correspondedvery well to tumor tissue in the week was observed with 103.6 MBq 355·MAb SZ39. The tumor inhibitoryrate H.E. stained sections, the maximalintensityof fluorescence after correction for was 50% at 26 days afteradministrationof 35S-MAb SZ39. Conclusion:35S-MAb5Z39 has a good prospect as an immunoradiotheraautofluorescencewas reached within 2 h. Conclusion:M -THPC and 5-ALA is a good tumor localizer in the rat glioma peutic agent and is worth further studying. model, thusphotodynamictherapy and diagnosis with 5-ALA and M-THPC is a promising approach for the treatmentof glial tumors .
I
I P-3-245I
IP-3-24S! studied Glial componentof differenttypes of braintumors byGFAP immunoreactivity
Chromosal aberration and DNA-aneuploidy of brain tumorswith use offluorescencein situhybridization and flowcytometry
V. Plperski. S. Jovanovic. M. Papov ic, K. Drabek , M. Rakic1, M. Janicijevic1 .
CenterforBiomedicalResearchICN Galenika, YugoslaVia. Institute for Neurosurgery,ClinicalCenterofSerbia. Belgrade, Yugoslavia
K. Kawamoto, H. Kasal, Y. NumaT. , Tsuchida. X. Liu,Y. Tsukazaki. Dept. of
Introduction:GFAP is the majorconstituentof intermediatefilaments in normal , reactive and neoplastic astrocytes . It serves asmarkerof a glialdifferentialion . An analysiswas made ofchromosomalaberrations in brain tumors using the Materials and Methods: In this study GFAPimmunoreactivitywas invesfluorescencein situ hybridization(FISH) technique. DNA histograms were sitigated in different types of brain tumors , includastrocytomas(7), ing glioblastomas (5). meningiomas (5) and metastatic tumors (5). TIssue samples obtained multaneouslyobtained by flowcytometry(FCM) to make a comparative study of histological malignancy of 30 gliomas and 26 meningiomas. In the study offrom neurosurgery were fixed in buffered 4% formaldehyde, sectioned on a cryostat and stainedimmunohistochemically lor GFAP using a polyc!onal rabbit FISH, DNA probes forchromosomes7, 9, 10 and 17 were used to cause a peroxidasemethod. reaction, withchromosome22 added for meningiomas. In gliomas as a whole, anti·GFAP antibody and avidin-biotin Results:Our results showed different expression of GFAP immunoreactivity chromosomes7 and 17 showed high values and chromosomes 9 and 10 low In gradus II, III and IV, values . Grade IV gliomas showed higher values for chromosome 17 and lower in different types of brain tumors . astrocytomasWHO characteristicmorphology. GFAP for chromosome10. In mininqlomas,many cases showed a low value for chro- GFAP was present in virtually all cells with in cell mosome 22. In gliomas, the DNA index showed a correlation with the grade, was also present in many cells and cell processesglioblastomas.Some popuiatlons in metastatic brain tumors also expressed GFAP immunoreactivity, and a positive correlationparticularlywith chromosome 17 in FISH. Recurrent whereas in meningiomas there was no positive GFAP staining. and atypicalmeningiomashad a high DNA index. Conclusion:The results provide furtherevidence for the significanceof GFAP as a marker of glial differentiation in different types of brain tumors .
Neurosurgery,Kansai MedicalUniversity.Osaka, Japan
IP-3-246I preferentially AXL, a transformingreceptortyrosinekinase, is not expressed inastrocyticbraintumors 3, F.V. Landeghem 3, D.R.R. Krex 1, E. Guthmann2 , G. Stoltenburg-Dietinger H.•J. Gruss4, M. Schmidt2 , A. Neubauer2 . 1 NeurosurgicalDep., Carl Gustav
Caws UniversityofDresden, Germany, 2 Dep. ofHaematologyandOncology, VirchowKlinikum, Humboldt-University of Berlin,Germany, 3 Instituteof Neuropathology,Free Universityof Berlin, Germany, 4 Dep. ofHaematology andOncology,Universityof ULM, Germany
Intratumoral delivery of an anti-BFGF IP-3-2491 counteractsgliomaprogression antibody in vivo M. Saini 1, M. Bellinzona1 , A. Stan 2, M. Samii 1. 1 Dept. ofNeurosurgery, NordstadtHospital,Hannover. Germany, 21nslitute ofNeuropathology,Medical School,Hannover, Germany
Introduction:Malignant gliomas are the most common of human brain tuReceptor tyrosine kinases p layacentral role in transducing extracellularsignals mors ; they are characterized by hypervascu/arityand rapid cellular proliferation. across the cell membrane into intracellularsignalling pathways. This in tum The main treatment modalities are surgical excision and radiotherapy . Several chemotherapeuticschemas have been employed with only very limited success leads to cell prolifera tion, differentiationor other responses. Axl (also called Ufo/Ark) is the founding member of a growing subgroup and relevant side effects. Basic fibroblast growth factor (bFGF) polypeptide is a 01 these transmembraneousreceptor proteins characterized by a unique ex- with mitogenic activity on glial cells and one of the most potent angiogeneticfacco-expressingbFGF and tracellularstructure resembling that of neuronal adhesion molecules . Axl is a tors.GIi