- Email: [email protected]
209 Enhancing radiation tumor response using protease inhibitor ritonavir in HPV-positive head and neck carcinoma
CARO2004
September 9-12 S63
radiation. Many cell lines have been observed to exhibit a hypersensitivity to radiation doses below 50 cGy, which manifests as a significant deviation from the response predicted by a linear-quadratic fit to higher doses. However, the underlying processes for this phenomenon remain unclear. Using a gel microdrop/flow cytometry assay to monitor single cell proliferation at early times post irradiation, we examined the response of human A549 lung carcinoma, T98G glioma and MCF7 breast carcinoma cell lines exposed to radiation doses from 0 to 200 cGy delivered at 0.18 and 22 cGy/min. No significant difference was observed between cell proliferation curves at these low dose rates. The A549 and T98G cells, but not MCF7 cells, showed the marked hypersensitivity at doses.
cells. As previously reported, chloroquine was accumulated in the acidic organelles, mostly in the lysosome. We further found that chloroquine accumulation in the organelle resulted in increased volume and decreased membrane potential of lysosomes. The loss of membrane potential was further amplified by ionizing radiation, which appears to be correlated with increased cell death by necrosis. We also found that the rate of radiation-mediated apoptosis, which occurred later than chloroquine-mediated necrosis, did not appear to be affected by 10 mM chloroquine treatments.
206 Antiviral Agent Cidofovir Decreases Human Papillomaviruses (HPVs) Oncoproteins E6 and E7 and Enhances Tumor Radiosensitivity in HPV-related Malignancies. B. Abdulkarim ~, E. Deutsch z, M. Parliament ~, D. Murray 1. ICross Cancer Institute, University of Alberta, Edmonton, Alberta; 2Gustave Roussy Institute, Paris IX University, Villejuif, France
W. Roa, W. Finlay, R. Lobenberg. University of Alberta, Edmonton, Alberta
High-risk Human papillomavirus (HPVs) is now established as the primary surrogate for the development of cervical cancer. Most of HPV-positive cervix cancer cells express E6 and E7 oncoproteins, which are able to bind to p53 and retinoblastoma (Rb) tumor suppressor proteins respectively and neutralize their function. Suppression of viral oncoprotein expression would be expected to disrupt the immortalization process and hence restore growth control in these cells by targeting E6 and E7. For this purpose, the antiviral agent Cidofovir has been tested in HPV-positive cervix cancer cell lines. Here, we show that Cidofovir was able to down-regulate the constitutive expression of HPV E6 and E7, induces expression of the p53 and Rb proteins, and restores p53 function only in HPV-positive cells. In addition, Cidofovir was able to alter cell-cycle progression by inducing accumulation of HPV-expressing cells in S-phase. Cidofovir exposure combined with irradiation increased cells in G1 phase with concomitant decrease in S-phase cell cycle. Cidofovir inhibited cell proliferation and enhanced radiosensitivity only in HPV-positive cells in vitro and in mice xenografts. In order to overcome apoptosis-resistance, and to improve response to concurrent radio-chemotherapy (CRC), we also combined Cidofovir with CRC. Our purpose was to address how Cidofovir could alter a CRC tumor response in established cervix cancer cell lines in vivo, by monitoring new surrogate markers related to viral oncoproteins expression and tumor proliferation using high resolution small animal PET scanner with [18F] FLT ([18F] 3-deoxy-3-[18F] fluorothymidine), which has been proposed as a new marker for imaging tumor proliferation by PET. This study, by establishing the proof of principle, provides the basis for a new anticancer strategy to enhance radiation tumor response in HPV-related cancers, without increase deleterious effects. 207 Chloroquine, An Antimalarial Agent with Promise in Cancer Therapy.
H. Zhao, H. Lee. Northeastern Ontario Regional Cancer Centre, Ontario
Sudbury,
The well-known antimalarial chloroquine is also a safe drug for the treatment of inflammatory diseases such as rheumatoid arthritis. It has also been suggested for its potential as an anticancer drug. We treated human breast cancer cells with chloroquine in combination with ionizing radiation, and found that chloroquine could significantly radiosensitize the cancer
2O8 Cytotoxicity of Drug-Loaded Nanoparticle and Liposome Carried by Aerosol "Cluster Bomb" in Lung Cancer.
While aerosol drug therapy has been established in the management of many benign respiratory diseases, current technology uses micrometer-sized particles. An entirely new approach to aerosol drug delivery using cluster bomb to carry drug-loaded nanoparticles and liposomes has been developed for lung cancer therapy. This study aims to identify the intracellular locations of the nanoparticle and liposome after application, and investigate the relative efficiencies of cell kill in vitro. Nanoparticles (less than 200 nm in diameter) were prepared by the solvent displacement method. Drug-loaded fluorescent nanoparticles and liposomes were carried by aerosolized cluster bombs so as to simulate dry powder inhalation. The cluster bomb carriers would dissolve after coming in contact with the aqueous medium. Particle size, Zeta potential, stability and degradation were characterized. The in vitro cytotoxicity of aerosol nanoparticles and liposomes with or without labeled cytotoxic agents (e.g., doxorubicin) was assessed by x-I-r cell viability assay in H460 and A549 lung cancer cell lines. Cellular uptakes of the particles were traced and quantified using confocal microscopy and fluorescence spectrometry over time. Confocal microscopy identified uptake of nanoparticles into the cytoplasmic and nuclear locations within the first hour of cluster bomb application. The rate of entrance appeared to be faster than the corresponding liposomes and free drug alone. In contrast to the control nanoparticles that induced little cytotoxicity, the drug-loaded nanoparticles induced a gradation of cytotoxicity in proportion to the applied drug concentration. Percent cell kill here was consistently higher in the chemo-sensitive lung cancer (H460 cell line) than the chemo-resistant one (A549 cell line). Labeled nanoparticles could kill cells more efficiently than the corresponding liposomes and drug alone. Surface and designer modifications of the nanoparticles could also enhance cell internalization and cytotoxicity. Drug-loaded nanoparticles carried by aerosol cluster bomb can kill lung cancer cells efficiently. This study supports the approach as a potential aerosol treatment for lung cancer. 209 Enhancing Radiation Tumor Response Using Protease Inhibitor Ritonavir In HPV-Positive Head and Neck Carcinoma.
E. Deutsch I, B. Abdulkarimz, B. Wen ~, P. Opolon ~. I Gustave Roussy Institute, Paris XI University Villejuif, France; 2Cross Cancer Institute, Univsrsity of Alberta, Edmonton, Alberta; 3CNRS Unit Mixte de Recherche 1582, Villejuif, France The antiproliferative activity of HIV-1 protease inhibitor has been reported in non HIV-related human cancers. The purpose of this study was to evaluate the antiproliferative and antiangiogenic activity of these drugs human papillomaviruses (HPVs)-related cancers. For this proposal, we have tested the
$64 September 9-12
anti-tumor effect of Ritonavir in HPV tumor xenografts with or without irradiation. 3 x 106 HEP-2 squamous carcinoma cells were implanted subcutaneously in nude mice. Mice were treated with Ritonavir alone (Ritonavir 2 to 8 mg, twice per day, 5 days per week) and/or irradiation (15 Gy). Inhibition of tumour growth was observed when mice were treated with Ritonavir alone and this effect was maximal when combined with radiation. A marked reduction of intra-tumoral vascularization within the tumor sections from the Ritonavir alone or combined with irradiation compared to the control was observed. Western blot had shown increasing apoptosis by increased Bax expression and decreased Bcl-2 expression of after Ritonavir treatment. Ritonavir showed antiproliferative activity in HPVpositive head and neck carcinoma xenograffs and the effect was more pronounced when combined with irradiation. Its antitumor effect was associated with induction of apoptosis and inhibition of angiogenesis formation. This study provides evidence of anti-tumour effect of the HIV protease inhibitor, and suggested that Ritonavir could maximize radiation tumor response especially in head and neck carcinoma. 210 Generation of Adenovirus 5/3 Chimera for Improving Transduction of Lymphocytes.
J. Li, A. L,; J. Mocanu, F. Liu. Ontario Cancer Institute, University of Toronto, Toronto, Ontario We have successfully achieved recombinant adenovirus mediated selective gene expression in human nasopharyngeal carcinoma (NPC) by exploiting the presence of the Epstein-Barr virus (EBV), utilizing a transcriptional targeting strategy. However, such rAd do not readily infect EBV-associated lymphoma cells due to the lack of the coxackievirus-adenovirus receptor. A chimeric adenovirus vector which is modified from Adv5 fiber knob to Adv3 fiber knob have reported can expand tropism to facilitate entry of rAd into a number of cell types such as EBV-transformed B lymphocytes. To investigate such a chimera can be used for our targeting gene therapy strategy in EBV-associated B-cell tumors, we have developed a slightly unique method of rAd construction, and generated an adenovirus vector containing chimeric fiber with the receptorbinding knob domain of the Ad3 fiber. We therefore investigated whether the chimeric Ad5/3 can improve Adv infection efficacy and subsequent expression of rAd-encoded gene in lymphoma cells and leukemia cells. Four lymphoma cell lines and two leukemia cell lines were infected with Ad5/3.CMV-BgaI and isogenically matched Ad5.CMV-Bgal. X-gal staining results demonstrated both of the lymphoma lines and leukemia lines were infected more efficiently by the chimeric Ad5/3 virus but poorly by Ad5 virus. More than 60% of lymphoma cells in the four lymphoma cell lines and 35% of leukemia cells in the two leukemia cell lines can be infected with 50 ifu of Ad5/3.CMVBgal In contrast, less than 10% of cells were positive staining in the Ad5.CMV-Bgal infected groups. Bgal activity assay showed that the chimeric Ad5/3 virus mediated transgene expression were 3 to 8 fold higher compared with its Ad5 counterpart. These results indicate that the chimeric Ad5/3 virus vector generated in our Lab can be used to improve infection and subsequent transgene expression in lymphomas and leukamias which are inefficiently infected with Ad5. 211 RadiosensiUzation of a Rat Glioma Model by Bromodeoxyuridine.
Y. Li, S. Lehnert. Radiation Oncology, McGill University, Montreal, Quebec The potential of halogenated pyrimidines as radiosensitizers in the treatment of high grade gliomas has never been realized. A reason why this approach may fail is that insufficient thymidine
CARO 2004
analog is incorporated into DNA to create a useful level of radiosensitization. We evaluated two approaches to deal with this problem; the use an intra-tumoral drug delivery system and the addition of a second drug to the protocol, a biomodulator aimed to enhance the incorporation of BrdUrd into DNA. In the present study the glioma model chosen, the C6 rat astrocytoma proved to be extremely refractory to radiosensitization by BrdUrd in vitro Combination of a biomodulator phosphonacetylL-aspartic acid (PALA) with BrdUrd achieved some degree of radiosensitization in vitro, but was only modestly effective; BrdUrd + PALA had a dose modifying effect of 1.25 at 10 Gy. In the in vivo studies, on the other hand, 40% of rats treated with 10 Gy + BrdUrd were still alive at 180 days after tumor implant while for 10 Gy + BrdUrd + PALA the survival was 83% A similar result was achieved with fractionated radiation (5 x 3.2 Gy). The proportion of cells incorporating BrdUrd, measured by flow cytometry and immunohistochemistry , did not achieve a level above 30% under either in vitro or in vivo conditions. Cells which were labeled with BrdUrd in vivo but irradiated in vitro as a single cell suspension showed no more radiosensitization than did cells labeled and irradiated in vitro. In other in vivo experiments it was determined that the high level of response was not attributable to independent cytotoxic or radiosensitizing effects of PALA. We are currently doing experiments using C6 and other cell lines labeled with BrdUrd and irradiated in three dimensional tissue culture to determine if the apparently paradoxical in vivo response could involve a bystander effect. 212 Relative Biological Efficiency in Terms of Tumor Response of 125-1 Seeds Compared with 60-Co Gamma Rays.
S. Lehnert. Department of Radiation Oncology, McGill University, Montreal, Quebec 125-1 has been used extensively in clinical brachytherapy since its introduction in 1975 and 125-1 seeds are used routinely as permanent or temporary implants for the treatment of a number of tumors. The Relative Biological Effectiveness (RBE) of 125-1 radiation with respect to external beam radiation is a matter of interest since certain types of disease may be appropriately treated by either modality. Earlier studies of RBE have compared response of cells in Tissue Culture to 125-1 or external beam radiation on the basis of clonogenic cell survival in vivo and the values obtained have ranged from 1.0-1.4. We have measured the RBE for 125-1 seeds with respect to 60-Co gamma rays in a more clinically relevant setting using a transplantable mouse tumors treated under the same conditions with either time a temporary implant of a 125-1 or with 60-Co gamma rays. The endpoint was inhibition of tumor growth. Tumors were irradiated with a range of acute or fractionated doses and the dose was normalized to 2 Gy/fraction using the linear quadratic model. 125-1 seeds (dose rates 20-100 cGyh-1) were implanted in the tumor for 24-96 hours. The dose response was close to linear and independent of initial 125-1 activity (i.e. dose rate) over the range investigated. If the total dose is taken to be the lowest dose to which the cells are exposed ie. that at the surface of the tumor the ratio of slopes for dose response curves for 125-1 seeds and 60-Co gamma rays is 1.39. Thus 1.4 can be assumed to be the highest value possible for RBE under these circumstances. RBE values determined when more sophisticated methods of computing tumor dose are used will be discussed.
September 9-12 S63
radiation. Many cell lines have been observed to exhibit a hypersensitivity to radiation doses below 50 cGy, which manifests as a significant deviation from the response predicted by a linear-quadratic fit to higher doses. However, the underlying processes for this phenomenon remain unclear. Using a gel microdrop/flow cytometry assay to monitor single cell proliferation at early times post irradiation, we examined the response of human A549 lung carcinoma, T98G glioma and MCF7 breast carcinoma cell lines exposed to radiation doses from 0 to 200 cGy delivered at 0.18 and 22 cGy/min. No significant difference was observed between cell proliferation curves at these low dose rates. The A549 and T98G cells, but not MCF7 cells, showed the marked hypersensitivity at doses.
cells. As previously reported, chloroquine was accumulated in the acidic organelles, mostly in the lysosome. We further found that chloroquine accumulation in the organelle resulted in increased volume and decreased membrane potential of lysosomes. The loss of membrane potential was further amplified by ionizing radiation, which appears to be correlated with increased cell death by necrosis. We also found that the rate of radiation-mediated apoptosis, which occurred later than chloroquine-mediated necrosis, did not appear to be affected by 10 mM chloroquine treatments.
206 Antiviral Agent Cidofovir Decreases Human Papillomaviruses (HPVs) Oncoproteins E6 and E7 and Enhances Tumor Radiosensitivity in HPV-related Malignancies. B. Abdulkarim ~, E. Deutsch z, M. Parliament ~, D. Murray 1. ICross Cancer Institute, University of Alberta, Edmonton, Alberta; 2Gustave Roussy Institute, Paris IX University, Villejuif, France
W. Roa, W. Finlay, R. Lobenberg. University of Alberta, Edmonton, Alberta
High-risk Human papillomavirus (HPVs) is now established as the primary surrogate for the development of cervical cancer. Most of HPV-positive cervix cancer cells express E6 and E7 oncoproteins, which are able to bind to p53 and retinoblastoma (Rb) tumor suppressor proteins respectively and neutralize their function. Suppression of viral oncoprotein expression would be expected to disrupt the immortalization process and hence restore growth control in these cells by targeting E6 and E7. For this purpose, the antiviral agent Cidofovir has been tested in HPV-positive cervix cancer cell lines. Here, we show that Cidofovir was able to down-regulate the constitutive expression of HPV E6 and E7, induces expression of the p53 and Rb proteins, and restores p53 function only in HPV-positive cells. In addition, Cidofovir was able to alter cell-cycle progression by inducing accumulation of HPV-expressing cells in S-phase. Cidofovir exposure combined with irradiation increased cells in G1 phase with concomitant decrease in S-phase cell cycle. Cidofovir inhibited cell proliferation and enhanced radiosensitivity only in HPV-positive cells in vitro and in mice xenografts. In order to overcome apoptosis-resistance, and to improve response to concurrent radio-chemotherapy (CRC), we also combined Cidofovir with CRC. Our purpose was to address how Cidofovir could alter a CRC tumor response in established cervix cancer cell lines in vivo, by monitoring new surrogate markers related to viral oncoproteins expression and tumor proliferation using high resolution small animal PET scanner with [18F] FLT ([18F] 3-deoxy-3-[18F] fluorothymidine), which has been proposed as a new marker for imaging tumor proliferation by PET. This study, by establishing the proof of principle, provides the basis for a new anticancer strategy to enhance radiation tumor response in HPV-related cancers, without increase deleterious effects. 207 Chloroquine, An Antimalarial Agent with Promise in Cancer Therapy.
H. Zhao, H. Lee. Northeastern Ontario Regional Cancer Centre, Ontario
Sudbury,
The well-known antimalarial chloroquine is also a safe drug for the treatment of inflammatory diseases such as rheumatoid arthritis. It has also been suggested for its potential as an anticancer drug. We treated human breast cancer cells with chloroquine in combination with ionizing radiation, and found that chloroquine could significantly radiosensitize the cancer
2O8 Cytotoxicity of Drug-Loaded Nanoparticle and Liposome Carried by Aerosol "Cluster Bomb" in Lung Cancer.
While aerosol drug therapy has been established in the management of many benign respiratory diseases, current technology uses micrometer-sized particles. An entirely new approach to aerosol drug delivery using cluster bomb to carry drug-loaded nanoparticles and liposomes has been developed for lung cancer therapy. This study aims to identify the intracellular locations of the nanoparticle and liposome after application, and investigate the relative efficiencies of cell kill in vitro. Nanoparticles (less than 200 nm in diameter) were prepared by the solvent displacement method. Drug-loaded fluorescent nanoparticles and liposomes were carried by aerosolized cluster bombs so as to simulate dry powder inhalation. The cluster bomb carriers would dissolve after coming in contact with the aqueous medium. Particle size, Zeta potential, stability and degradation were characterized. The in vitro cytotoxicity of aerosol nanoparticles and liposomes with or without labeled cytotoxic agents (e.g., doxorubicin) was assessed by x-I-r cell viability assay in H460 and A549 lung cancer cell lines. Cellular uptakes of the particles were traced and quantified using confocal microscopy and fluorescence spectrometry over time. Confocal microscopy identified uptake of nanoparticles into the cytoplasmic and nuclear locations within the first hour of cluster bomb application. The rate of entrance appeared to be faster than the corresponding liposomes and free drug alone. In contrast to the control nanoparticles that induced little cytotoxicity, the drug-loaded nanoparticles induced a gradation of cytotoxicity in proportion to the applied drug concentration. Percent cell kill here was consistently higher in the chemo-sensitive lung cancer (H460 cell line) than the chemo-resistant one (A549 cell line). Labeled nanoparticles could kill cells more efficiently than the corresponding liposomes and drug alone. Surface and designer modifications of the nanoparticles could also enhance cell internalization and cytotoxicity. Drug-loaded nanoparticles carried by aerosol cluster bomb can kill lung cancer cells efficiently. This study supports the approach as a potential aerosol treatment for lung cancer. 209 Enhancing Radiation Tumor Response Using Protease Inhibitor Ritonavir In HPV-Positive Head and Neck Carcinoma.
E. Deutsch I, B. Abdulkarimz, B. Wen ~, P. Opolon ~. I Gustave Roussy Institute, Paris XI University Villejuif, France; 2Cross Cancer Institute, Univsrsity of Alberta, Edmonton, Alberta; 3CNRS Unit Mixte de Recherche 1582, Villejuif, France The antiproliferative activity of HIV-1 protease inhibitor has been reported in non HIV-related human cancers. The purpose of this study was to evaluate the antiproliferative and antiangiogenic activity of these drugs human papillomaviruses (HPVs)-related cancers. For this proposal, we have tested the
$64 September 9-12
anti-tumor effect of Ritonavir in HPV tumor xenografts with or without irradiation. 3 x 106 HEP-2 squamous carcinoma cells were implanted subcutaneously in nude mice. Mice were treated with Ritonavir alone (Ritonavir 2 to 8 mg, twice per day, 5 days per week) and/or irradiation (15 Gy). Inhibition of tumour growth was observed when mice were treated with Ritonavir alone and this effect was maximal when combined with radiation. A marked reduction of intra-tumoral vascularization within the tumor sections from the Ritonavir alone or combined with irradiation compared to the control was observed. Western blot had shown increasing apoptosis by increased Bax expression and decreased Bcl-2 expression of after Ritonavir treatment. Ritonavir showed antiproliferative activity in HPVpositive head and neck carcinoma xenograffs and the effect was more pronounced when combined with irradiation. Its antitumor effect was associated with induction of apoptosis and inhibition of angiogenesis formation. This study provides evidence of anti-tumour effect of the HIV protease inhibitor, and suggested that Ritonavir could maximize radiation tumor response especially in head and neck carcinoma. 210 Generation of Adenovirus 5/3 Chimera for Improving Transduction of Lymphocytes.
J. Li, A. L,; J. Mocanu, F. Liu. Ontario Cancer Institute, University of Toronto, Toronto, Ontario We have successfully achieved recombinant adenovirus mediated selective gene expression in human nasopharyngeal carcinoma (NPC) by exploiting the presence of the Epstein-Barr virus (EBV), utilizing a transcriptional targeting strategy. However, such rAd do not readily infect EBV-associated lymphoma cells due to the lack of the coxackievirus-adenovirus receptor. A chimeric adenovirus vector which is modified from Adv5 fiber knob to Adv3 fiber knob have reported can expand tropism to facilitate entry of rAd into a number of cell types such as EBV-transformed B lymphocytes. To investigate such a chimera can be used for our targeting gene therapy strategy in EBV-associated B-cell tumors, we have developed a slightly unique method of rAd construction, and generated an adenovirus vector containing chimeric fiber with the receptorbinding knob domain of the Ad3 fiber. We therefore investigated whether the chimeric Ad5/3 can improve Adv infection efficacy and subsequent expression of rAd-encoded gene in lymphoma cells and leukemia cells. Four lymphoma cell lines and two leukemia cell lines were infected with Ad5/3.CMV-BgaI and isogenically matched Ad5.CMV-Bgal. X-gal staining results demonstrated both of the lymphoma lines and leukemia lines were infected more efficiently by the chimeric Ad5/3 virus but poorly by Ad5 virus. More than 60% of lymphoma cells in the four lymphoma cell lines and 35% of leukemia cells in the two leukemia cell lines can be infected with 50 ifu of Ad5/3.CMVBgal In contrast, less than 10% of cells were positive staining in the Ad5.CMV-Bgal infected groups. Bgal activity assay showed that the chimeric Ad5/3 virus mediated transgene expression were 3 to 8 fold higher compared with its Ad5 counterpart. These results indicate that the chimeric Ad5/3 virus vector generated in our Lab can be used to improve infection and subsequent transgene expression in lymphomas and leukamias which are inefficiently infected with Ad5. 211 RadiosensiUzation of a Rat Glioma Model by Bromodeoxyuridine.
Y. Li, S. Lehnert. Radiation Oncology, McGill University, Montreal, Quebec The potential of halogenated pyrimidines as radiosensitizers in the treatment of high grade gliomas has never been realized. A reason why this approach may fail is that insufficient thymidine
CARO 2004
analog is incorporated into DNA to create a useful level of radiosensitization. We evaluated two approaches to deal with this problem; the use an intra-tumoral drug delivery system and the addition of a second drug to the protocol, a biomodulator aimed to enhance the incorporation of BrdUrd into DNA. In the present study the glioma model chosen, the C6 rat astrocytoma proved to be extremely refractory to radiosensitization by BrdUrd in vitro Combination of a biomodulator phosphonacetylL-aspartic acid (PALA) with BrdUrd achieved some degree of radiosensitization in vitro, but was only modestly effective; BrdUrd + PALA had a dose modifying effect of 1.25 at 10 Gy. In the in vivo studies, on the other hand, 40% of rats treated with 10 Gy + BrdUrd were still alive at 180 days after tumor implant while for 10 Gy + BrdUrd + PALA the survival was 83% A similar result was achieved with fractionated radiation (5 x 3.2 Gy). The proportion of cells incorporating BrdUrd, measured by flow cytometry and immunohistochemistry , did not achieve a level above 30% under either in vitro or in vivo conditions. Cells which were labeled with BrdUrd in vivo but irradiated in vitro as a single cell suspension showed no more radiosensitization than did cells labeled and irradiated in vitro. In other in vivo experiments it was determined that the high level of response was not attributable to independent cytotoxic or radiosensitizing effects of PALA. We are currently doing experiments using C6 and other cell lines labeled with BrdUrd and irradiated in three dimensional tissue culture to determine if the apparently paradoxical in vivo response could involve a bystander effect. 212 Relative Biological Efficiency in Terms of Tumor Response of 125-1 Seeds Compared with 60-Co Gamma Rays.
S. Lehnert. Department of Radiation Oncology, McGill University, Montreal, Quebec 125-1 has been used extensively in clinical brachytherapy since its introduction in 1975 and 125-1 seeds are used routinely as permanent or temporary implants for the treatment of a number of tumors. The Relative Biological Effectiveness (RBE) of 125-1 radiation with respect to external beam radiation is a matter of interest since certain types of disease may be appropriately treated by either modality. Earlier studies of RBE have compared response of cells in Tissue Culture to 125-1 or external beam radiation on the basis of clonogenic cell survival in vivo and the values obtained have ranged from 1.0-1.4. We have measured the RBE for 125-1 seeds with respect to 60-Co gamma rays in a more clinically relevant setting using a transplantable mouse tumors treated under the same conditions with either time a temporary implant of a 125-1 or with 60-Co gamma rays. The endpoint was inhibition of tumor growth. Tumors were irradiated with a range of acute or fractionated doses and the dose was normalized to 2 Gy/fraction using the linear quadratic model. 125-1 seeds (dose rates 20-100 cGyh-1) were implanted in the tumor for 24-96 hours. The dose response was close to linear and independent of initial 125-1 activity (i.e. dose rate) over the range investigated. If the total dose is taken to be the lowest dose to which the cells are exposed ie. that at the surface of the tumor the ratio of slopes for dose response curves for 125-1 seeds and 60-Co gamma rays is 1.39. Thus 1.4 can be assumed to be the highest value possible for RBE under these circumstances. RBE values determined when more sophisticated methods of computing tumor dose are used will be discussed.